# Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study

Elsa Lorthe, Laetitia Marchand-Martin, Mathilde Letouzey, Adrien M Aubert, Véronique Pierrat, Valérie Benhammou, Pierre Delorme, Stéphane Marret, Pierre-Yves Ancel, François Goffinet, et al.

► To cite this version:

Elsa Lorthe, Laetitia Marchand-Martin, Mathilde Letouzey, Adrien M Aubert, Véronique Pierrat, et al. Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study. American Journal of Obstetrics and Gynecology, 2023, 10.1016/j.ajog.2023.10.010. hal-04272387

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# Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study

Elsa Lorthe, RM, PhD; Laetitia Marchand-Martin, MSc; Mathilde Letouzey, MD, PhD; Adrien M. Aubert, PhD; Véronique Pierrat, MD, PhD; Valérie Benhammou, PhD; Pierre Delorme, MD, PhD; Stéphane Marret, MD, PhD; Pierre-Yves Ancel, MD, PhD; François Goffinet, MD, PhD; Laurence Foix L'Hélias, MD, PhD; Gilles Kayem, MD, PhD; On behalf of the EPIPAGE-2 Obstetric Writing Group

**BACKGROUND:** The administration of tocolytics after preterm prelabor rupture of membranes remains a controversial practice. In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, thereby reducing the risks for prematurity and adverse consequences over the life course. However, tocolysis may be associated with neonatal death or long-term adverse neurodevelopmental outcomes, mainly related to prolonged fetal exposure to intrauterine infection or inflammation. In a previous study, we showed that tocolysis administration was not associated with short-term benefits. There are currently no data available to evaluate the impact of tocolysis on neurodevelopmental outcomes in school-aged children born prematurely in this clinical setting.

**OBJECTIVE:** This study aimed to investigate whether tocolysis administered after preterm prelabor rupture of membranes is associated with neurodevelopmental outcomes at 5.5 years of age.

**STUDY DESIGN:** We used data from a prospective, population-based cohort study of preterm births recruited in 2011 (referred to as the EPIPAGE-2 study) and for whom the results of a comprehensive medical and neurodevelopmental assessment of the infant at age 5.5 years were available. We included pregnant individuals with preterm prelabor rupture of membranes at 24 to 32 weeks' gestation in singleton pregnancies with a live fetus at the time of rupture, birth at 24 to 34 weeks' gestation, and participation of the infant in an assessment at 5.5 years of age. Exposure was the administration of any tocolytic treatment after preterm prelabor rupture of membranes. The main outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years of age. Secondary

outcomes included survival without any neurodevelopmental disabilities, cerebral palsy, full-scale intelligence quotient, developmental coordination disorders, and behavioral difficulties. A propensity-score analysis was used to minimize the indication bias in the estimation of the treatment effect on outcomes.

**RESULTS:** Overall, 596 of 803 pregnant individuals (73.4%) received tocolytics after preterm prelabor rupture of membranes. At the 5.5-year follow-up, 82.7% and 82.5% of the children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1%, respectively, were alive without any neurodevelopmental disabilities. After applying multiple imputations and inverse probability of treatment weighting, we found no association between the exposure to tocolytics and survival without moderate to severe neurodevelopmental disabilities (odds ratio, 0.93; 95% confidence interval, 0.55–1.60), survival without any neurodevelopmental disabilities (odds ratio, 1.02; 95% confidence interval, 0.65–1.61), or any of the other outcomes.

**CONCLUSION:** There was no difference in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolysis after preterm prelabor rupture of membranes. To date, the health benefits of tocolytics remain unproven, both in the short- and long-term.

**Key words:** EPIPAGE-2, neurodevelopment, neurodevelopmental disabilities, obstetrical intervention, preterm children, preterm prelabor rupture of membranes, propensity score, school age, tocolysis

## Introduction

Preterm prelabor rupture of membranes (PPROM) complicates 3% of pregnancies and accounts for one-third of preterm births.<sup>1-3</sup> It is a leading cause of

neonatal mortality and morbidity and increases the risk for maternal infectious morbidity.<sup>2,4</sup> Currently, expectant management is recommended before 34 weeks' gestation in the absence of labor, chorioamnionitis, or fetal distress.<sup>5-8</sup> However, the use of a short-course of tocolytics after PROM remains controversial,<sup>4</sup> because no data with a sufficient level of evidence is available to recommend or advise against it.<sup>6,7,9</sup>

In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, including in utero transfer if necessary, corticosteroids, and antibiotics.<sup>4</sup> This approach aims to reduce the risks of prematurity and adverse consequences

over the life course.<sup>10</sup> In contrast, tocolytics may have a direct effect on the fetal brain<sup>11-13</sup> or an indirect effect related to prolonged fetal exposure to intrauterine infection or inflammation.<sup>14-19</sup> It may also impart a higher risk for neonatal sepsis<sup>15,20</sup> that is potentially associated with neonatal death or long-term adverse neurodevelopmental outcomes.<sup>18,21,22</sup> Neurodevelopment at school age is of particular interest to parents and medical and educational teams in this clinical setting given the aforementioned pathophysiological processes that contribute to adverse outcomes in neonates and beyond.<sup>23</sup>

The optimal treatment strategy should be defined by taking both short- and long-

**Cite this article as:** Lorthe E, Marchand-Martin L, Letouzey M, et al. Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study. Am J Obstet Gynecol 2024;230:570.e1-18.

0002-9378
© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://doi.org/10.1016/j.ajog.2023.10.010

<figure><img src="image_2.png" /></figure>

Click Video under article
title in Contents at ajog.org
<figure><img src="image_2.png" /></figure>

# Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study

Elsa Lorthe, RM, PhD; Laetitia Marchand-Martin, MSc; Mathilde Letouzey, MD, PhD; Adrien M. Aubert, PhD; Véronique Pierrat, MD, PhD; Valérie Benhammou, PhD; Pierre Delorme, MD, PhD; Stéphane Marret, MD, PhD; Pierre-Yves Ancel, MD, PhD; François Goffinet, MD, PhD; Laurence Foix L'Hélias, MD, PhD; Gilles Kayem, MD, PhD; On behalf of the EPIPAGE-2 Obstetric Writing Group

**BACKGROUND:** The administration of tocolytics after preterm prelabor rupture of membranes remains a controversial practice. In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, thereby reducing the risks for prematurity and adverse consequences over the life course. However, tocolysis may be associated with neonatal death or long-term adverse neurodevelopmental outcomes, mainly related to prolonged fetal exposure to intrauterine infection or inflammation. In a previous study, we showed that tocolysis administration was not associated with short-term benefits. There are currently no data available to evaluate the impact of tocolysis on neurodevelopmental outcomes in school-aged children born prematurely in this clinical setting.

**OBJECTIVE:** This study aimed to investigate whether tocolysis administered after preterm prelabor rupture of membranes is associated with neurodevelopmental outcomes at 5.5 years of age.

**STUDY DESIGN:** We used data from a prospective, population-based cohort study of preterm births recruited in 2011 (referred to as the EPIPAGE-2 study) and for whom the results of a comprehensive medical and neurodevelopmental assessment of the infant at age 5.5 years were available. We included pregnant individuals with preterm prelabor rupture of membranes at 24 to 32 weeks' gestation in singleton pregnancies with a live fetus at the time of rupture, birth at 24 to 34 weeks' gestation, and participation of the infant in an assessment at 5.5 years of age. Exposure was the administration of any tocolytic treatment after preterm prelabor rupture of membranes. The main outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years of age. Secondary

outcomes included survival without any neurodevelopmental disabilities, cerebral palsy, full-scale intelligence quotient, developmental coordination disorders, and behavioral difficulties. A propensity-score analysis was used to minimize the indication bias in the estimation of the treatment effect on outcomes.

**RESULTS:** Overall, 596 of 803 pregnant individuals (73.4%) received tocolytics after preterm prelabor rupture of membranes. At the 5.5-year follow-up, 82.7% and 82.5% of the children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1%, respectively, were alive without any neurodevelopmental disabilities. After applying multiple imputations and inverse probability of treatment weighting, we found no association between the exposure to tocolytics and survival without moderate to severe neurodevelopmental disabilities (odds ratio, 0.93; 95% confidence interval, 0.55–1.60), survival without any neurodevelopmental disabilities (odds ratio, 1.02; 95% confidence interval, 0.65–1.61), or any of the other outcomes.

**CONCLUSION:** There was no difference in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolysis after preterm prelabor rupture of membranes. To date, the health benefits of tocolytics remain unproven, both in the short- and long-term.

**Key words:** EPIPAGE-2, neurodevelopment, neurodevelopmental disabilities, obstetrical intervention, preterm children, preterm prelabor rupture of membranes, propensity score, school age, tocolysis

## Introduction

Preterm prelabor rupture of membranes (PPROM) complicates 3% of pregnancies and accounts for one-third of preterm births.<sup>1-3</sup> It is a leading cause of

neonatal mortality and morbidity and increases the risk for maternal infectious morbidity.<sup>2,4</sup> Currently, expectant management is recommended before 34 weeks' gestation in the absence of labor, chorioamnionitis, or fetal distress.<sup>5-8</sup> However, the use of a short-course of tocolytics after PROM remains controversial,<sup>4</sup> because no data with a sufficient level of evidence is available to recommend or advise against it.<sup>6,7,9</sup>

In theory, reducing uterine contractility should delay delivery and allow for optimal antenatal management, including in utero transfer if necessary, corticosteroids, and antibiotics.<sup>4</sup> This approach aims to reduce the risks of prematurity and adverse consequences

over the life course.<sup>10</sup> In contrast, tocolytics may have a direct effect on the fetal brain<sup>11-13</sup> or an indirect effect related to prolonged fetal exposure to intrauterine infection or inflammation.<sup>14-19</sup> It may also impart a higher risk for neonatal sepsis<sup>15,20</sup> that is potentially associated with neonatal death or long-term adverse neurodevelopmental outcomes.<sup>18,21,22</sup> Neurodevelopment at school age is of particular interest to parents and medical and educational teams in this clinical setting given the aforementioned pathophysiological processes that contribute to adverse outcomes in neonates and beyond.<sup>23</sup>

The optimal treatment strategy should be defined by taking both short- and long-

**Cite this article as:** Lorthe E, Marchand-Martin L, Letouzey M, et al. Tocolysis after preterm prelabor rupture of membranes and 5-year outcomes: a population-based cohort study. Am J Obstet Gynecol 2024;230:570.e1-18.

0002-9378
© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
https://doi.org/10.1016/j.ajog.2023.10.010

<figure><img src="image_3.png" /></figure>

Click Video under article
title in Contents at ajog.org
## AJOG at a Glance

### Why was this study conducted?

There are currently no data to properly assess the impact of tocolysis on the neurodevelopmental outcomes of school-aged children born prematurely after preterm prelabor rupture of membranes (PPROM).

### Key findings

Most pregnant individuals with PPROM who delivered prematurely received tocolytics. There were no differences in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolytics after PPROM.

### What does this add to what is known?

Our findings provide reassurance about the safety of tocolytic administration but also question its use because no health improvement was evidenced. These results complement and extend previous research, which showed that administering tocolytics after PPROM did not translate into improved short-term obstetrical or neonatal outcomes. To date, its health benefits remain unproven, both in the short- and long-term.

term outcomes into account. There is currently no evidence to suggest that the administration of tocolytics improves short-term neonatal outcomes.⁴,²⁴,²⁵ Only a few clinical studies have evaluated the impact of tocolysis after PPROM beyond the neonatal period.²⁶⁻³⁰ None have yielded robust conclusions, because they investigated outdated treatment strategies (eg, maintenance tocolysis),²⁷,²⁸ compared to two tocolytic treatments,²⁸⁻³⁰ had very limited sample sizes (usually less than 100),²⁷,³⁰ or co-included pregnant individuals with preterm labor and intact membranes.²⁸,²⁹ In addition, these studies had follow-up periods that were limited to early childhood (2 years of age)²⁷,²⁸ or covering a wide age range.²⁹ The World Health Organization has classified this gap in knowledge as a high priority research question related to tocolytic treatments.⁹

Therefore, building upon a large cohort of preterm infants and previous research focusing on neonatal and obstetrical outcomes,²⁴ we aimed to investigate if the administration of tocolytics after PPROM was associated with neurodevelopmental outcomes at 5.5 years of age.

## Materials and Methods

### Study design and setting

Briefly, EPIPAGE-2 is a prospective, population-based birth cohort of

extremely, very, and moderately preterm infants, that aimed to estimate the short- and long-term outcomes and their association with individual characteristics and unit practices.³¹ All births (terminations of pregnancy, stillbirths, and live births) from 22⁰⁰/⁷ to 34⁶⁰/⁷ weeks' gestation that occurred in all 546 maternity units of the 25 of 26 regions in France in 2011 were eligible. Recruitment was conducted over 3 distinct periods based on gestational age at birth, namely an 8-month recruitment period for births at 22 to 26 weeks' gestation, a 6-month period for births at 27 to 31 weeks' gestation, and a 5-week period for births at 32 to 34 weeks' gestation. A total of 7804 newborns were included at baseline (participation rate, 93%). Of those, 4312 were eligible for follow-up. Maternal, obstetrical, and neonatal data were collected from medical records following a standardized protocol.

All survivors were invited to participate in a comprehensive neurodevelopmental assessment at age 5.5 years, along with a sample of 600 term born children from the French Longitudinal Study since Childhood (ELFE) cohort³² intended to serve as a reference for developmental tests.³³ Parents completed a self-administered questionnaire, whereas children had a clinical examination by a physician and a

cognitive assessment by a neuropsychologist that were both performed in dedicated examination centers with specifically trained professionals to ensure homogeneity in data collection. At 5.5 years, at least 1 assessment was performed for 3083 (78%) children. Full details of the cohort recruitment and data collection were previously reported elsewhere.³¹,³³

### Ethical approval

Assessments occurred only after families had received information and provided written informed consent. This study was approved by the National Data Protection Authority (CNIL DR-2016-290) and by the appropriate ethics committees (Consultative Committee on the Treatment of Data on Personal Health for Research Purposes, reference No 16.263; Committee for the Protection of People Participating in Biomedical Research, reference 2016-A00333-48).

### Study population

We included the exact same sample as in our previous publication²⁴ with the eligibility criteria being PPROM occurring at 24⁰⁰/⁷ to 32⁶⁰/⁷ weeks' gestation in viable singleton pregnancies with a live fetus at the time of PPROM and birth at 24⁰⁰/⁷ to 34⁶⁰/⁷ weeks' gestation. PPROM was defined as spontaneous rupture of membranes before admission to the delivery room and diagnosed at least 2 hours before birth. As recommended, the diagnosis was based on maternal history and a sterile speculum examination with a diagnostic test performed if necessary. A further inclusion criterion was participation in the assessment at 5.5 years of age.

Pregnant individuals with multiples pregnancies (n=2020), terminations of pregnancies (n=1292), home births (n=54), fetal death before maternal admission to the hospital (n=675), lethal malformations (n=103), and precursor to delivery other than PPROM (n=2220) were excluded. Finally, we excluded all women with any contraindications to tocolysis or with care limitations because of an antenatal diagnosis of poor prognosis (Figure 1).
## AJOG at a Glance

### Why was this study conducted?

There are currently no data to properly assess the impact of tocolysis on the neurodevelopmental outcomes of school-aged children born prematurely after preterm prelabor rupture of membranes (PPROM).

### Key findings

Most pregnant individuals with PPROM who delivered prematurely received tocolytics. There were no differences in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolytics after PPROM.

### What does this add to what is known?

Our findings provide reassurance about the safety of tocolytic administration but also question its use because no health improvement was evidenced. These results complement and extend previous research, which showed that administering tocolytics after PPROM did not translate into improved short-term obstetrical or neonatal outcomes. To date, its health benefits remain unproven, both in the short- and long-term.

term outcomes into account. There is currently no evidence to suggest that the administration of tocolytics improves short-term neonatal outcomes.⁴,²⁴,²⁵ Only a few clinical studies have evaluated the impact of tocolysis after PPROM beyond the neonatal period.²⁶⁻³⁰ None have yielded robust conclusions, because they investigated outdated treatment strategies (eg, maintenance tocolysis),²⁷,²⁸ compared two tocolytic treatments,²⁸⁻³⁰ had very limited sample sizes (usually less than 100),²⁷,³⁰ or co-included pregnant individuals with preterm labor and intact membranes.²⁸,²⁹ In addition, these studies had follow-up periods that were limited to early childhood (2 years of age)²⁷,²⁸ or covering a wide age range.²⁹ The World Health Organization has classified this gap in knowledge as a high priority research question related to tocolytic treatments.⁹

Therefore, building upon a large cohort of preterm infants and previous research focusing on neonatal and obstetrical outcomes,²⁴ we aimed to investigate if the administration of tocolytics after PPROM was associated with neurodevelopmental outcomes at 5.5 years of age.

## Materials and Methods

### Study design and setting

Briefly, EPIPAGE-2 is a prospective, population-based birth cohort of

extremely, very, and moderately preterm infants, that aimed to estimate the short- and long-term outcomes and their association with individual characteristics and unit practices.³¹ All births (terminations of pregnancy, stillbirths, and live births) from 22⁰⁰/⁷ to 34⁶⁰/⁷ weeks' gestation that occurred in all 546 maternity units of the 25 of 26 regions in France in 2011 were eligible. Recruitment was conducted over 3 distinct periods based on gestational age at birth, namely an 8-month recruitment period for births at 22 to 26 weeks' gestation, a 6-month period for births at 27 to 31 weeks' gestation, and a 5-week period for births at 32 to 34 weeks' gestation. A total of 7804 newborns were included at baseline (participation rate, 93%). Of those, 4312 were eligible for follow-up. Maternal, obstetrical, and neonatal data were collected from medical records following a standardized protocol.

All survivors were invited to participate in a comprehensive neurodevelopmental assessment at age 5.5 years, along with a sample of 600 term born children from the French Longitudinal Study since Childhood (ELFE) cohort³² intended to serve as a reference for developmental tests.³³ Parents completed a self-administered questionnaire, whereas children had a clinical examination by a physician and a

cognitive assessment by a neuropsychologist that were both performed in dedicated examination centers with specifically trained professionals to ensure homogeneity in data collection. At 5.5 years, at least 1 assessment was performed for 3083 (78%) children. Full details of the cohort recruitment and data collection were previously reported elsewhere.³¹,³³

### Ethical approval

Assessments occurred only after families had received information and provided written informed consent. This study was approved by the National Data Protection Authority (CNIL DR-2016-290) and by the appropriate ethics committees (Consultative Committee on the Treatment of Data on Personal Health for Research Purposes, reference No 16.263; Committee for the Protection of People Participating in Biomedical Research, reference 2016-A00333-48).

### Study population

We included the exact same sample as in our previous publication²⁴ with the eligibility criteria being PPROM occurring at 24⁰⁰/⁷ to 32⁶⁰/⁷ weeks' gestation in viable singleton pregnancies with a live fetus at the time of PPROM and birth at 24⁰⁰/⁷ to 34⁶⁰/⁷ weeks' gestation. PPROM was defined as spontaneous rupture of membranes before admission to the delivery room and diagnosed at least 2 hours before birth. As recommended, the diagnosis was based on maternal history and a sterile speculum examination with a diagnostic test performed if necessary. A further inclusion criterion was participation in the assessment at 5.5 years of age.

Pregnant individuals with multiples pregnancies (n=2020), terminations of pregnancies (n=1292), home births (n=54), fetal death before maternal admission to the hospital (n=675), lethal malformations (n=103), and precursor to delivery other than PPROM (n=2220) were excluded. Finally, we excluded all women with any contraindications to tocolysis or with care limitations because of an antenatal diagnosis of poor prognosis (Figure 1).
FIGURE 1

Flow chart

<figure><img src="image_3.png" /></figure>

PPROM, preterm prelabor rupture of membranes.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

Exposure and outcome measures

The exposure was the administration of any tocolytic treatment after PPROM diagnosis (classified as tocolysis vs no tocolysis). The first-line tocolytics used in France were atosiban and nifedipine.

The primary composite outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years.³³ Survival was defined as the number of children alive at 5.5 years relative to the number of fetuses alive at the time of PPROM. We defined severe neurodevelopmental disabilities as severe cerebral palsy (Gross Motor Function Classification System [GMFCS] 4 or

5), bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss >70 dB and/or Full-Scale Intelligence Quotient (FSIQ) score of <−3 standard deviations (SDs) from the mean (Wechsler Preschool and Primary Scale of Intelligence, 4th edition). Moderate neurodevelopmental disabilities included cerebral palsy with a GMFCS score of 2 or 3, bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss of 40 to 70 dB and/or FSIQ between −3 to −2 SDs from the mean. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1), visual disability

≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss <40 dB and/or FSIQ score between −2 and −1 SDs from the mean and/or developmental coordination disorders (Movement Assessment Battery for Children, 2nd edition [MABC-2], total score ≤5th percentile), and/or behavioral difficulties (Strengths and Difficulties Questionnaire [SDQ], total score ≥90th percentile). All cutoffs were those of the distribution related to the reference group born at term.³³ We also assessed survival without any neurodevelopmental disabilities as a secondary outcome and all the aforementioned criteria taken separately.

Other variables

We considered the following variables in the analysis: sociodemographic characteristics (maternal age, country of birth, education, parental socioeconomic position—which was added to this analysis because of its strong impact on childhood outcomes), clinical factors (parity, uterine contractions at admission, gestational age at PPROM, PPROM before hospitalization), fetal characteristics (sex, presentation, and birthweight ≤third percentile), and obstetrical management (in utero transfer, administration of antenatal steroids or antibiotics, type of maternity unit). Uterine contractions were identified based on tracings of uterine activity recorded at admission. Gestational age was estimated based on the best obstetrical estimate, which combined information from the last menstrual period and the first trimester ultrasonography assessment. Administration of antenatal steroids was categorized as receiving at least 1 injection vs no injection. Babies were considered small for gestational age if their birth weight was ≤third percentile of the French intrauterine growth curves adjusted for sex and gestational age.³⁴ Socioeconomic position was defined by the highest occupational position between the occupations of the parents or of the mother only if living alone.

Statistical analysis

Maternal and child characteristics and outcomes were described as frequencies and percentages in each group (with and
FIGURE 1

Flow chart

<figure><img src="image_4.png" /></figure>

PPROM, preterm prelabor rupture of membranes.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

Exposure and outcome measures

The exposure was the administration of any tocolytic treatment after PPROM diagnosis (classified as tocolysis vs no tocolysis). The first-line tocolytics used in France were atosiban and nifedipine.

The primary composite outcome was survival without moderate to severe neurodevelopmental disabilities at 5.5 years.³³ Survival was defined as the number of children alive at 5.5 years relative to the number of fetuses alive at the time of PPROM. We defined severe neurodevelopmental disabilities as severe cerebral palsy (Gross Motor Function Classification System [GMFCS] 4 or

5), bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss >70 dB and/or Full-Scale Intelligence Quotient (FSIQ) score of <−3 standard deviations (SDs) from the mean (Wechsler Preschool and Primary Scale of Intelligence, 4th edition). Moderate neurodevelopmental disabilities included cerebral palsy with a GMFCS score of 2 or 3, bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss of 40 to 70 dB and/or FSIQ between −3 to −2 SDs from the mean. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1), visual disability

≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss <40 dB and/or FSIQ score between −2 and −1 SDs from the mean and/or developmental coordination disorders (Movement Assessment Battery for Children, 2nd edition [MABC-2], total score ≤5th percentile), and/or behavioral difficulties (Strengths and Difficulties Questionnaire [SDQ], total score ≥90th percentile). All cutoffs were those of the distribution related to the reference group born at term.³³ We also assessed survival without any neurodevelopmental disabilities as a secondary outcome and all the aforementioned criteria taken separately.

Other variables

We considered the following variables in the analysis: sociodemographic characteristics (maternal age, country of birth, education, parental socioeconomic position—which was added to this analysis because of its strong impact on childhood outcomes), clinical factors (parity, uterine contractions at admission, gestational age at PPROM, PPROM before hospitalization), fetal characteristics (sex, presentation, and birthweight ≤third percentile), and obstetrical management (in utero transfer, administration of antenatal steroids or antibiotics, type of maternity unit). Uterine contractions were identified based on tracings of uterine activity recorded at admission. Gestational age was estimated based on the best obstetrical estimate, which combined information from the last menstrual period and the first trimester ultrasonography assessment. Administration of antenatal steroids was categorized as receiving at least 1 injection vs no injection. Babies were considered small for gestational age if their birth weight was ≤third percentile of the French intrauterine growth curves adjusted for sex and gestational age.³⁴ Socioeconomic position was defined by the highest occupational position between the occupations of the parents or of the mother only if living alone.

Statistical analysis

Maternal and child characteristics and outcomes were described as frequencies and percentages in each group (with and
without tocolysis). Percentages were weighted according to the duration of the recruitment periods (in weeks) for each gestational age group; weights were 1.0 (35/35) for births at 24 to 26 weeks' gestation, 1.34 (35/26) for births at 27 to 31 weeks' gestation, and 7.0 (35/5) for births at 32 to 34 weeks' gestation. Weighting allowed us to account for the sampling scheme of the cohort and to ensure representativeness.

We compared the characteristics of the children with an incomplete assessment (n=82) and no assessment (n=226) at 5.5 years with those of children with a complete follow-up evaluation. Categorical variables were compared using chi-square or Fisher exact tests as appropriate.

We used a propensity-score analysis intended to minimize the indication bias when estimating the treatment effect.³⁵ The propensity score was defined as the pregnant individual's probability of receiving tocolysis based on their characteristics at baseline (excluding covariates that may be affected by the treatment, such as gestational age at birth), namely all the aforementioned sociodemographic characteristics, clinical factors, obstetrical management, and fetal characteristics. We then applied inverse probability of treatment weighting (IPTW) based on the estimated propensity scores to obtain 2 groups with balanced observed baseline covariates (as confirmed by postweighting standardized differences all <10%) (Supplemental Figure), which only differed by treatment allocation. The association between tocolysis and each outcome was estimated using a logistic regression model within the weighted sample, obtaining odds ratios (ORs) and 95% confidence intervals (CIs) with robust standard errors.

The proportion of missing data for baseline characteristics ranged from 0% to 17.9% for each covariate but exceeded 5.0% only for contractions at admission (5.5%), socioeconomic status (6.5%), and maternal level of education (17.9%). Overall, the primary outcome was missing for 43.3%. Complete case analysis for the composite survival outcomes may undermine the representativeness

of the estimates and introduce selection biases. The main results were therefore presented after multiple imputations to account for selective dropouts and missing information at follow-up. Missing baseline and outcome variables were handled by multiple imputations by chained equations with the SAS multiple imputation procedure (SAS Institute, Cary, NC).³⁶ Considering missing data as missing at random based on the variables included in the imputation model, we generated 50 independent imputed data sets with 20 iterations each by using all the baseline and outcome variables and those potentially predicting attrition and/or outcomes. A propensity score analysis was performed in each imputed data set to estimate the exposure effect, and estimates were pooled according to Rubin's rules.

We performed the following sensitivity analyses. First, we presented the results of the analyses of complete cases with restriction to children with a follow-up at 5.5 years. Second, we reported a greedy matching on the propensity score, performed using the PSMATCH SAS procedure without replacement within a caliper of 0.2 SDs of the logit of the propensity score. Each exposed infant was matched to the closest non-exposed infant, leading to matching 202 children exposed to tocolytics with 202 non-exposed children. This procedure estimated the average treatment effect on the treated (ATT). Third, we investigated the association between the initial tocolytic drug administered (oxytocin receptor antagonists, calcium channel blockers, no tocolysis) and the outcomes by applying a 3-group propensity score based on a generalized boosted modeling to calculate the average treatment effect (ATE) weights for optimal balance between the 3 groups using the mnps function in the twang statistical package in R (R Core Team, Vienna, Austria).³⁷ Fourth, considering French clinical practices in 2011, antenatal management may have differed for the earliest gestational age group, leading to poorer outcomes. We therefore replicated our analyses in a subgroup of participants with PPROM at 26 to 31 weeks' gestation. Fifth, we also

applied a stricter definition of PPROM (ie, latency ≥12 hours), which is commonly reported in the literature² and excludes women with membranes ruptured during labor. Finally, we tried to disentangle the efficacy of tocolytics among pregnant individuals with and without contractions by replicating the analyses in these 2 subgroups of patients.

Statistical analyses were performed using SAS, version 9.4, and R, version 4.0.2.

## Results

A total of 803 pregnant individuals were included in our previous analysis that focused on perinatal outcomes among whom 596 (weighted percentage, 73.4%) received tocolytics after PPROM and 207 (weighted percentage, 26.6%) did not (Figure 1). Among 712 children alive at 5.5 years, 300 of 531 (56.5%) in the tocolysis group and 104 of 181 (57.5%) in the no tocolysis group had a complete follow-up assessment, whereas 63 of 531 (11.9%) and 19 of 181 (10.5%) in the respective groups had a partial assessment. Children lost to follow-up had younger mothers, with a lower education level, and lower socioeconomic positions than those with a complete assessment (Supplemental Table 1). However, there were no differences in clinical management across these groups, including tocolytic administration.

Baseline sociodemographic and clinical characteristics by exposure to tocolysis are reported in Table 1. Tocolytics were more frequently administered to women with uterine contractions and in utero transfer. All baseline covariates were well-balanced after creating propensity scores and applying IPTW (Supplemental Figure).

At the 5.5-year follow-up, 82.7% and 82.5% of children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1% in the respective groups were alive without any disabilities (Table 2). The frequency of all other outcomes by exposure group is detailed in Table 2 and Supplemental Table 2. After applying multiple imputations and IPTW, we found no association between exposure
without tocolysis). Percentages were weighted according to the duration of the recruitment periods (in weeks) for each gestational age group; weights were 1.0 (35/35) for births at 24 to 26 weeks' gestation, 1.34 (35/26) for births at 27 to 31 weeks' gestation, and 7.0 (35/5) for births at 32 to 34 weeks' gestation. Weighting allowed us to account for the sampling scheme of the cohort and to ensure representativeness.

We compared the characteristics of the children with an incomplete assessment (n=82) and no assessment (n=226) at 5.5 years with those of children with a complete follow-up evaluation. Categorical variables were compared using chi-square or Fisher exact tests as appropriate.

We used a propensity-score analysis intended to minimize the indication bias when estimating the treatment effect.³⁵ The propensity score was defined as the pregnant individual's probability of receiving tocolysis based on their characteristics at baseline (excluding covariates that may be affected by the treatment, such as gestational age at birth), namely all the aforementioned sociodemographic characteristics, clinical factors, obstetrical management, and fetal characteristics. We then applied inverse probability of treatment weighting (IPTW) based on the estimated propensity scores to obtain 2 groups with balanced observed baseline covariates (as confirmed by postweighting standardized differences all <10%) (Supplemental Figure), which only differed by treatment allocation. The association between tocolysis and each outcome was estimated using a logistic regression model within the weighted sample, obtaining odds ratios (ORs) and 95% confidence intervals (CIs) with robust standard errors.

The proportion of missing data for baseline characteristics ranged from 0% to 17.9% for each covariate but exceeded 5.0% only for contractions at admission (5.5%), socioeconomic status (6.5%), and maternal level of education (17.9%). Overall, the primary outcome was missing for 43.3%. Complete case analysis for the composite survival outcomes may undermine the representativeness

of the estimates and introduce selection biases. The main results were therefore presented after multiple imputations to account for selective dropouts and missing information at follow-up. Missing baseline and outcome variables were handled by multiple imputations by chained equations with the SAS multiple imputation procedure (SAS Institute, Cary, NC).³⁶ Considering missing data as missing at random based on the variables included in the imputation model, we generated 50 independent imputed data sets with 20 iterations each by using all the baseline and outcome variables and those potentially predicting attrition and/or outcomes. A propensity score analysis was performed in each imputed data set to estimate the exposure effect, and estimates were pooled according to Rubin's rules.

We performed the following sensitivity analyses. First, we presented the results of the analyses of complete cases with restriction to children with a follow-up at 5.5 years. Second, we reported a greedy matching on the propensity score, performed using the PSMATCH SAS procedure without replacement within a caliper of 0.2 SDs of the logit of the propensity score. Each exposed infant was matched to the closest non-exposed infant, leading to matching 202 children exposed to tocolytics with 202 non-exposed children. This procedure estimated the average treatment effect on the treated (ATT). Third, we investigated the association between the initial tocolytic drug administered (oxytocin receptor antagonists, calcium channel blockers, no tocolysis) and the outcomes by applying a 3-group propensity score based on a generalized boosted modeling to calculate the average treatment effect (ATE) weights for optimal balance between the 3 groups using the mnps function in the twang statistical package in R (R Core Team, Vienna, Austria).³⁷ Fourth, considering French clinical practices in 2011, antenatal management may have differed for the earliest gestational age group, leading to poorer outcomes. We therefore replicated our analyses in a subgroup of participants with PPROM at 26 to 31 weeks' gestation. Fifth, we also

applied a stricter definition of PPROM (ie, latency ≥12 hours), which is commonly reported in the literature² and excludes women with membranes ruptured during labor. Finally, we tried to disentangle the efficacy of tocolytics among pregnant individuals with and without contractions by replicating the analyses in these 2 subgroups of patients.

Statistical analyses were performed using SAS, version 9.4, and R, version 4.0.2.

## Results

A total of 803 pregnant individuals were included in our previous analysis that focused on perinatal outcomes among whom 596 (weighted percentage, 73.4%) received tocolytics after PPROM and 207 (weighted percentage, 26.6%) did not (Figure 1). Among 712 children alive at 5.5 years, 300 of 531 (56.5%) in the tocolysis group and 104 of 181 (57.5%) in the no tocolysis group had a complete follow-up assessment, whereas 63 of 531 (11.9%) and 19 of 181 (10.5%) in the respective groups had a partial assessment. Children lost to follow-up had younger mothers, with a lower education level, and lower socioeconomic positions than those with a complete assessment (Supplemental Table 1). However, there were no differences in clinical management across these groups, including tocolytic administration.

Baseline sociodemographic and clinical characteristics by exposure to tocolysis are reported in Table 1. Tocolytics were more frequently administered to women with uterine contractions and in utero transfer. All baseline covariates were well-balanced after creating propensity scores and applying IPTW (Supplemental Figure).

At the 5.5-year follow-up, 82.7% and 82.5% of children in the tocolysis and no tocolysis groups, respectively, were alive without moderate to severe neurodevelopmental disabilities; 52.7% and 51.1% in the respective groups were alive without any disabilities (Table 2). The frequency of all other outcomes by exposure group is detailed in Table 2 and Supplemental Table 2. After applying multiple imputations and IPTW, we found no association between exposure
<table><caption>TABLE 1
Baseline characteristics according to exposure to tocolysis</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Tocolysis (n=596)</th><th colspan="2">No tocolysis (n=207)</th></tr><tr><th>n</th><th>%<sup>a</sup></th><th>n</th><th>%<sup>a</sup></th></tr></thead><tbody><tr><td>Maternal characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Age (y) (n=803)</td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25 y</td><td>33</td><td>4.7</td><td>8</td><td>2.4</td></tr><tr><td>25-34 y</td><td>469</td><td>80.8</td><td>158</td><td>78.1</td></tr><tr><td>≥35 y</td><td>94</td><td>14.5</td><td>41</td><td>19.5</td></tr><tr><td>Nulliparity (n=786)</td><td>280</td><td>51.9</td><td>98</td><td>48.4</td></tr><tr><td>Born in France or Europe (n=786)</td><td>463</td><td>78.7</td><td>149</td><td>75.9</td></tr><tr><td>Level of education (n=659)</td><td></td><td></td><td></td><td></td></tr><tr><td>Less than high school</td><td>164</td><td>31.6</td><td>57</td><td>36.4</td></tr><tr><td>High school, 1-2 y of graduate studies</td><td>217</td><td>43.9</td><td>65</td><td>38.4</td></tr><tr><td>≥3 y of graduate studies</td><td>121</td><td>24.4</td><td>35</td><td>25.2</td></tr><tr><td>Parents' socioeconomic position<sup>b</sup> (n=751)</td><td></td><td></td><td></td><td></td></tr><tr><td>Executive</td><td>119</td><td>20.2</td><td>39</td><td>19.7</td></tr><tr><td>Intermediate</td><td>87</td><td>16.4</td><td>21</td><td>10.2</td></tr><tr><td>Administration</td><td>167</td><td>30.9</td><td>70</td><td>40.5</td></tr><tr><td>Service, trade</td><td>83</td><td>16.5</td><td>25</td><td>14.5</td></tr><tr><td>Worker, unemployed</td><td>108</td><td>16.0</td><td>32</td><td>15.1</td></tr><tr><td>Obstetrical characteristics and management</td><td></td><td></td><td></td><td></td></tr><tr><td>PPROM before hospitalization (n=803)</td><td>515</td><td>88.3</td><td>155</td><td>81.3</td></tr><tr><td>Contractions at admission (n=759)</td><td>249</td><td>44.1</td><td>71</td><td>33.0</td></tr><tr><td>Gestational age at PPROM (wk) (n=803), median (IQR)</td><td>30 (27-31)</td><td></td><td>30 (27-32)</td><td></td></tr><tr><td>24</td><td>56</td><td>6.4</td><td>25</td><td>6.5</td></tr><tr><td>25</td><td>89</td><td>8.7</td><td>28</td><td>7.5</td></tr><tr><td>26</td><td>58</td><td>6.8</td><td>16</td><td>4.4</td></tr><tr><td>27</td><td>58</td><td>6.9</td><td>25</td><td>9.6</td></tr><tr><td>28</td><td>65</td><td>8.8</td><td>17</td><td>7.0</td></tr><tr><td>29</td><td>75</td><td>10.5</td><td>22</td><td>8.6</td></tr><tr><td>30</td><td>81</td><td>12.2</td><td>29</td><td>11.0</td></tr><tr><td>31</td><td>76</td><td>16.1</td><td>27</td><td>14.5</td></tr><tr><td>32</td><td>38</td><td>23.6</td><td>18</td><td>30.9</td></tr><tr><td>In utero transfer (n=803)</td><td>415</td><td>63.3</td><td>72</td><td>27.4</td></tr><tr><td>Antibiotics (n=803)</td><td>579</td><td>97.0</td><td>193</td><td>95.8</td></tr><tr><td>Antenatal steroids (n=803)</td><td>552</td><td>89.0</td><td>179</td><td>89.0</td></tr><tr><td>Neonatal characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Cephalic presentation (n=785)</td><td>413</td><td>72.4</td><td>134</td><td>73.7</td></tr><tr><td>Male fetus (n=803)</td><td>325</td><td>54.3</td><td>116</td><td>57.9</td></tr><tr><td>Birth weight ≤third percentile (n=802)</td><td>35</td><td>5.4</td><td>18</td><td>8.4</td></tr></tbody></table>

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

(continued)
<table><caption>TABLE 1
Baseline characteristics according to exposure to tocolysis</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Tocolysis (n=596)</th><th colspan="2">No tocolysis (n=207)</th></tr><tr><th>n</th><th>%<sup>a</sup></th><th>n</th><th>%<sup>a</sup></th></tr></thead><tbody><tr><td>Maternal characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Age (y) (n=803)</td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25 y</td><td>33</td><td>4.7</td><td>8</td><td>2.4</td></tr><tr><td>25-34 y</td><td>469</td><td>80.8</td><td>158</td><td>78.1</td></tr><tr><td>≥35 y</td><td>94</td><td>14.5</td><td>41</td><td>19.5</td></tr><tr><td>Nulliparity (n=786)</td><td>280</td><td>51.9</td><td>98</td><td>48.4</td></tr><tr><td>Born in France or Europe (n=786)</td><td>463</td><td>78.7</td><td>149</td><td>75.9</td></tr><tr><td>Level of education (n=659)</td><td></td><td></td><td></td><td></td></tr><tr><td>Less than high school</td><td>164</td><td>31.6</td><td>57</td><td>36.4</td></tr><tr><td>High school, 1-2 y of graduate studies</td><td>217</td><td>43.9</td><td>65</td><td>38.4</td></tr><tr><td>≥3 y of graduate studies</td><td>121</td><td>24.4</td><td>35</td><td>25.2</td></tr><tr><td>Parents' socioeconomic position<sup>b</sup> (n=751)</td><td></td><td></td><td></td><td></td></tr><tr><td>Executive</td><td>119</td><td>20.2</td><td>39</td><td>19.7</td></tr><tr><td>Intermediate</td><td>87</td><td>16.4</td><td>21</td><td>10.2</td></tr><tr><td>Administration</td><td>167</td><td>30.9</td><td>70</td><td>40.5</td></tr><tr><td>Service, trade</td><td>83</td><td>16.5</td><td>25</td><td>14.5</td></tr><tr><td>Worker, unemployed</td><td>108</td><td>16.0</td><td>32</td><td>15.1</td></tr><tr><td>Obstetrical characteristics and management</td><td></td><td></td><td></td><td></td></tr><tr><td>PPROM before hospitalization (n=803)</td><td>515</td><td>88.3</td><td>155</td><td>81.3</td></tr><tr><td>Contractions at admission (n=759)</td><td>249</td><td>44.1</td><td>71</td><td>33.0</td></tr><tr><td>Gestational age at PPROM (wk) (n=803), median (IQR)</td><td>30 (27-31)</td><td></td><td>30 (27-32)</td><td></td></tr><tr><td>24</td><td>56</td><td>6.4</td><td>25</td><td>6.5</td></tr><tr><td>25</td><td>89</td><td>8.7</td><td>28</td><td>7.5</td></tr><tr><td>26</td><td>58</td><td>6.8</td><td>16</td><td>4.4</td></tr><tr><td>27</td><td>58</td><td>6.9</td><td>25</td><td>9.6</td></tr><tr><td>28</td><td>65</td><td>8.8</td><td>17</td><td>7.0</td></tr><tr><td>29</td><td>75</td><td>10.5</td><td>22</td><td>8.6</td></tr><tr><td>30</td><td>81</td><td>12.2</td><td>29</td><td>11.0</td></tr><tr><td>31</td><td>76</td><td>16.1</td><td>27</td><td>14.5</td></tr><tr><td>32</td><td>38</td><td>23.6</td><td>18</td><td>30.9</td></tr><tr><td>In utero transfer (n=803)</td><td>415</td><td>63.3</td><td>72</td><td>27.4</td></tr><tr><td>Antibiotics (n=803)</td><td>579</td><td>97.0</td><td>193</td><td>95.8</td></tr><tr><td>Antenatal steroids (n=803)</td><td>552</td><td>89.0</td><td>179</td><td>89.0</td></tr><tr><td>Neonatal characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Cephalic presentation (n=785)</td><td>413</td><td>72.4</td><td>134</td><td>73.7</td></tr><tr><td>Male fetus (n=803)</td><td>325</td><td>54.3</td><td>116</td><td>57.9</td></tr><tr><td>Birth weight ≤third percentile (n=802)</td><td>35</td><td>5.4</td><td>18</td><td>8.4</td></tr></tbody></table>

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

(continued)
<table><caption>**TABLE 1**
**Baseline characteristics according to exposure to tocolysis (continued)**</caption><thead><tr><th>Characteristics</th><th colspan="2">Tocolysis (n=596)</th><th colspan="2">No tocolysis (n=207)</th></tr></thead><tbody><tr><td>Maternity unit characteristics</td><td></td><td></td><td></td><td></td></tr><tr><td>Type of maternity unit (n=803)</td><td></td><td></td><td></td><td></td></tr><tr><td>Type 1 (no neonatal department)</td><td>4</td><td>0.4</td><td>2</td><td>2.0</td></tr><tr><td>Type 2 (with neonatal department)</td><td>56</td><td>23.2</td><td>30</td><td>20.6</td></tr><tr><td>Type 3 (with neonatal intensive care department)</td><td>536</td><td>76.4</td><td>175</td><td>77.4</td></tr></tbody></table>

The data for n=803 participants are presented.

IQR, interquartile range; PPROM, preterm prelabor rupture of membranes; SD, standardized difference.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

to tocolysis and survival without moderate to severe neurodevelopmental disabilities (OR, 0.93; 95% CI, 0.55–1.60), survival without any neurodevelopmental disabilities (OR, 1.02; 95% CI, 0.65–1.61), or any of the other outcomes (Table 2). Similar results were obtained after complete cases analyses, matching on the propensity score, and in all subgroup analyses (Figure 2, Figure 3, Supplemental Table 3). The frequency of survival without moderate to severe neurodevelopmental disabilities was 80.7% and 83.7% after antenatal exposure to oxytocin receptor antagonists and calcium channel blockers, respectively (Supplemental Table 2). Once again, there was no association between the initial tocolytic treatment and any of the neurodevelopmental outcomes under investigation (Supplemental Table 3).

## Comment

### Principal findings

We found no differences in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolytics after PPROM. These results complement and extend previous research, which showed that administering tocolytics after PPROM did not translate into improved short-term obstetrical or neonatal outcomes.

### Strengths and limitations

Our study was based on a large, prospective, population-based sample of

participants exposed to PPROM at a national level and detailed high-quality data. Furthermore, obstetrical management was consistent with the current clinical guidelines, particular in terms of antenatal administration of steroids and antibiotics, thereby ensuring that our findings accurately reflect routine clinical practice. The follow-up at 5.5 years of age included both parental insights and a standardized medical and neuropsychological evaluation conducted by trained professionals, further enhancing the reliability and validity of our results. Given the dearth of evidence-based data regarding school-age outcomes after antenatal exposure to pregnancy complications and treatments, such observational studies provide valuable insights for evaluating routine clinical practices in a real-life setting.

The findings should be interpreted in light of the study's limitations. Loss to follow-up and selection bias are inherently associated with any long-term follow-up of cohort participants.³³ If this sample is representative of the preterm population in terms of neonatal characteristics, attrition over time was relatively high and socially determined as classically reported in longitudinal cohort studies.³¹,³³,³⁸ Social factors, such as a low socioeconomic position, are known to be associated with both loss to follow-up and poor long-term outcomes.³³ Therefore, the proportion of children with suboptimal neurodevelopmental outcomes is likely

underestimated in our study sample and in complete-cases analyses which is why we presented the main results after multiple imputations. Treatment allocation was not randomized in this observational study. We therefore performed analyses that minimized indication bias as much as possible. By design, babies born after 34⁶/⁷ weeks' gestation were not included in the EPIPAGE-2 cohort. We restricted our analyses to cases of PPROM before 33 weeks' gestation and likely missed a small proportion of PPROM cases that occurred before 33 weeks' gestation with delivery after 34⁶/⁷ weeks, that is, those with the longest latency durations and the best prognoses.

## Results in the context of what is known

Although most women with PPROM who delivered prematurely received tocolytics, the treatment was not associated with either prolonged gestation by ≥48 hours, neonatal outcomes,²⁴ or neurodevelopment at 5.5 years of age. Together with our previous article, we think that this study makes an important contribution to our understanding of the short- and long-term consequences of administering tocolytics after PPROM.

Very few observational studies and randomized trials have examined the benefits and harms of tocolysis in women with PPROM and their children.⁴,²⁵,²⁷⁻³⁰,³⁹ Most had limited external validity and reliability and

<footnote>a Denominators vary according to the number of missing data for each variable. Percentages are weighted to take into account the differences in survey design between gestational age groups, thus proportions are not exact number of events or number in groups because of the weighting; b Defined as the highest occupational status between occupations of the mother and the father or mother only if living alone.</footnote>
<table><caption>**TABLE 1**
**Baseline characteristics according to exposure to tocolysis (continued)**</caption><thead><tr><th>Characteristics</th><th colspan="2">Tocolysis (n=596)</th><th colspan="2">No tocolysis (n=207)</th></tr></thead><tbody><tr><td colspan="5">Maternity unit characteristics</td></tr><tr><td>Type of maternity unit (n=803)</td><td></td><td></td><td></td><td></td></tr><tr><td>Type 1 (no neonatal department)</td><td>4</td><td>0.4</td><td>2</td><td>2.0</td></tr><tr><td>Type 2 (with neonatal department)</td><td>56</td><td>23.2</td><td>30</td><td>20.6</td></tr><tr><td>Type 3 (with neonatal intensive care department)</td><td>536</td><td>76.4</td><td>175</td><td>77.4</td></tr></tbody></table>

The data for n=803 participants are presented.

IQR, interquartile range; PPROM, preterm prelabor rupture of membranes; SD, standardized difference.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

to tocolysis and survival without moderate to severe neurodevelopmental disabilities (OR, 0.93; 95% CI, 0.55-1.60), survival without any neurodevelopmental disabilities (OR, 1.02; 95% CI, 0.65-1.61), or any of the other outcomes (Table 2). Similar results were obtained after complete cases analyses, matching on the propensity score, and in all subgroup analyses (Figure 2, Figure 3, Supplemental Table 3). The frequency of survival without moderate to severe neurodevelopmental disabilities was 80.7% and 83.7% after antenatal exposure to oxytocin receptor antagonists and calcium channel blockers, respectively (Supplemental Table 2). Once again, there was no association between the initial tocolytic treatment and any of the neurodevelopmental outcomes under investigation (Supplemental Table 3).

## Comment

### Principal findings

We found no differences in the neurodevelopmental outcomes at age 5.5 years among children with and without antenatal exposure to tocolytics after PPROM. These results complement and extend previous research, which showed that administering tocolytics after PPROM did not translate into improved short-term obstetrical or neonatal outcomes.

### Strengths and limitations

Our study was based on a large, prospective, population-based sample of

participants exposed to PPROM at a national level and detailed high-quality data. Furthermore, obstetrical management was consistent with the current clinical guidelines, particular in terms of antenatal administration of steroids and antibiotics, thereby ensuring that our findings accurately reflect routine clinical practice. The follow-up at 5.5 years of age included both parental insights and a standardized medical and neuropsychological evaluation conducted by trained professionals, further enhancing the reliability and validity of our results. Given the dearth of evidence-based data regarding school-age outcomes after antenatal exposure to pregnancy complications and treatments, such observational studies provide valuable insights for evaluating routine clinical practices in a real-life setting.

The findings should be interpreted in light of the study's limitations. Loss to follow-up and selection bias are inherently associated with any long-term follow-up of cohort participants.³³ If this sample is representative of the preterm population in terms of neonatal characteristics, attrition over time was relatively high and socially determined as classically reported in longitudinal cohort studies.³¹,³³,³⁸ Social factors, such as a low socioeconomic position, are known to be associated with both loss to follow-up and poor long-term outcomes.³³ Therefore, the proportion of children with suboptimal neurodevelopmental outcomes is likely

underestimated in our study sample and in complete-cases analyses which is why we presented the main results after multiple imputations. Treatment allocation was not randomized in this observational study. We therefore performed analyses that minimized indication bias as much as possible. By design, babies born after 34<sup>6/7</sup> weeks' gestation were not included in the EPIPAGE-2 cohort. We restricted our analyses to cases of PPROM before 33 weeks' gestation and likely missed a small proportion of PPROM cases that occurred before 33 weeks' gestation with delivery after 34<sup>6/7</sup> weeks, that is, those with the longest latency durations and the best prognoses.

## Results in the context of what is known

Although most women with PPROM who delivered prematurely received tocolytics, the treatment was not associated with either prolonged gestation by ≥48 hours, neonatal outcomes,²⁴ or neurodevelopment at 5.5 years of age. Together with our previous article, we think that this study makes an important contribution to our understanding of the short- and long-term consequences of administering tocolytics after PPROM.

Very few observational studies and randomized trials have examined the benefits and harms of tocolysis in women with PPROM and their children.⁴,²⁵,²⁷⁻³⁰,³⁹ Most had limited external validity and reliability and

<footnote><sup>a</sup> Denominators vary according to the number of missing data for each variable. Percentages are weighted to take into account the differences in survey design between gestational age groups, thus proportions are not exact number of events or number in groups because of the weighting; <sup>b</sup> Defined as the highest occupational status between occupations of the mother and the father or mother only if living alone.</footnote>
<table><caption>**TABLE 2**
Association between tocolysis and 5-year outcomes, after multiple imputation and inverse probability treatment weighting</caption><thead><tr><th rowspan="3">Outcome</th><th colspan="2">Tocolysis</th><th colspan="2">After inverse probability of treatment<br>weighting</th></tr><tr><th>%<sup>a</sup></th><th>No tocolysis</th><th colspan="2">OR or MD (95% CI)</th></tr><tr><th>n=596</th><th>%<sup>a</sup><br>n=207</th><th>Tocolysis vs no tocolysis</th><th>P value</th></tr></thead><tbody><tr><td>Survival without moderate to severe neurodevelopmental<br>disabilities at 5.5 y<sup>b</sup></td><td>82.7</td><td>82.5</td><td>0.93 (0.55-1.60)</td><td>.56</td></tr><tr><td>Survival without any neurodevelopmental disabilities at 5.5 y<sup>b</sup></td><td>52.7</td><td>51.1</td><td>1.02 (0.65-1.61)</td><td>.62</td></tr><tr><td>Survival at 5.5 y</td><td>93.2</td><td>93.1</td><td>0.78 (0.43-1.42)</td><td>.41</td></tr><tr><td>Among survivors at 5.5 y</td><td>n=531</td><td>n=181</td><td></td><td></td></tr><tr><td>Neurodevelopmental disabilities<sup>b</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Severe</td><td>1.6</td><td>2.5</td><td>0.68 (0.17-2.71)</td><td>.65</td></tr><tr><td>Moderate</td><td>9.6</td><td>8.9</td><td>1.00 (0.53-1.85)</td><td></td></tr><tr><td>Mild</td><td>38.2</td><td>42.2</td><td>0.94 (0.66-1.32)</td><td></td></tr><tr><td>None</td><td>50.6</td><td>46.4</td><td>Ref</td><td></td></tr><tr><td>Cerebral palsy</td><td>4.6</td><td>8.6</td><td>0.86 (0.36-2.02)</td><td>.60</td></tr><tr><td>FSIQ score</td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>97.1 (13.6)</td><td>97.0 (13.5)</td><td>1.1 (-2.5 to 4.7)</td><td>.38</td></tr><tr><td>&lt;79 (&lt;-2 SD)<sup>c</sup></td><td>8.2</td><td>8.1</td><td>1.06 (0.42-2.71)</td><td>.51</td></tr><tr><td>Behavioral difficulties</td><td></td><td></td><td></td><td></td></tr><tr><td>Total SDQ score, mean (SD)</td><td>10.8 (5.3)</td><td>11.2 (5.1)</td><td>-0.0 (-1.2 to 1.1)</td><td>.63</td></tr><tr><td>Total SDQ score ≥90th percentile<sup>c</sup></td><td>9.5</td><td>9.7</td><td>1.31 (0.53-3.21)</td><td>.45</td></tr><tr><td>Developmental Coordination Disorders<sup>d</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Total MABC-2 score, mean (SD)</td><td>10.5 (3.1)</td><td>9.7 (2.9)</td><td>0.7 (-0.1 to 1.5)</td><td>.11</td></tr><tr><td>Total MABC-2 score ≤5th percentile<sup>c</sup></td><td>6.4</td><td>7.7</td><td>0.65 (0.26-1.61)</td><td>.32</td></tr></tbody></table>

CI, confidence interval; dB, decibels; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System; MABC-2, Movement Assessment Battery for Children - Second Edition (Henderson, 2007); MD, mean difference; OR, odd ratios; SD, standard deviation; SDQ, Strengths and Difficulties Questionnaire (Goodman, 1997).

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

almost none reported long-term outcomes. Briefly, the 2-year follow-up in the Assessment of Perinatal Outcome after Sustained Tocolysis in Early Labor II (APOSTEL II) trial (maintenance tocolysis with nifedipine vs placebo after threatened preterm labor) focused on maintenance tocolysis, which is not recommended.²⁷ Furthermore, this study was largely underpowered to show any differences in outcomes (n=46 women with PPROM). Similarly, another study

reported the 2-year follow-up of a small sample of children exposed to nifedipine vs ritodrine for 7 days.²⁸ The proportion of women with PPROM was not reported, and a non-validated parental questionnaire was used to assess developmental outcomes. Children born to participants in the APOSTEL III trial (tocolysis with nifedipine vs atosiban after threatened preterm labor) were followed once over a wide age range (2.5 to 5.5 years of age).²⁹ No results were

reported specifically for the small subgroup of children born after PPROM. The only long-term follow-up study (9-12 years) of children exposed in utero to tocolytics compared behavioral-emotional outcomes, quality of life, motor function, parenting distress, and education of children exposed to nifedipine with those exposed to ritodrine.³⁰ No significant differences in the long-term outcomes were observed, but fewer than 100 children were evaluated.

<footnote><sup>a</sup> Weighted to take into account the differences in survey design between gestational age groups; <sup>b</sup> Severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss >70 dB and/or FSIQ score <-3 SDs. Moderate neurodevelopmental disabilities were defined as cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between -3 to -2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB and/or FSIQ score between -2 and -1 SDs and/or MABC-2 score <5th percentile and/or SDQ score ≥90th percentile). Cutoffs of the distribution was related to a reference group born at term; <sup>c</sup> Cutoff of the distribution related to a reference group born at term; <sup>d</sup> Among children without cerebral palsy, severe or moderate sensory disabilities, and with Full-Scale Intelligence Quotient score ≥2 SDs.</footnote>
<table><caption>**TABLE 2**
Association between tocolysis and 5-year outcomes, after multiple imputation and inverse probability treatment weighting</caption><thead><tr><th rowspan="3">Outcome</th><th colspan="2">Tocolysis</th><th colspan="2">After inverse probability of treatment weighting</th></tr><tr><th>%<sup>a</sup></th><th>No tocolysis</th><th colspan="2">OR or MD (95% CI)</th></tr><tr><th>n=596</th><th>%<sup>a</sup><br>n=207</th><th>Tocolysis vs no tocolysis</th><th>P value</th></tr></thead><tbody><tr><td>Survival without moderate to severe neurodevelopmental disabilities at 5.5 y<sup>b</sup></td><td>82.7</td><td>82.5</td><td>0.93 (0.55-1.60)</td><td>.56</td></tr><tr><td>Survival without any neurodevelopmental disabilities at 5.5 y<sup>b</sup></td><td>52.7</td><td>51.1</td><td>1.02 (0.65-1.61)</td><td>.62</td></tr><tr><td>Survival at 5.5 y</td><td>93.2</td><td>93.1</td><td>0.78 (0.43-1.42)</td><td>.41</td></tr><tr><td>Among survivors at 5.5 y</td><td>n=531</td><td>n=181</td><td></td><td></td></tr><tr><td>Neurodevelopmental disabilities<sup>b</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Severe</td><td>1.6</td><td>2.5</td><td>0.68 (0.17-2.71)</td><td>.65</td></tr><tr><td>Moderate</td><td>9.6</td><td>8.9</td><td>1.00 (0.53-1.85)</td><td></td></tr><tr><td>Mild</td><td>38.2</td><td>42.2</td><td>0.94 (0.66-1.32)</td><td></td></tr><tr><td>None</td><td>50.6</td><td>46.4</td><td>Ref</td><td></td></tr><tr><td>Cerebral palsy</td><td>4.6</td><td>8.6</td><td>0.86 (0.36-2.02)</td><td>.60</td></tr><tr><td>FSIQ score</td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>97.1 (13.6)</td><td>97.0 (13.5)</td><td>1.1 (-2.5 to 4.7)</td><td>.38</td></tr><tr><td>&lt;79 (&lt;-2 SD)<sup>c</sup></td><td>8.2</td><td>8.1</td><td>1.06 (0.42-2.71)</td><td>.51</td></tr><tr><td>Behavioral difficulties</td><td></td><td></td><td></td><td></td></tr><tr><td>Total SDQ score, mean (SD)</td><td>10.8 (5.3)</td><td>11.2 (5.1)</td><td>-0.0 (-1.2 to 1.1)</td><td>.63</td></tr><tr><td>Total SDQ score ≥90th percentile<sup>c</sup></td><td>9.5</td><td>9.7</td><td>1.31 (0.53-3.21)</td><td>.45</td></tr><tr><td>Developmental Coordination Disorders<sup>d</sup></td><td></td><td></td><td></td><td></td></tr><tr><td>Total MABC-2 score, mean (SD)</td><td>10.5 (3.1)</td><td>9.7 (2.9)</td><td>0.7 (-0.1 to 1.5)</td><td>.11</td></tr><tr><td>Total MABC-2 score ≤5th percentile<sup>c</sup></td><td>6.4</td><td>7.7</td><td>0.65 (0.26-1.61)</td><td>.32</td></tr></tbody></table>

CI, confidence interval; dB, decibels; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System; MABC-2, Movement Assessment Battery for Children - Second Edition (Henderson, 2007); MD, mean difference; OR, odd ratios; SD, standard deviation; SDQ, Strengths and Difficulties Questionnaire (Goodman, 1997).

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

almost none reported long-term outcomes. Briefly, the 2-year follow-up in the Assessment of Perinatal Outcome after Sustained Tocolysis in Early Labor II (APOSTEL II) trial (maintenance tocolysis with nifedipine vs placebo after threatened preterm labor) focused on maintenance tocolysis, which is not recommended.²⁷ Furthermore, this study was largely underpowered to show any differences in outcomes (n=46 women with PPROM). Similarly, another study

reported the 2-year follow-up of a small sample of children exposed to nifedipine vs ritodrine for 7 days.²⁸ The proportion of women with PPROM was not reported, and a non-validated parental questionnaire was used to assess developmental outcomes. Children born to participants in the APOSTEL III trial (tocolysis with nifedipine vs atosiban after threatened preterm labor) were followed once over a wide age range (2.5 to 5.5 years of age).²⁹ No results were

reported specifically for the small subgroup of children born after PPROM. The only long-term follow-up study (9-12 years) of children exposed in utero to tocolytics compared behavioral-emotional outcomes, quality of life, motor function, parenting distress, and education of children exposed to nifedipine with those exposed to ritodrine.³⁰ No significant differences in the long-term outcomes were observed, but fewer than 100 children were evaluated.

<footnote><sup>a</sup> Weighted to take into account the differences in survey design between gestational age groups; <sup>b</sup> Severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss >70 dB and/or FSIQ score <-3 SDs. Moderate neurodevelopmental disabilities were defined as cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between -3 to -2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB and/or FSIQ score between -2 and -1 SDs and/or MABC-2 score <5th percentile and/or SDQ score ≥90th percentile). Cutoffs of the distribution was related to a reference group born at term; <sup>c</sup> Cutoff of the distribution related to a reference group born at term; <sup>d</sup> Among children without cerebral palsy, severe or moderate sensory disabilities, and with Full-Scale Intelligence Quotient score ≥2 SDs.</footnote>
FIGURE 2

Association between tocolysis and 5-year outcomes: sensitivity analyses

<figure><img src="image_4.png" /></figure>

Superscript letter *a* denotes severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss at >70 dB and/or FSIQ score <−3 SDs. Moderate neurodevelopmental disabilities were defined cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between −3 to −2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB, and/or FSIQ score between −2 and −1 SDs and/or MADC-2 score ≤5th percentile and/or SDQ score ≥90th percentile. Cutoffs of the distribution were compared with a reference group born at term; *Superscript letter b* denotes main analysis, inverse probability of treatment weighting with multiple imputation of missing data; *Superscript letter c* denotes inverse probability of treatment weighting only for children with complete neurodevelopmental evaluation at 5.5 years and included n=104 infants exposed to tocolysis and n=300 not exposed to tocolysis; *Superscript letter d* denotes a total of 202 exposed infants (of which 177 survived to 5 years) were matched to 202 nonexposed infants (of which 174 survived to 5 years).

CI, confidence interval; dB, decibel; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System; MABC-2, Movement Assessment Battery for Children-Second Edition; OR, odds ratio; SD, standard deviation; SDQ, Strengths and Difficulties Questionnaire.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

Clinical implications

On a positive note, we found no evidence of adverse long-term outcomes associated with tocolytic administration. There is indeed a body of evidence that has linked exposure to obstetrical infections or antenatal inflammation to the activation of innate immune cells in the fetal brain, which contributes to abnormal oligodendrocyte and interneuron production and migration and to secondary dysmyelination and connectome dysfunction and may increase the risk for a spectrum

of neuropsychiatric disorders in chil-
dren.¹⁸ This implies that the children’s
long-term development may be affected,
even if an intervention is not associated
with differences in short-term outcomes.
The administration of diethylstilbestrol in
the 1950s or, more recently, the adminis-
tration of antibiotics for spontaneous
preterm labor are prime examples of in-
terventions that turned out to have
important negative long-term effects.⁴⁰
Our findings provide some reassurance
regarding the safety of tocolytic

administration in pregnant individuals
with PPROM, although we cannot
exclude differences in minor or mild
neurodevelopmental outcomes or other
important outcomes (eg, respiratory or
digestive complications).

However, from a less positive
perspective, it can be argued that we did
not show any improvement in the neu-
rodevelopment at school age, which is
perhaps not surprising given the lack of
benefits in terms of prolonging gestation
or neonatal outcomes. Although our
FIGURE 2

Association between tocolysis and 5-year outcomes: sensitivity analyses

<figure><img src="image_5.png" /></figure>

Superscript letter *a* denotes severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss at >70 dB and/or FSIQ score <−3 SDs. Moderate neurodevelopmental disabilities were defined cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between −3 to −2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB, and/or FSIQ score between −2 and −1 SDs and/or MADC-2 score ≤5th percentile and/or SDQ score ≥90th percentile. Cutoffs of the distribution were compared with a reference group born at term; Superscript letter *b* denotes main analysis, inverse probability of treatment weighting with multiple imputation of missing data; Superscript letter *c* denotes inverse probability of treatment weighting only for children with complete neurodevelopmental evaluation at 5.5 years and included n=104 infants exposed to tocolysis and n=300 not exposed to tocolysis; Superscript letter *d* denotes a total of 202 exposed infants (of which 177 survived to 5 years) were matched to 202 nonexposed infants (of which 174 survived to 5 years).

CI, confidence interval; dB, decibel; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System; MABC-2, Movement Assessment Battery for Children-Second Edition; OR, odds ratio; SD, standard deviation; SDQ, Strengths and Difficulties Questionnaire.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

Clinical implications

On a positive note, we found no evidence of adverse long-term outcomes associated with tocolytic administration. There is indeed a body of evidence that has linked exposure to obstetrical infections or antenatal inflammation to the activation of innate immune cells in the fetal brain, which contributes to abnormal oligodendrocyte and interneuron production and migration and to secondary dysmyelination and connectome dysfunction and may increase the risk for a spectrum

of neuropsychiatric disorders in chil-
dren.¹⁸ This implies that the children’s
long-term development may be affected,
even if an intervention is not associated
with differences in short-term outcomes.
The administration of diethylstilbestrol in
the 1950s or, more recently, the adminis-
tration of antibiotics for spontaneous
preterm labor are prime examples of in-
terventions that turned out to have
important negative long-term effects.⁴⁰
Our findings provide some reassurance
regarding the safety of tocolytic

administration in pregnant individuals
with PPROM, although we cannot
exclude differences in minor or mild
neurodevelopmental outcomes or other
important outcomes (eg, respiratory or
digestive complications).

However, from a less positive
perspective, it can be argued that we did
not show any improvement in the neu-
rodevelopment at school age, which is
perhaps not surprising given the lack of
benefits in terms of prolonging gestation
or neonatal outcomes. Although our
<table><caption>**FIGURE 3**
Association between tocolysis and 5-year outcomes: subgroup analyses</caption><thead><tr><th></th><th>After Inverse Probability<br>of Treatment Weighting,<br>OR (95%CI)<br>Tocolysis vs<br>No Tocolysis</th><th>Pvalue</th></tr></thead><tbody><tr><td colspan="3"><strong>Among survivors at 5½ years</strong></td></tr><tr><td colspan="3"><strong>Severe or Moderate<br>neurodevelopmental disabilities<sup>a</sup></strong></td></tr><tr><td><strong>Total (n=712)</strong></td><td><strong>0.93 (0.44;1.97)</strong></td><td><strong>0.55</strong></td></tr><tr><td>PPROM at 26-31 wk (n=523)</td><td>0.85 (0.32;2.20)</td><td>0.51</td></tr><tr><td>Latency ≥ 12 hr (n=609)</td><td>0.99 (0.43;2.30)</td><td>0.56</td></tr><tr><td>With uterine contractions at admission (n=241)</td><td>1.19 (0.13;10.49)</td><td>0.51</td></tr><tr><td>Without uterine contractions at admission (n=357)</td><td>1.04 (0.49;2.23)</td><td>0.66</td></tr><tr><td colspan="3"><strong>Survival without severe or moderate<br>neurodevelopmental disabilities at 5½ years<sup>a</sup></strong></td></tr><tr><td><strong>Total (n=803)</strong></td><td><strong>0.93 (0.55;1.60)</strong></td><td><strong>0.56</strong></td></tr><tr><td>PPROM at 26-31 wk (n=549)</td><td>1.13 (0.52;2.48)</td><td>0.55</td></tr><tr><td>Latency ≥ 12 hr (n=686)</td><td>0.91 (0.50;1.65)</td><td>0.58</td></tr><tr><td>With uterine contractions at admission (n=279)</td><td>0.75 (0.14;4.00)</td><td>0.57</td></tr><tr><td>Without uterine contractions at admission (n=390)</td><td>1.04 (0.49;2.23)</td><td>0.66</td></tr></tbody></table>

Superscript letter *a* denotes severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss at >70 dB and/or FSIQ score <−3 SDs. Moderate neurodevelopmental disabilities were defined cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between −3 to −2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB, and/or FSIQ score between −2 and −1 SDs and/or MADC-2 score ≤5th percentile and/or SDQ score ≥90th percentile. Cutoffs of the distribution were compared with a reference group born at term.

CI, confidence interval; dB, decibel; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System; MABC-2, Movement Assessment Battery for Children- Second Edition; OR, odd ratios; PPROM, preterm prelabor rupture of membranes; SD, standard deviation; SDQ, Strengths and difficulties questionnaire.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

findings need replication, they further support that tocolysis may be an ineffective intervention in the setting of PPROM.⁴¹

Until further evidence is available, clinicians need to be aware of these findings when taking care of patients with PPROM and should consider that tocolysis may

provide more reassurance to medical teams, giving them the impression that they are taking action, than actual health benefits to patients.
FIGURE 3

Association between tocolysis and 5-year outcomes: subgroup analyses

<figure><img src="image_6.png" /></figure>

Superscript letter a denotes severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss at >70 dB and/or FSIQ score <-3 SDs. Moderate neurodevelopmental disabilities were defined cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between -3 to -2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB, and/or FSIQ score between -2 and -1 SDs and/or MADC-2 score ≤5th percentile and/or SDQ score ≥90th percentile. Cutoffs of the distribution were compared with a reference group born at term.

CI, confidence interval; dB, decibel; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System; MABC-2, Movement Assessment Battery for Children- Second Edition; OR, odd ratios; PPROM, preterm prelabor rupture of membranes; SD, standard deviation; SDQ, Strengths and difficulties questionnaire.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

findings need replication, they further support that tocolysis may be an ineffective intervention in the setting of PPROM.⁴¹

Until further evidence is available, clinicians need to be aware of these findings when taking care of patients with PPROM and should consider that tocolysis may

provide more reassurance to medical teams, giving them the impression that they are taking action, than actual health benefits to patients.
**Research implications**

Tocolysis after PPROM is a paradoxical and controversial practice; there is no evidence of short-term neonatal benefits, but a large number of medical teams administer it routinely.42 This may be explained by the lack of reliable, up-to-date, and robust scientific evidence.39 To better inform and tailor clinical practices and policies, we are conducting a randomized controlled trial aimed at assessing if 48-hour tocolysis by nifedipine reduces perinatal mortality or morbidity in PPROM at 22 to 33 weeks' gestation.39 Follow-up evaluations at 2 and 6 years of age are planned. We hope that these efforts will advance scientific knowledge, permit optimization of antenatal management of pregnant individuals worldwide, and ultimately improve the prognosis for children born preterm after PPROM.

**Conclusion**

The administration of tocolytics after PPROM aims to improve neonatal outcomes and promote healthy development in later life, which should therefore be taken into account when defining the optimal treatment strategy for a pregnant individual. We showed no differences in the neurodevelopmental outcomes at 5.5 years of age among children with and without antenatal exposure to tocolytics after PPROM. To date, the health benefits of tocolysis remain unproven, both in the short- and in the long-term.

**Acknowledgments**

We are grateful to the participating children and their families, all maternity and neonatal units in France, and all national and regional collaborators who made EPIPAGE-2 possible. We also would like to thank the collaborators of the EPIPAGE-2 Obstetric Writing Group: Pierre-Yves Ancel, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Unité de Recherche Clinique - Centre d'Investigations Cliniques P1419, Département Hospitalo-Universitaire Risks in Pregnancy, Cochin Hotel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris F-75014, France); Catherine Arnaud, MD, PhD (Research Unit on Perinatal Epidemiology, Childhood Disabilities and Adolescent Health, Inserm UMR 1027, Paul Sabatier University, Toulouse, France); Chloé

Arthuis, MD, PhD (Department of Gynecology and Obstetrics, CIC, University hospital of Nantes, Nantes, France); Julie Blanc, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Aix Marseille University, Marseille, France); Pascal Boileau, MD, PhD (Department of Neonatal Pediatrics, Poissy Saint Germain Hospital, France, EA7285 Versailles Saint Quentin en Yvelines University, France); Thierry Debillon, MD, PhD (Department of Neonatal Pediatrics, University Hospital, Grenoble, France); Pierre Delorme, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Trousseau Hospital, AP-HP, Paris, France); Claude D'Ercole, MD (Department of Obstetrics and Gynecology, Nord Hospital, Assistance Publique des Hôpitaux de Marseille (AP-HM), Aix Marseille Université, AMU, Marseille, France); Thomas Desplanches, RM, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Caroline Diguisto, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Maternité Olympé de Gougès, University François Rabelais, Tours, France); Laurence Foix-L'Hélias, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Neonatal Pediatrics, Trousseau Hospital, AP-HP, Paris, France); Géraldine Gascoin, MD, PhD (Department of Neonatal Medicine, University Hospital, Toulouse, France, Research Unit on Perinatal Epidemiology, Childhood Disabilities and Adolescent Health, Inserm UMR 1027, Paul Sabatier University, Toulouse, France); Catherine Gire, MD (Department of Neonatology, North Hospital, Marseille, France); François Goffinet, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Cochin, Broca, Hôtel Dieu Hospital, AP-HP, Paris, France); Isabelle Guellec, MD, PhD (Pediatric and Neonatal Intensive Care Unit, University Hospital, Nice, France, Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Gilles Kayem, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Sorbonne Universités, UPMC Univ Paris 06, IFD, 4 Place Jussieu, 75252 PARIS cedex 05, Paris, France, Department of Obstetrics and Gynecology, Trousseau Hospital, AP-HP, Paris, France); Bruno Langer, MD (Department of Obstetrics and Gynecology, Hautepierre Hospital, Strasbourg, France); Mathilde Letouzey, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Neonatal Pediatrics,

Poissy Saint Germain Hospital, France); Elsa Lorthe, RM, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Emeline Maisonneuve, MD, MSc (Department of Obstetrics and Gynecology, Trousseau Hospital, APHP, Paris, France); Stéphane Marret, MD, PhD (Department of Neonatal Medicine, Rouen University Hospital and Région-Inserm (ERI 28), Normandy University, Rouen, France); Isabelle Monier, RM, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Andrei Morgan, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Jean-Christophe Rozé, MD, PhD (Department of Neonatal Medicine, Nantes University Hospital, Nantes, France, Epidémiologie Clinique, Centre d'Investigation Clinique (CIC004), Nantes University Hospital, Nantes, France); Thomas Schmitz, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France); Loïc Sentilhes, MD, PhD (Department of Obstetrics and Gynecology, Bordeaux University Hospital, Bordeaux, France); Damien Subtil, MD, PhD (Department of Obstetrics and Gynecology, Jeanne de Flandre Hospital, Lille, France); Héloïse Torchin, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Neonatal Medicine and Resuscitation Service, Port-Royal, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France); Barthélémy Tosello, MD, PhD (Department of Neonatology, Assistance Publique Hopitaux de Marseille, Marseille, France); Christophe Vaysière, MD, PhD (Department of Obstetrics and Gynecology, University Hospital, Toulouse, France, Research Unit on Perinatal Epidemiology, Childhood Disabilities and Adolescent Health, Inserm UMR 1027, Paul Sabatier University, Toulouse, France); Norbert Winer, MD, PhD (Department of Obstetrics and Gynecology, University Hospital, INRAE, UMR 1280 Physiologie des adaptations nutritionnelles, Nantes, France); Jennifer Zeitlin, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France).

All the collaborators of the EPIPAGE2 Obstetric writing group have no conflict of interest or compensation in relation with this article to disclose. All of them consented to such acknowledgment.

**References**

1. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003;101: 178-93.

2. Lorthé E. [Epidemiology, risk factors and child prognosis: CNGOF preterm premature
## Research implications

Tocolysis after PPROM is a paradoxical and controversial practice; there is no evidence of short-term neonatal benefits, but a large number of medical teams administer it routinely.42 This may be explained by the lack of reliable, up-to-date, and robust scientific evidence.39 To better inform and tailor clinical practices and policies, we are conducting a randomized controlled trial aimed at assessing if 48-hour tocolysis by nifedipine reduces perinatal mortality or morbidity in PPROM at 22 to 33 weeks' gestation.39 Follow-up evaluations at 2 and 6 years of age are planned. We hope that these efforts will advance scientific knowledge, permit optimization of antenatal management of pregnant individuals worldwide, and ultimately improve the prognosis for children born preterm after PPROM.

## Conclusion

The administration of tocolytics after PPROM aims to improve neonatal outcomes and promote healthy development in later life, which should therefore be taken into account when defining the optimal treatment strategy for a pregnant individual. We showed no differences in the neurodevelopmental outcomes at 5.5 years of age among children with and without antenatal exposure to tocolytics after PPROM. To date, the health benefits of tocolysis remain unproven, both in the short- and in the long-term.

## Acknowledgments

We are grateful to the participating children and their families, all maternity and neonatal units in France, and all national and regional collaborators who made EPIPAGE-2 possible. We also would like to thank the collaborators of the EPIPAGE-2 Obstetric Writing Group: Pierre-Yves Ancel, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Unité de Recherche Clinique - Centre d'Investigations Cliniques P1419, Département Hospitalo-Universitaire Risks in Pregnancy, Cochin Hotel-Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris F-75014, France); Catherine Arnaud, MD, PhD (Research Unit on Perinatal Epidemiology, Childhood Disabilities and Adolescent Health, Inserm UMR 1027, Paul Sabatier University, Toulouse, France); Chloé

Arthuis, MD, PhD (Department of Gynecology and Obstetrics, CIC, University hospital of Nantes, Nantes, France); Julie Blanc, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Aix Marseille University, Marseille, France); Pascal Boileau, MD, PhD (Department of Neonatal Pediatrics, Poissy Saint Germain Hospital, France, EA7285 Versailles Saint Quentin en Yvelines University, France); Thierry Debillon, MD, PhD (Department of Neonatal Pediatrics, University Hospital, Grenoble, France); Pierre Delorme, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Trousseau Hospital, AP-HP, Paris, France); Claude D'Ercole, MD (Department of Obstetrics and Gynecology, Nord Hospital, Assistance Publique des Hôpitaux de Marseille (AP-HM), Aix Marseille Université, AMU, Marseille, France); Thomas Desplanches, RM, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Caroline Diguisto, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Maternité Olympé de Gougès, University François Rabelais, Tours, France); Laurence Foix-L'Hélias, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Neonatal Pediatrics, Trousseau Hospital, AP-HP, Paris, France); Géraldine Gascoin, MD, PhD (Department of Neonatal Medicine, University Hospital, Toulouse, France, Research Unit on Perinatal Epidemiology, Childhood Disabilities and Adolescent Health, Inserm UMR 1027, Paul Sabatier University, Toulouse, France); Catherine Gire, MD (Department of Neonatology, North Hospital, Marseille, France); François Goffinet, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Cochin, Broca, Hôtel Dieu Hospital, AP-HP, Paris, France); Isabelle Guellec, MD, PhD (Pediatric and Neonatal Intensive Care Unit, University Hospital, Nice, France, Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Gilles Kayem, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Sorbonne Universités, UPMC Univ Paris 06, IFD, 4 Place Jussieu, 75252 PARIS cedex 05, Paris, France, Department of Obstetrics and Gynecology, Trousseau Hospital, AP-HP, Paris, France); Bruno Langer, MD (Department of Obstetrics and Gynecology, Hautepierre Hospital, Strasbourg, France); Mathilde Letouzey, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Neonatal Pediatrics,

Poissy Saint Germain Hospital, France); Elsa Lorthe, RM, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Emeline Maisonneuve, MD, MSc (Department of Obstetrics and Gynecology, Trousseau Hospital, APHP, Paris, France); Stéphane Marret, MD, PhD (Department of Neonatal Medicine, Rouen University Hospital and Région-Inserm (ERI 28), Normandy University, Rouen, France); Isabelle Monier, RM, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Andrei Morgan, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France); Jean-Christophe Rozé, MD, PhD (Department of Neonatal Medicine, Nantes University Hospital, Nantes, France, Epidémiologie Clinique, Centre d'Investigation Clinique (CIC004), Nantes University Hospital, Nantes, France); Thomas Schmitz, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Department of Obstetrics and Gynecology, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France); Loïc Sentilhes, MD, PhD (Department of Obstetrics and Gynecology, Bordeaux University Hospital, Bordeaux, France); Damien Subtil, MD, PhD (Department of Obstetrics and Gynecology, Jeanne de Flandre Hospital, Lille, France); Héloïse Torchin, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France, Neonatal Medicine and Resuscitation Service, Port-Royal, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France); Barthélémy Tosello, MD, PhD (Department of Neonatology, Assistance Publique Hopitaux de Marseille, Marseille, France); Christophe Vaysière, MD, PhD (Department of Obstetrics and Gynecology, University Hospital, Toulouse, France, Research Unit on Perinatal Epidemiology, Childhood Disabilities and Adolescent Health, Inserm UMR 1027, Paul Sabatier University, Toulouse, France); Norbert Winer, MD, PhD (Department of Obstetrics and Gynecology, University Hospital, INRAE, UMR 1280 Physiologie des adaptations nutritionnelles, Nantes, France); Jennifer Zeitlin, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, Inserm, INRAE, F-75004 Paris, France).

All the collaborators of the EPIPAGE2 Obstetric writing group have no conflict of interest or compensation in relation with this article to disclose. All of them consented to such acknowledgment.

## References

1. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003;101: 178-93.

2. Lorthé E. [Epidemiology, risk factors and child prognosis: CNGOF preterm premature
rupture of membranes Guidelines]. Gynecol Obstet Fertil Senol 2018;46:1004-21.

3. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75-84.

4. Mackeen AD, Seibel-Seamon J, Muhammad J, Baxter JK, Berghella V. Tocolytics for preterm premature rupture of membranes. Cochrane Database Syst Rev 2014;2: CD007062.

5. Bond DM, Middleton P, Levett KM, et al. Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome. In: Cochrane Database Syst Rev. Chichester, United Kingdom: John Wiley & Sons, Ltd 2017;3:CD004735.

6. Schmitz T, Sentilhes L, Lorthe E, et al. Preterm premature rupture of the membranes: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol 2019;236:1-6.

7. Prelabor rupture of membranes: ACOG Practice Bulletin, Number 217. Obstet Gynecol 2020;135:e80-97.

8. Thomson AJ; Royal College of Obstetricians and Gynaecologists. Care of women presenting with suspected preterm prelabour rupture of membranes from 24+0 weeks of gestation: Green-top Guideline No. 73. BJOG 2019;126: e152-66.

9. World Health Organization. WHO recommendation on tocolytic therapy for improving preterm birth outcomes. Available at: https:// www.who.int/publications-detail-redirect/9789 240057227. Accessed May 12, 2023.

10. Lorthe E, Santos C, Ornelas JP, et al. Using digital tools to study the health of adults born preterm at a large scale: e-cohort pilot study. J Med Internet Res 2023;25:e39854.

11. Berger R, Lehmann T, Karcher J, Garnier Y, Jensen A. Low dose flunarizine protects the fetal brain from ischemic injury in sheep. Pediatr Res 1998;44:277-82.

12. Pinto Cardoso G, Houivet E, Marchand-Martin L, et al. Association of intraventricular hemorrhage and death with tocolytic exposure in preterm infants. JAMA Netw Open 2018;1:e182355.

13. de Heus R, Mulder EJH, Derks JB, Visser GHA. The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow. J Matern Fetal Neonatal Med 2009;22:485-90.

14. van Vliet EOG, de Kieviet JF, Oosterlaan J, van Elburg RM. Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis. JAMA Pediatr 2013;167:662-8.

15. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292:2357-65.

16. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA 2000;284:1417-24.

17. Shi Z, Ma L, Luo K, et al. Chorioamnionitis in the development of cerebral palsy: a meta-analysis and systematic review. Pediatrics 2017;139:e20163781.

18. Al-Haddad BJS, Oler E, Armistead B, et al. The fetal origins of mental illness. Am J Obstet Gynecol 2019;221:549-62.

19. Gall AR, Amoah S, Kitase Y, Jantzie LL. Placental mediated mechanisms of perinatal brain injury: evolving inflammation and exosomes. Exp Neurol 2022;347:113914.

20. Beck C, Gallagher K, Taylor LA, Goldstein JA, Mithal LB, Gernand AD. Chorioamnionitis and risk for maternal and neonatal sepsis: a systematic review and meta-analysis. Obstet Gynecol 2021;137:1007-22.

21. Mitha A, Foix-L'Hélias L, Arnaud C, et al. Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants. Pediatrics 2013;132:e372-80.

22. Cai S, Thompson DK, Anderson PJ, Yang JYM. Short- and long-term neurodevelopmental outcomes of very preterm infants with neonatal sepsis: a systematic review and meta-analysis. Children (Basel) 2019;6:131.

23. van 't Hooft J, Duffy JMN, Daly M, et al. A core outcome set for evaluation of interventions to prevent preterm birth. Obstet Gynecol 2016;127:49-58.

24. Lorthe E, Goffinet F, Marret S, et al. Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis. Am J Obstet Gynecol 2017;217:212.e1-12.

25. Lorthe E, Moreira C, Weber T, et al. Unit policies regarding tocolysis after preterm premature rupture of membranes: association with latency, neonatal and 2-year outcomes (EPICE cohort). Sci Rep 2020;10:9535.

26. Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DNM. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2014, (6) :CD004452.

27. van Vliet E, Seinen L, Roos C, et al. Maintenance tocolysis with nifedipine in threatened preterm labour: 2-year follow up of the offspring in the APOSTEL II trial. BJOG 2016;123:1107-14.

28. Van De Water M, Kessel ET, De Kleine MJ, Oei SG. Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial. Acta Obstet Gynecol Scand 2008;87:340-5.

29. van Winden T, Klumper J, Kleinrouweler CE, et al. Effects of tocolysis with nifedipine or atosiban on child outcome: follow-up of the APOSTEL III trial. BJOG 2020;127:1129-37.

30. Houtzager BA, Hogendoorn SM, Papatsonis DNM, et al. Long-term follow up of children exposed in utero to nifedipine or ritodrine for the management of preterm labour. BJOG 2006;113:324-31.

31. Lorthe E, Benhammou V, Marchand-Martin L, et al. Cohort Profile: the Etude Epidémiologique sur les Petits Ages

Gestationnels-2 (EPIPAGE-2) preterm birth cohort. Int J Epidemiol 2021;50:1428-1429m.

32. Charles MA, Thierry X, Lanoe JL, et al. Cohort profile: the French National cohort of children (ELFE): birth to 5 years. Int J Epidemiol 2020;49:368-369].

33. Pierrat V, Marchand-Martin L, Marret S, et al. Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study. BMJ 2021;373:n741.

34. Ego A, Prunet C, Lebreton E, et al. [Customized and non-customized French intruterine growth curves. I - Methodology]. J Gynecol Obstet Biol Reprod (Paris) 2016;45: 155-64.

35. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399-424.

36. White IR, Royston P, Wood AM. Multiple imputation using chained equations: issues and guidance for practice. Stat Med 2011;30: 377-99.

37. McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med 2013;32:3388-414.

38. Teixeira R, Queiroga AC, Freitas AI, et al. Completeness of retention data and determinants of attrition in birth cohorts of very preterm infants: a systematic review. Front Pediatr 2021;9:529733.

39. Lorthe E, Kayem G. TOCOPROM Study Group and the GROG (Groupe de Recherche en Obstétrique et Gynécologie). Tocolysis in the management of preterm prelabour rupture of membranes at 22-33 weeks of gestation: study protocol for a multicenter, double-blind, randomized controlled trial comparing nifedipine with placebo (TOCOPROM). BMC Pregnancy Childbirth 2021;21:614.

40. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the Oracle II trial. Lancet 2008;372:1319-27.

41. Nijman TAJ, van Vliet EOG, Naaktgeboren CA, et al. Nifedipine versus placebo in the treatment of preterm prelabour rupture of membranes: a randomized controlled trial: assessment of perinatal outcome by use of tocolysis in early labor-APOSTEL IV trial. Eur J Obstet Gynecol Reprod Biol 2016;205:79-84.

42. Stelzl P, Kehl S, Oppelt P, et al. Maintenance tocolysis, tocolysis in preterm premature rupture of membranes and in cervical cerclage - a Germany-wide survey on the current practice after dissemination of the German guideline. J Perinat Med 2023;51: 775-81.

**Author and article information**

From the Unit of Population Epidemiology, Department of Primary Care Medicine, Geneva University Hospitals,
rupture of membranes Guidelines]. Gynecol Obstet Fertil Senol 2018;46:1004-21.

3. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet 2008;371:75-84.

4. Mackeen AD, Seibel-Seamon J, Muhammad J, Baxter JK, Berghella V. Tocolytics for preterm premature rupture of membranes. Cochrane Database Syst Rev 2014;2: CD007062.

5. Bond DM, Middleton P, Levett KM, et al. Planned early birth versus expectant management for women with preterm prelabour rupture of membranes prior to 37 weeks' gestation for improving pregnancy outcome. In: Cochrane Database Syst Rev. Chichester, United Kingdom: John Wiley & Sons, Ltd 2017;3:CD004735.

6. Schmitz T, Sentilhes L, Lorthe E, et al. Preterm premature rupture of the membranes: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol 2019;236:1-6.

7. Prelabor rupture of membranes: ACOG Practice Bulletin, Number 217. Obstet Gynecol 2020;135:e80-97.

8. Thomson AJ; Royal College of Obstetricians and Gynaecologists. Care of women presenting with suspected preterm prelabour rupture of membranes from 24+0 weeks of gestation: Green-top Guideline No. 73. BJOG 2019;126: e152-66.

9. World Health Organization. WHO recommendation on tocolytic therapy for improving preterm birth outcomes. Available at: https:// www.who.int/publications-detail-redirect/9789 240057227. Accessed May 12, 2023.

10. Lorthe E, Santos C, Ornelas JP, et al. Using digital tools to study the health of adults born preterm at a large scale: e-cohort pilot study. J Med Internet Res 2023;25:e39854.

11. Berger R, Lehmann T, Karcher J, Garnier Y, Jensen A. Low dose flunarizine protects the fetal brain from ischemic injury in sheep. Pediatr Res 1998;44:277-82.

12. Pinto Cardoso G, Houivet E, Marchand-Martin L, et al. Association of intraventricular hemorrhage and death with tocolytic exposure in preterm infants. JAMA Netw Open 2018;1:e182355.

13. de Heus R, Mulder EJH, Derks JB, Visser GHA. The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow. J Matern Fetal Neonatal Med 2009;22:485-90.

14. van Vliet EOG, de Kieviet JF, Oosterlaan J, van Elburg RM. Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis. JAMA Pediatr 2013;167:662-8.

15. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292:2357-65.

16. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA 2000;284:1417-24.

17. Shi Z, Ma L, Luo K, et al. Chorioamnionitis in the development of cerebral palsy: a meta-analysis and systematic review. Pediatrics 2017;139:e20163781.

18. Al-Haddad BJS, Oler E, Armistead B, et al. The fetal origins of mental illness. Am J Obstet Gynecol 2019;221:549-62.

19. Gall AR, Amoah S, Kitase Y, Jantzie LL. Placental mediated mechanisms of perinatal brain injury: evolving inflammation and exosomes. Exp Neurol 2022;347:113914.

20. Beck C, Gallagher K, Taylor LA, Goldstein JA, Mithal LB, Gernand AD. Chorioamnionitis and risk for maternal and neonatal sepsis: a systematic review and meta-analysis. Obstet Gynecol 2021;137:1007-22.

21. Mitha A, Foix-L'Hélias L, Arnaud C, et al. Neonatal infection and 5-year neurodevelopmental outcome of very preterm infants. Pediatrics 2013;132:e372-80.

22. Cai S, Thompson DK, Anderson PJ, Yang JYM. Short- and long-term neurodevelopmental outcomes of very preterm infants with neonatal sepsis: a systematic review and meta-analysis. Children (Basel) 2019;6:131.

23. van 't Hooft J, Duffy JMN, Daly M, et al. A core outcome set for evaluation of interventions to prevent preterm birth. Obstet Gynecol 2016;127:49-58.

24. Lorthe E, Goffinet F, Marret S, et al. Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis. Am J Obstet Gynecol 2017;217:212.e1-12.

25. Lorthe E, Moreira C, Weber T, et al. Unit policies regarding tocolysis after preterm premature rupture of membranes: association with latency, neonatal and 2-year outcomes (EPICE cohort). Sci Rep 2020;10:9535.

26. Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DNM. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2014, (6) :CD004452.

27. van Vliet E, Seinen L, Roos C, et al. Maintenance tocolysis with nifedipine in threatened preterm labour: 2-year follow up of the offspring in the APOSTEL II trial. BJOG 2016;123:1107-14.

28. Van De Water M, Kessel ET, De Kleine MJ, Oei SG. Tocolytic effectiveness of nifedipine versus ritodrine and follow-up of newborns: a randomised controlled trial. Acta Obstet Gynecol Scand 2008;87:340-5.

29. van Winden T, Klumper J, Kleinrouweler CE, et al. Effects of tocolysis with nifedipine or atosiban on child outcome: follow-up of the APOSTEL III trial. BJOG 2020;127:1129-37.

30. Houtzager BA, Hogendoorn SM, Papatsonis DNM, et al. Long-term follow up of children exposed in utero to nifedipine or ritodrine for the management of preterm labour. BJOG 2006;113:324-31.

31. Lorthe E, Benhammou V, Marchand-Martin L, et al. Cohort Profile: the Etude Epidémiologique sur les Petits Ages

Gestationnels-2 (EPIPAGE-2) preterm birth cohort. Int J Epidemiol 2021;50:1428-1429m.

32. Charles MA, Thierry X, Lanoe JL, et al. Cohort profile: the French National cohort of children (ELFE): birth to 5 years. Int J Epidemiol 2020;49:368-369].

33. Pierrat V, Marchand-Martin L, Marret S, et al. Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study. BMJ 2021;373:n741.

34. Ego A, Prunet C, Lebreton E, et al. [Customized and non-customized French intruterine growth curves. I - Methodology]. J Gynecol Obstet Biol Reprod (Paris) 2016;45: 155-64.

35. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399-424.

36. White IR, Royston P, Wood AM. Multiple imputation using chained equations: issues and guidance for practice. Stat Med 2011;30: 377-99.

37. McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med 2013;32:3388-414.

38. Teixeira R, Queiroga AC, Freitas AI, et al. Completeness of retention data and determinants of attrition in birth cohorts of very preterm infants: a systematic review. Front Pediatr 2021;9:529733.

39. Lorthe E, Kayem G. TOCOPROM Study Group and the GROG (Groupe de Recherche en Obstétrique et Gynécologie). Tocolysis in the management of preterm prelabour rupture of membranes at 22-33 weeks of gestation: study protocol for a multicenter, double-blind, randomized controlled trial comparing nifedipine with placebo (TOCOPROM). BMC Pregnancy Childbirth 2021;21:614.

40. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the Oracle II trial. Lancet 2008;372:1319-27.

41. Nijman TAJ, van Vliet EOG, Naaktgeboren CA, et al. Nifedipine versus placebo in the treatment of preterm prelabour rupture of membranes: a randomized controlled trial: assessment of perinatal outcome by use of tocolysis in early labor-APOSTEL IV trial. Eur J Obstet Gynecol Reprod Biol 2016;205:79-84.

42. Stelzl P, Kehl S, Oppelt P, et al. Maintenance tocolysis, tocolysis in preterm premature rupture of membranes and in cervical cerclage - a Germany-wide survey on the current practice after dissemination of the German guideline. J Perinat Med 2023;51: 775-81.

Author and article information

From the Unit of Population Epidemiology, Department of Primary Care Medicine, Geneva University Hospitals,
Geneva, Switzerland (Dr Lorthe); Université Paris Cité, Inserm, INRAE, Centre for Research in Epidemiology and Statistics (CRESS), Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Paris, France (Dr Lorthe, Ms Marchand-Martin, and Drs Letouzey, Aubert, Pierrat, Benhammou, Delorme, Ancel, Goffinet, Foix L'Hélias, and Kayem); Department of Neonatal Pediatrics, Poissy Saint Germain Hospital, Poissy, France (Dr Letouzey); Department of Neonatology, Centre Hospitalier Intercommunal Créteil, Créteil, France (Dr Pierrat); Department of Gynecology and Obstetrics, Armand Trousseau Hospital, APHP, FHU Prema, Paris Sorbonne University, Paris, France (Drs Delorme and Kayem); Department of Neonatal Pediatrics, Intensive Care, and Neuropediatrics, Rouen University Hospital, Rouen, France (Dr Marret); Inserm Unit 1245, Team Perinatal Handicap, School of Medicine of Rouen, Normandy

University, Normandy, France (Dr Marret); Clinical Research Unit, Center for Clinical Investigation P1419, Assistance Publique-Hôpitaux de Paris, Paris, France (Dr Ancel); AP-HP Centre, Maternité Port-Royal, Department of Obstetrics and Gynaecology, Université Paris Cité, FHU PREMA, Paris, France (Dr Goffinet); and Department of Neonatal Pediatrics, Armand Trousseau Hospital, APHP, FHU Prema, Paris Sorbonne University, Paris, France (Dr Foix L'Hélias).

Received July 12, 2023; revised Sept. 29, 2023; accepted Oct. 6, 2023.

The authors report no conflict of interest.

During the preparation of this work the authors used ChatGPT in order to improve readability and language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

This project was funded by the French Institute of Public Health Research (IRESP TGIR 2009-01 program), the Institute of Public Health, and its partners. The partners include the French Health Ministry, the National Institute of Health and Medical Research (Inserm), the National Institute of Cancer, the National Solidarity Fund for Autonomy (CNSA), the National Research Agency through the French EQUIPEX program of investments in the future (grant no. ANR-11-EQPX-0038), the PREMUP Foundation, the Foundation of France (00050329 and R18202KK), the Foundation for Medical Research (SPF20160936356), and the hospital clinical research program Epinutri (DGOS13-040). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Corresponding author: Elsa Lorthe, RM, PhD. elsa.lorthe@gmail.com
Geneva, Switzerland (Dr Lorthe); Université Paris Cité, Inserm, INRAE, Centre for Research in Epidemiology and Statistics (CRESS), Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Paris, France (Dr Lorthe, Ms Marchand-Martin, and Drs Letouzey, Aubert, Pierrat, Benhammou, Delorme, Ancel, Goffinet, Foix L'Hélias, and Kayem); Department of Neonatal Pediatrics, Poissy Saint Germain Hospital, Poissy, France (Dr Letouzey); Department of Neonatology, Centre Hospitalier Intercommunal Créteil, Créteil, France (Dr Pierrat); Department of Gynecology and Obstetrics, Armand Trousseau Hospital, APHP, FHU Prema, Paris Sorbonne University, Paris, France (Drs Delorme and Kayem); Department of Neonatal Pediatrics, Intensive Care, and Neuropediatrics, Rouen University Hospital, Rouen, France (Dr Marret); Inserm Unit 1245, Team Perinatal Handicap, School of Medicine of Rouen, Normandy

University, Normandy, France (Dr Marret); Clinical Research Unit, Center for Clinical Investigation P1419, Assistance Publique-Hôpitaux de Paris, Paris, France (Dr Ancel); AP-HP Centre, Maternité Port-Royal, Department of Obstetrics and Gynaecology, Université Paris Cité, FHU PREMA, Paris, France (Dr Goffinet); and Department of Neonatal Pediatrics, Armand Trousseau Hospital, APHP, FHU Prema, Paris Sorbonne University, Paris, France (Dr Foix L'Hélias).

Received July 12, 2023; revised Sept. 29, 2023; accepted Oct. 6, 2023.

The authors report no conflict of interest.

During the preparation of this work the authors used ChatGPT in order to improve readability and language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

This project was funded by the French Institute of Public Health Research (IRESP TGIR 2009-01 program), the Institute of Public Health, and its partners. The partners include the French Health Ministry, the National Institute of Health and Medical Research (Inserm), the National Institute of Cancer, the National Solidarity Fund for Autonomy (CNSA), the National Research Agency through the French EQUIPEX program of investments in the future (grant no. ANR-11-EQPX-0038), the PREMUP Foundation, the Foundation of France (00050329 and R18202KK), the Foundation for Medical Research (SPF20160936356), and the hospital clinical research program Epinutri (DGOS13-040). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Corresponding author: Elsa Lorthe, RM, PhD. elsa.lorthe@gmail.com
SUPPLEMENTAL FIGURE

Standardized differences for covariates used in the propensity score

<figure><img src="image_5.png" /></figure>

Each point illustrates the standardized difference for each variable in the initial sample (red circles) and the propensity score IPTW model (blue triangle). The vertical line at 10% illustrates the standard cutoff for acceptable imbalance between groups.

IPTW, inverse probability of treatment weighting; PPROM, preterm prelabor rupture of membranes.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.
SUPPLEMENTAL FIGURE

Standardized differences for covariates used in the propensity score

<figure><img src="image_7.png" /></figure>

Each point illustrates the standardized difference for each variable in the initial sample (red circles) and the propensity score IPTW model (blue triangle). The vertical line at 10% illustrates the standard cutoff for acceptable imbalance between groups.

IPTW, inverse probability of treatment weighting; PPROM, preterm prelabor rupture of membranes.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.
SUPPLEMENTAL TABLE 1

Comparison of participating and nonparticipating children

Analysis population: children alive at 5½ y (n=712)

<table><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Complete assessment (n=404)</th><th colspan="2">Incomplete assessment<sup>a</sup> (n=82)</th><th colspan="2">No assessment (n=226)</th><th rowspan="2">Chi-square<br>P value</th></tr><tr><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th></tr></thead><tbody><tr><td colspan="8"><strong>Maternal characteristics</strong></td></tr><tr><td>Age (y)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25</td><td>14/404</td><td>2.1</td><td>3/82</td><td>2.9</td><td>18/226</td><td>7.5</td><td>.002</td></tr><tr><td>25-34</td><td>319/404</td><td>80.1</td><td>63/82</td><td>78.0</td><td>181/226</td><td>83.6</td><td></td></tr><tr><td>≥35</td><td>71/404</td><td>17.8</td><td>16/82</td><td>19.2</td><td>27/226</td><td>8.9</td><td></td></tr><tr><td>Nulliparity</td><td>195/401</td><td>53.9</td><td>34/82</td><td>43.3</td><td>108/224</td><td>49.9</td><td>.42</td></tr><tr><td>Born in France or Europe</td><td>321/398</td><td>80.2</td><td>69/81</td><td>89.1</td><td>154/222</td><td>71.1</td><td>.011</td></tr><tr><td>Level of education</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Less than high school</td><td>112/389</td><td>29.1</td><td>26/75</td><td>31.7</td><td>74/181</td><td>39.1</td><td>&lt;.001</td></tr><tr><td>High school, 1-2 y of graduate studies</td><td>161/389</td><td>39.7</td><td>30/75</td><td>34.9</td><td>86/181</td><td>51.9</td><td></td></tr><tr><td>≥3 y of graduate studies</td><td>116/389</td><td>31.2</td><td>19/75</td><td>33.5</td><td>21/181</td><td>9.0</td><td></td></tr><tr><td>Parents' socioeconomic position<sup>c</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Executive</td><td>107/386</td><td>27.1</td><td>20/78</td><td>27.6</td><td>20/207</td><td>6.0</td><td>&lt;.001</td></tr><tr><td>Intermediate</td><td>62/386</td><td>16.8</td><td>15/78</td><td>18.4</td><td>20/207</td><td>10.3</td><td></td></tr><tr><td>Administration</td><td>113/386</td><td>31.1</td><td>20/78</td><td>27.6</td><td>77/207</td><td>40.0</td><td></td></tr><tr><td>Service, trade</td><td>56/386</td><td>14.2</td><td>10/78</td><td>9.7</td><td>32/207</td><td>20.8</td><td></td></tr><tr><td>Worker, unemployed</td><td>48/386</td><td>10.8</td><td>13/78</td><td>16.7</td><td>58/207</td><td>22.9</td><td></td></tr><tr><td>Obstetrical characteristics and management</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>PPROM before hospitalization</td><td>348/404</td><td>88.8</td><td>64/81</td><td>84.5</td><td>186/226</td><td>85.4</td><td>.45</td></tr><tr><td>Contractions at admission</td><td>147/382</td><td>36.7</td><td>29/79</td><td>31.5</td><td>97/214</td><td>48.2</td><td>.047</td></tr><tr><td>Gestational age at PPROM (wk)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>24</td><td>24/404</td><td>4.8</td><td>4/82</td><td>2.9</td><td>20/226</td><td>4.6</td><td>.39</td></tr><tr><td>25</td><td>50/404</td><td>6.7</td><td>12/82</td><td>10.0</td><td>24/226</td><td>5.8</td><td></td></tr><tr><td>26</td><td>40/404</td><td>6.6</td><td>5/82</td><td>4.3</td><td>18/226</td><td>4.7</td><td></td></tr><tr><td>27</td><td>46/404</td><td>8.2</td><td>8/82</td><td>7.7</td><td>19/226</td><td>5.6</td><td></td></tr><tr><td>28</td><td>50/404</td><td>9.5</td><td>13/82</td><td>12.5</td><td>17/226</td><td>6.2</td><td></td></tr><tr><td>29</td><td>55/404</td><td>9.6</td><td>11/82</td><td>14.6</td><td>30/226</td><td>11.2</td><td></td></tr><tr><td>30</td><td>54/404</td><td>11.5</td><td>17/82</td><td>20.4</td><td>37/226</td><td>12.0</td><td></td></tr><tr><td>31</td><td>53/404</td><td>16.1</td><td>8/82</td><td>7.7</td><td>42/226</td><td>20.9</td><td></td></tr><tr><td>32</td><td>32/404</td><td>27.0</td><td>4/82</td><td>20.0</td><td>19/226</td><td>28.9</td><td></td></tr><tr><td>In utero transfer</td><td>242/404</td><td>50.7</td><td>58/82</td><td>65.1</td><td>136/226</td><td>56.2</td><td>.21</td></tr><tr><td>Antibiotics</td><td>389/404</td><td>97.0</td><td>78/82</td><td>96.4</td><td>218/226</td><td>96.5</td><td>.94</td></tr><tr><td>Antenatal steroids</td><td>373/404</td><td>90.4</td><td>78/82</td><td>92.4</td><td>204/226</td><td>86.3</td><td>.50</td></tr><tr><td>Tocolysis</td><td>300/404</td><td>72.3</td><td>63/82</td><td>83.6</td><td>168/226</td><td>86.3</td><td>.71</td></tr><tr><td>Neonatal characteristics</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cephalic presentation</td><td>275/395</td><td>68.5</td><td>62/80</td><td>83.6</td><td>159/223</td><td>79.5</td><td>.004</td></tr></tbody></table>

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

(continued)
SUPPLEMENTAL TABLE 1

Comparison of participating and nonparticipating children

Analysis population: children alive at 5½ y (n=712)

<table><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Complete assessment (n=404)</th><th colspan="2">Incomplete assessment<sup>a</sup> (n=82)</th><th colspan="2">No assessment (n=226)</th><th rowspan="2">Chi-square<br>P value</th></tr><tr><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Maternal characteristics</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age (y)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25</td><td>14/404</td><td>2.1</td><td>3/82</td><td>2.9</td><td>18/226</td><td>7.5</td><td>.002</td></tr><tr><td>25-34</td><td>319/404</td><td>80.1</td><td>63/82</td><td>78.0</td><td>181/226</td><td>83.6</td><td></td></tr><tr><td>≥35</td><td>71/404</td><td>17.8</td><td>16/82</td><td>19.2</td><td>27/226</td><td>8.9</td><td></td></tr><tr><td>Nulliparity</td><td>195/401</td><td>53.9</td><td>34/82</td><td>43.3</td><td>108/224</td><td>49.9</td><td>.42</td></tr><tr><td>Born in France or Europe</td><td>321/398</td><td>80.2</td><td>69/81</td><td>89.1</td><td>154/222</td><td>71.1</td><td>.011</td></tr><tr><td><strong>Level of education</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Less than high school</td><td>112/389</td><td>29.1</td><td>26/75</td><td>31.7</td><td>74/181</td><td>39.1</td><td>&lt;.001</td></tr><tr><td>High school, 1-2 y of graduate studies</td><td>161/389</td><td>39.7</td><td>30/75</td><td>34.9</td><td>86/181</td><td>51.9</td><td></td></tr><tr><td>≥3 y of graduate studies</td><td>116/389</td><td>31.2</td><td>19/75</td><td>33.5</td><td>21/181</td><td>9.0</td><td></td></tr><tr><td><strong>Parents' socioeconomic position<sup>c</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Executive</td><td>107/386</td><td>27.1</td><td>20/78</td><td>27.6</td><td>20/207</td><td>6.0</td><td>&lt;.001</td></tr><tr><td>Intermediate</td><td>62/386</td><td>16.8</td><td>15/78</td><td>18.4</td><td>20/207</td><td>10.3</td><td></td></tr><tr><td>Administration</td><td>113/386</td><td>31.1</td><td>20/78</td><td>27.6</td><td>77/207</td><td>40.0</td><td></td></tr><tr><td>Service, trade</td><td>56/386</td><td>14.2</td><td>10/78</td><td>9.7</td><td>32/207</td><td>20.8</td><td></td></tr><tr><td>Worker, unemployed</td><td>48/386</td><td>10.8</td><td>13/78</td><td>16.7</td><td>58/207</td><td>22.9</td><td></td></tr><tr><td><strong>Obstetrical characteristics and management</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>PPROM before hospitalization</td><td>348/404</td><td>88.8</td><td>64/81</td><td>84.5</td><td>186/226</td><td>85.4</td><td>.45</td></tr><tr><td>Contractions at admission</td><td>147/382</td><td>36.7</td><td>29/79</td><td>31.5</td><td>97/214</td><td>48.2</td><td>.047</td></tr><tr><td><strong>Gestational age at PPROM (wk)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>24</td><td>24/404</td><td>4.8</td><td>4/82</td><td>2.9</td><td>20/226</td><td>4.6</td><td>.39</td></tr><tr><td>25</td><td>50/404</td><td>6.7</td><td>12/82</td><td>10.0</td><td>24/226</td><td>5.8</td><td></td></tr><tr><td>26</td><td>40/404</td><td>6.6</td><td>5/82</td><td>4.3</td><td>18/226</td><td>4.7</td><td></td></tr><tr><td>27</td><td>46/404</td><td>8.2</td><td>8/82</td><td>7.7</td><td>19/226</td><td>5.6</td><td></td></tr><tr><td>28</td><td>50/404</td><td>9.5</td><td>13/82</td><td>12.5</td><td>17/226</td><td>6.2</td><td></td></tr><tr><td>29</td><td>55/404</td><td>9.6</td><td>11/82</td><td>14.6</td><td>30/226</td><td>11.2</td><td></td></tr><tr><td>30</td><td>54/404</td><td>11.5</td><td>17/82</td><td>20.4</td><td>37/226</td><td>12.0</td><td></td></tr><tr><td>31</td><td>53/404</td><td>16.1</td><td>8/82</td><td>7.7</td><td>42/226</td><td>20.9</td><td></td></tr><tr><td>32</td><td>32/404</td><td>27.0</td><td>4/82</td><td>20.0</td><td>19/226</td><td>28.9</td><td></td></tr><tr><td>In utero transfer</td><td>242/404</td><td>50.7</td><td>58/82</td><td>65.1</td><td>136/226</td><td>56.2</td><td>.21</td></tr><tr><td>Antibiotics</td><td>389/404</td><td>97.0</td><td>78/82</td><td>96.4</td><td>218/226</td><td>96.5</td><td>.94</td></tr><tr><td>Antenatal steroids</td><td>373/404</td><td>90.4</td><td>78/82</td><td>92.4</td><td>204/226</td><td>86.3</td><td>.50</td></tr><tr><td>Tocolysis</td><td>300/404</td><td>72.3</td><td>63/82</td><td>83.6</td><td>168/226</td><td>86.3</td><td>.71</td></tr><tr><td><strong>Neonatal characteristics</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cephalic presentation</td><td>275/395</td><td>68.5</td><td>62/80</td><td>83.6</td><td>159/223</td><td>79.5</td><td>.004</td></tr></tbody></table>

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

(continued)
SUPPLEMENTAL TABLE 1

Comparison of participating and nonparticipating children (continued)

Analysis population: children alive at 5½ y (n=712)

<table><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Complete assessment (n=404)</th><th colspan="2">Incomplete assessment<sup>a</sup> (n=82)</th><th colspan="2">No assessment (n=226)</th><th rowspan="2">Chi-square<br>P value</th></tr><tr><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th></tr></thead><tbody><tr><td>Male fetus</td><td>237/404</td><td>61.0</td><td>36/82</td><td>41.4</td><td>116/226</td><td>48.2</td><td>.010</td></tr><tr><td>Birth weight ≤third percentile</td><td>19/404</td><td>5.7</td><td>7/82</td><td>6.7</td><td>16/226</td><td>5.8</td><td>.96</td></tr><tr><td colspan="8"><strong>Maternity unit characteristics</strong></td></tr><tr><td colspan="8"><strong>Type of maternity unit</strong></td></tr><tr><td>Type 1 (no neonatal department)</td><td>1/404</td><td>0.8</td><td>0/82</td><td>0</td><td>2/226</td><td>0.5</td><td>.75</td></tr><tr><td>Type 2 (with neonatal department)</td><td>43/404</td><td>22.0</td><td>9/82</td><td>20.7</td><td>25/226</td><td>25.7</td><td></td></tr><tr><td>Type 3 (with neonatal intensive care department)</td><td>360/404</td><td>77.2</td><td>73/82</td><td>79.3</td><td>199/226</td><td>73.8</td><td></td></tr></tbody></table>

PPROM, preterm premature rupture of membranes; SD, standardized difference.

<sup>a</sup> Including 23 children with an incomplete neurodevelopmental assessment and 59 with only a postal questionnaire; <sup>b</sup> Denominators vary according to the number of missing data for each variable. Percentages are weighted to take into account the differences in survey design between gestational age groups, and thus proportions are not exactly the number of events or number in groups because of the weighting; <sup>c</sup> Defined as the highest occupational status between occupations of the mother and the father or of the mother only if living alone.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.
SUPPLEMENTAL TABLE 1

Comparison of participating and nonparticipating children (continued)

Analysis population: children alive at 5½ y (n=712)

<table><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Complete<br>assessment<br>(n=404)</th><th colspan="2">Incomplete<br>assessment<sup>a</sup><br>(n=82)</th><th colspan="2">No assessment<br>(n=226)</th><th rowspan="2">Chi-square<br>P value</th></tr><tr><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th><th>n/N<sup>b</sup></th><th>%<sup>b</sup></th></tr></thead><tbody><tr><td>Male fetus</td><td>237/404</td><td>61.0</td><td>36/82</td><td>41.4</td><td>116/226</td><td>48.2</td><td>.010</td></tr><tr><td>Birth weight ≤third percentile</td><td>19/404</td><td>5.7</td><td>7/82</td><td>6.7</td><td>16/226</td><td>5.8</td><td>.96</td></tr><tr><td colspan="8"><strong>Maternity unit characteristics</strong></td></tr><tr><td colspan="8"><strong>Type of maternity unit</strong></td></tr><tr><td>Type 1 (no neonatal department)</td><td>1/404</td><td>0.8</td><td>0/82</td><td>0</td><td>2/226</td><td>0.5</td><td>.75</td></tr><tr><td>Type 2 (with neonatal department)</td><td>43/404</td><td>22.0</td><td>9/82</td><td>20.7</td><td>25/226</td><td>25.7</td><td></td></tr><tr><td>Type 3 (with neonatal intensive care department)</td><td>360/404</td><td>77.2</td><td>73/82</td><td>79.3</td><td>199/226</td><td>73.8</td><td></td></tr></tbody></table>

PPROM, preterm premature rupture of membranes; SD, standardized difference.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

<footnote><sup>a</sup> Including 23 children with an incomplete neurodevelopmental assessment and 59 with only a postal questionnaire; <sup>b</sup> Denominators vary according to the number of missing data for each variable. Percentages are weighted to take into account the differences in survey design between gestational age groups, and thus proportions are not exactly the number of events or number in groups because of the weighting; <sup>c</sup> Defined as the highest occupational status between occupations of the mother and the father or of the mother only if living alone.</footnote>
SUPPLEMENTAL TABLE 2

Maternal, obstetrical, neonatal, and center characteristics according to tocolytic drug, after and before IPTW

<table><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Oxytocin receptor antagonists</th><th colspan="2">Calcium channel blockers</th><th colspan="2">No tocolysis</th><th rowspan="2">After inverse probability of treatment weighting<sup>a</sup><br>SD<sup>c</sup></th></tr><tr><th>(n=267)<br>n</th><th>%<sup>b</sup></th><th>(n=286)<br>n</th><th>%<sup>b</sup></th><th>(n=207)<br>n</th><th>%<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Maternal characteristics</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age (y)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25</td><td>15</td><td>5.5</td><td>17</td><td>4.7</td><td>8</td><td>2.4</td><td>8.0</td></tr><tr><td>25-34</td><td>214</td><td>82.9</td><td>219</td><td>77.8</td><td>158</td><td>78.1</td><td>5.5</td></tr><tr><td>≥35</td><td>38</td><td>11.6</td><td>50</td><td>17.6</td><td>41</td><td>19.5</td><td>10.5</td></tr><tr><td>Nulliparity</td><td>124</td><td>52.3</td><td>135</td><td>52.2</td><td>98</td><td>48.4</td><td>2.7</td></tr><tr><td>Born in France or Europe</td><td>231</td><td>91.3</td><td>200</td><td>68.3</td><td>149</td><td>75.9</td><td>0.7</td></tr><tr><td>Level of education</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Less than high school</td><td>72</td><td>30.4</td><td>78</td><td>32.4</td><td>57</td><td>36.4</td><td>3.4</td></tr><tr><td>High school, 1-2 y of graduate studies</td><td>97</td><td>45.6</td><td>104</td><td>40.5</td><td>65</td><td>38.4</td><td>0.1</td></tr><tr><td>≥3 y of graduate studies</td><td>53</td><td>24.0</td><td>64</td><td>27.1</td><td>35</td><td>25.2</td><td>4.0</td></tr><tr><td>Parents' socioeconomic status<sup>d</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Executive</td><td>48</td><td>18.1</td><td>65</td><td>22.3</td><td>39</td><td>19.7</td><td>6.6</td></tr><tr><td>Intermediate</td><td>41</td><td>17.8</td><td>39</td><td>16.1</td><td>21</td><td>10.2</td><td>1.5</td></tr><tr><td>Administration</td><td>79</td><td>35.1</td><td>78</td><td>26.5</td><td>70</td><td>40.5</td><td>4.3</td></tr><tr><td>Service, trade</td><td>37</td><td>12.0</td><td>43</td><td>20.6</td><td>25</td><td>14.5</td><td>1.7</td></tr><tr><td>Worker, unemployed</td><td>49</td><td>17.0</td><td>46</td><td>14.6</td><td>32</td><td>15.1</td><td>1.0</td></tr><tr><td><strong>Obstetrical characteristics and management</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>PPROM before hospitalization</td><td>232</td><td>88.3</td><td>240</td><td>86.8</td><td>155</td><td>81.3</td><td>6.0</td></tr><tr><td>Contractions at admission</td><td>122</td><td>45.1</td><td>112</td><td>45.2</td><td>71</td><td>33.0</td><td>5.1</td></tr><tr><td>Gestational age at PPROM (wk)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>24</td><td>22</td><td>6.5</td><td>29</td><td>5.3</td><td>25</td><td>6.5</td><td>13.5</td></tr><tr><td>25</td><td>43</td><td>10.5</td><td>40</td><td>7.5</td><td>28</td><td>7.5</td><td>1.3</td></tr><tr><td>26</td><td>29</td><td>7.7</td><td>24</td><td>5.0</td><td>16</td><td>4.4</td><td>0.0</td></tr><tr><td>27</td><td>24</td><td>7.1</td><td>28</td><td>6.4</td><td>25</td><td>9.6</td><td>0.2</td></tr><tr><td>28</td><td>34</td><td>12.6</td><td>26</td><td>5.9</td><td>17</td><td>7.0</td><td>0.8</td></tr></tbody></table>

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

(continued)
SUPPLEMENTAL TABLE 2

Maternal, obstetrical, neonatal, and center characteristics according to tocolytic drug, after and before IPTW

<table><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Oxytocin receptor antagonists</th><th colspan="2">Calcium channel blockers</th><th colspan="2">No tocolysis</th><th rowspan="2">After inverse probability of treatment weighting<sup>a</sup><br>SD<sup>c</sup></th></tr><tr><th>(n=267)<br>n</th><th>%<sup>b</sup></th><th>(n=286)<br>n</th><th>%<sup>b</sup></th><th>(n=207)<br>n</th><th>%<sup>b</sup></th></tr></thead><tbody><tr><td><strong>Maternal characteristics</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age (y)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;25</td><td>15</td><td>5.5</td><td>17</td><td>4.7</td><td>8</td><td>2.4</td><td>8.0</td></tr><tr><td>25-34</td><td>214</td><td>82.9</td><td>219</td><td>77.8</td><td>158</td><td>78.1</td><td>5.5</td></tr><tr><td>≥35</td><td>38</td><td>11.6</td><td>50</td><td>17.6</td><td>41</td><td>19.5</td><td>10.5</td></tr><tr><td>Nulliparity</td><td>124</td><td>52.3</td><td>135</td><td>52.2</td><td>98</td><td>48.4</td><td>2.7</td></tr><tr><td>Born in France or Europe</td><td>231</td><td>91.3</td><td>200</td><td>68.3</td><td>149</td><td>75.9</td><td>0.7</td></tr><tr><td>Level of education</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Less than high school</td><td>72</td><td>30.4</td><td>78</td><td>32.4</td><td>57</td><td>36.4</td><td>3.4</td></tr><tr><td>High school, 1-2 y of graduate studies</td><td>97</td><td>45.6</td><td>104</td><td>40.5</td><td>65</td><td>38.4</td><td>0.1</td></tr><tr><td>≥3 y of graduate studies</td><td>53</td><td>24.0</td><td>64</td><td>27.1</td><td>35</td><td>25.2</td><td>4.0</td></tr><tr><td>Parents' socioeconomic status<sup>d</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Executive</td><td>48</td><td>18.1</td><td>65</td><td>22.3</td><td>39</td><td>19.7</td><td>6.6</td></tr><tr><td>Intermediate</td><td>41</td><td>17.8</td><td>39</td><td>16.1</td><td>21</td><td>10.2</td><td>1.5</td></tr><tr><td>Administration</td><td>79</td><td>35.1</td><td>78</td><td>26.5</td><td>70</td><td>40.5</td><td>4.3</td></tr><tr><td>Service, trade</td><td>37</td><td>12.0</td><td>43</td><td>20.6</td><td>25</td><td>14.5</td><td>1.7</td></tr><tr><td>Worker, unemployed</td><td>49</td><td>17.0</td><td>46</td><td>14.6</td><td>32</td><td>15.1</td><td>1.0</td></tr><tr><td><strong>Obstetrical characteristics and management</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>PPROM before hospitalization</td><td>232</td><td>88.3</td><td>240</td><td>86.8</td><td>155</td><td>81.3</td><td>6.0</td></tr><tr><td>Contractions at admission</td><td>122</td><td>45.1</td><td>112</td><td>45.2</td><td>71</td><td>33.0</td><td>5.1</td></tr><tr><td>Gestational age at PPROM (wk)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>24</td><td>22</td><td>6.5</td><td>29</td><td>5.3</td><td>25</td><td>6.5</td><td>13.5</td></tr><tr><td>25</td><td>43</td><td>10.5</td><td>40</td><td>7.5</td><td>28</td><td>7.5</td><td>1.3</td></tr><tr><td>26</td><td>29</td><td>7.7</td><td>24</td><td>5.0</td><td>16</td><td>4.4</td><td>0.0</td></tr><tr><td>27</td><td>24</td><td>7.1</td><td>28</td><td>6.4</td><td>25</td><td>9.6</td><td>0.2</td></tr><tr><td>28</td><td>34</td><td>12.6</td><td>26</td><td>5.9</td><td>17</td><td>7.0</td><td>0.8</td></tr></tbody></table>

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

(continued)
SUPPLEMENTAL TABLE 2

Maternal, obstetrical, neonatal, and center characteristics according to tocolytic drug, after and before IPTW (continued)

<table><thead><tr><th rowspan="3">Characteristics</th><th colspan="2">Oxytocin receptor antagonists</th><th colspan="2">Calcium channel blockers</th><th colspan="2">No tocolysis</th><th rowspan="2">After inverse probability of treatment weighting<sup>a</sup></th></tr><tr><th colspan="2">(n=267)</th><th colspan="2">(n=286)</th><th colspan="2">(n=207)</th></tr><tr><th>n</th><th>%<sup>b</sup></th><th>n</th><th>%<sup>b</sup></th><th>n</th><th>%<sup>b</sup></th><th>SD<sup>c</sup></th></tr></thead><tbody><tr><td>29</td><td>37</td><td>13.5</td><td>34</td><td>8.7</td><td>22</td><td>8.6</td><td>9.9</td></tr><tr><td>30</td><td>34</td><td>11.4</td><td>40</td><td>12.0</td><td>29</td><td>11.0</td><td>2.7</td></tr><tr><td>31</td><td>32</td><td>12.0</td><td>41</td><td>20.8</td><td>27</td><td>14.5</td><td>2.0</td></tr><tr><td>32</td><td>12</td><td>18.6</td><td>24</td><td>28.4</td><td>18</td><td>30.9</td><td>11.9</td></tr><tr><td>In utero transfer</td><td>210</td><td>80.2</td><td>172</td><td>49.4</td><td>72</td><td>27.4</td><td>6.1</td></tr><tr><td>Antibiotics</td><td>248</td><td>86.9</td><td>263</td><td>90.3</td><td>179</td><td>89.0</td><td>7.6</td></tr><tr><td>Antenatal steroids</td><td>259</td><td>96.4</td><td>281</td><td>97.9</td><td>193</td><td>95.8</td><td>0.8</td></tr><tr><td colspan="8">Neonatal characteristics</td></tr><tr><td>Cephalic presentation</td><td>177</td><td>71.4</td><td>206</td><td>73.8</td><td>134</td><td>73.7</td><td>3.6</td></tr><tr><td>Male fetus</td><td>144</td><td>51.7</td><td>156</td><td>55.6</td><td>116</td><td>57.9</td><td>2.7</td></tr><tr><td>Birth weight ≤third percentile</td><td>20</td><td>8.0</td><td>14</td><td>4.1</td><td>18</td><td>8.4</td><td>0.2</td></tr><tr><td colspan="8">Maternity unit characteristics</td></tr><tr><td>Type of maternity unit</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Type 1</td><td>2</td><td>0.6</td><td>2</td><td>0.3</td><td>2</td><td>2.0</td><td>6.6</td></tr><tr><td>Type 2 (with neonatal department)</td><td>22</td><td>16.6</td><td>31</td><td>29.0</td><td>30</td><td>20.6</td><td>6.5</td></tr><tr><td>Type 3 (with neonatal intensive care department)</td><td>243</td><td>82.8</td><td>253</td><td>70.7</td><td>175</td><td>77.4</td><td>4.6</td></tr></tbody></table>

PPROM, preterm premature rupture of membranes; SD, standardized difference.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

<footnote>a After inverse probability of treatment weighting and multiple imputation for handling missing data; b Denominators vary according to the number of missing data for each variable. Percentages were weighted to take into account the differences in survey design between gestational age groups, and thus, proportions are not the exact number of events or number in groups because of the weighting; c Maximum standardized pairwise difference between the 3 groups; d Defined as the highest occupational status between occupations of the mother and the father or of the mother only if living alone.</footnote>
SUPPLEMENTAL TABLE 2

Maternal, obstetrical, neonatal, and center characteristics according to tocolytic drug, after and before IPTW (continued)

<table><thead><tr><th rowspan="3">Characteristics</th><th colspan="2">Oxytocin receptor antagonists</th><th colspan="2">Calcium channel blockers</th><th colspan="2">No tocolysis</th><th rowspan="2">After inverse probability of treatment weighting<sup>a</sup></th></tr><tr><th colspan="2">(n=267)</th><th colspan="2">(n=286)</th><th colspan="2">(n=207)</th></tr><tr><th>n</th><th>%<sup>b</sup></th><th>n</th><th>%<sup>b</sup></th><th>n</th><th>%<sup>b</sup></th><th>SD<sup>c</sup></th></tr></thead><tbody><tr><td>29</td><td>37</td><td>13.5</td><td>34</td><td>8.7</td><td>22</td><td>8.6</td><td>9.9</td></tr><tr><td>30</td><td>34</td><td>11.4</td><td>40</td><td>12.0</td><td>29</td><td>11.0</td><td>2.7</td></tr><tr><td>31</td><td>32</td><td>12.0</td><td>41</td><td>20.8</td><td>27</td><td>14.5</td><td>2.0</td></tr><tr><td>32</td><td>12</td><td>18.6</td><td>24</td><td>28.4</td><td>18</td><td>30.9</td><td>11.9</td></tr><tr><td>In utero transfer</td><td>210</td><td>80.2</td><td>172</td><td>49.4</td><td>72</td><td>27.4</td><td>6.1</td></tr><tr><td>Antibiotics</td><td>248</td><td>86.9</td><td>263</td><td>90.3</td><td>179</td><td>89.0</td><td>7.6</td></tr><tr><td>Antenatal steroids</td><td>259</td><td>96.4</td><td>281</td><td>97.9</td><td>193</td><td>95.8</td><td>0.8</td></tr><tr><td colspan="8">Neonatal characteristics</td></tr><tr><td>Cephalic presentation</td><td>177</td><td>71.4</td><td>206</td><td>73.8</td><td>134</td><td>73.7</td><td>3.6</td></tr><tr><td>Male fetus</td><td>144</td><td>51.7</td><td>156</td><td>55.6</td><td>116</td><td>57.9</td><td>2.7</td></tr><tr><td>Birth weight ≤third percentile</td><td>20</td><td>8.0</td><td>14</td><td>4.1</td><td>18</td><td>8.4</td><td>0.2</td></tr><tr><td colspan="8">Maternity unit characteristics</td></tr><tr><td>Type of maternity unit</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Type 1</td><td>2</td><td>0.6</td><td>2</td><td>0.3</td><td>2</td><td>2.0</td><td>6.6</td></tr><tr><td>Type 2 (with neonatal department)</td><td>22</td><td>16.6</td><td>31</td><td>29.0</td><td>30</td><td>20.6</td><td>6.5</td></tr><tr><td>Type 3 (with neonatal intensive care department)</td><td>243</td><td>82.8</td><td>253</td><td>70.7</td><td>175</td><td>77.4</td><td>4.6</td></tr></tbody></table>

PPROM, preterm premature rupture of membranes; SD, standardized difference.

Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.

<footnote>a After inverse probability of treatment weighting and multiple imputation for handling missing data; b Denominators vary according to the number of missing data for each variable. Percentages were weighted to take into account the differences in survey design between gestational age groups, and thus, proportions are not the exact number of events or number in groups because of the weighting; c Maximum standardized pairwise difference between the 3 groups; d Defined as the highest occupational status between occupations of the mother and the father or of the mother only if living alone.</footnote>
SUPPLEMENTAL TABLE 3

Neurodevelopmental outcomes according to tocolytic drug

<table><thead><tr><th rowspan="3">Outcome</th><th rowspan="3">n=267</th><th rowspan="3">n=286</th><th rowspan="3">n=207</th><th colspan="2">After inverse probability of treatment<br/>weighting</th><th rowspan="3">P value</th></tr><tr><th colspan="2">OR or MD (95%CI)</th></tr><tr><th>Oxytocin receptor<br/>antagonists<br/>vs no<br/>tocolysis</th><th>Calcium channel<br/>blockers<br/>vs no<br/>tocolysis</th></tr></thead><tbody><tr><td>Survival without moderate to severe neurodevelopmental<br/>disabilities at 5.5 y<sup>b</sup></td><td>80.7</td><td>83.7</td><td>82.5</td><td>1.03 (0.57-1.86)</td><td>0.92 (0.52-1.62)</td><td>.77</td></tr><tr><td>Survival without any disabilities at 5.5 y<sup>b</sup></td><td>53.4</td><td>52.9</td><td>51.1</td><td>1.04 (0.61-1.76)</td><td>0.98 (0.61-1.58)</td><td>.82</td></tr><tr><td>Survival at 5.5 y</td><td>92.8</td><td>93.7</td><td>93.1</td><td>1.02 (0.53-1.96)</td><td>0.85 (0.45-1.62)</td><td>.80</td></tr><tr><td>Among survivors at 5.5 y</td><td>n=237</td><td>n=257</td><td>n=181</td><td></td><td></td><td></td></tr><tr><td>Neurodevelopmental disabilities<sup>b</sup></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Severe</td><td>1.8</td><td>1.5</td><td>2.5</td><td>0.69 (0.14-3.28)</td><td>0.80 (0.22-2.91)</td><td>.92</td></tr><tr><td>Moderate</td><td>11.2</td><td>9.1</td><td>8.9</td><td>1.06 (0.57-1.97)</td><td>1.05 (0.57-1.95)</td><td></td></tr><tr><td>Mild</td><td>34.8</td><td>39.7</td><td>42.2</td><td>1.05 (0.72-1.52)</td><td>0.98 (0.69-1.39)</td><td></td></tr><tr><td>None</td><td>52.1</td><td>49.7</td><td>46.4</td><td>Ref</td><td>Ref</td><td></td></tr><tr><td>Cerebral palsy</td><td>6.2</td><td>3.9</td><td>8.6</td><td>0.91 (0.34-2.42)</td><td>0.96 (0.38-2.46)</td><td>.86</td></tr><tr><td>FSIQ score</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>97.4 (13.5)</td><td>97 (13.9)</td><td>97 (13.5)</td><td>0.4 (-3.7 to 4.4)</td><td>0.9 (-2.8 to 4.7)</td><td>.68</td></tr><tr><td>&lt;79 (&lt;-2 SD)<sup>c</sup></td><td>9.0</td><td>8.1</td><td>8.1</td><td>1.14 (0.41-3.14)</td><td>1.11 (0.41-2.99)</td><td>.79</td></tr><tr><td>Behavioral difficulties</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Total SDQ score, mean (SD)</td><td>10.5 (5.2)</td><td>11.0 (5.6)</td><td>11.2 (5.1)</td><td>0.2 (-1.3 to 1.6)</td><td>-0.0 (-1.3 to 1.2)</td><td>.82</td></tr><tr><td>Total SDQ score ≥90th percentile<sup>c</sup></td><td>7.8</td><td>11.8</td><td>9.7</td><td>1.63 (0.58-4.57)</td><td>1.22 (0.47-3.14)</td><td>.05</td></tr><tr><td>Developmental Coordination Disorders<sup>d</sup></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Total MABC-2 score, mean (SD)</td><td>10.2 (3.2)</td><td>10.7 (3)</td><td>9.7 (2.9)</td><td>0.0 (-1.0 to 1.1)</td><td>0.9 (-0.0 to 1.8)</td><td>.074</td></tr><tr><td>Total MABC-2 score ≤5th percentile<sup>c</sup></td><td>7.5</td><td>6.0</td><td>7.7</td><td>1.10 (0.36-3.36)</td><td>0.57 (0.21-1.55)</td><td>.32</td></tr></tbody></table>

CI, confidence interval; dB, decibel; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System (Ghassabian, 2016); MABC-2, Movement Assessment Battery for Children - Second Edition (Henderson, 2007); MD, mean difference; OR, odd ratios; SD, standard deviation; SDQ, Strengths and Difficulties Questionnaire (Goodman, 1997).

<footnote>ª Weighted to take into account the differences in survey design between gestational age groups; ᵇ Severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss >70 dB and/or FSIQ score <-3 SDs. Moderate neurodevelopmental disabilities were defined as cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between -3 to -2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB and/or FSIQ score between -2 and -1 SDs and/or MADC-2 score ≤5th percentile and/or SDQ score ≥90th percentile). Cutoffs of the distribution was related to a reference group born at term; ᶜ Cutoff of the distribution related to a reference group born at term; ᵈ Among children without cerebral palsy, severe or moderate sensory disabilities, and with Full-Scale Intelligence Quotient score ≥2 SDs.</footnote>

<footnote>Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.</footnote>
SUPPLEMENTAL TABLE 3

Neurodevelopmental outcomes according to tocolytic drug

<table><thead><tr><th rowspan="3">Outcome</th><th rowspan="2">Oxytocin receptor<br>antagonists<br>%<sup>a</sup></th><th rowspan="2">Calcium channel<br>blockers<br>%<sup>a</sup></th><th rowspan="2">No tocolysis<br>%<sup>a</sup></th><th colspan="2">After inverse probability of treatment<br>weighting</th><th rowspan="2">P value</th></tr><tr><th colspan="2">OR or MD (95%CI)</th></tr><tr><th>n=267</th><th>n=286</th><th>n=207</th><th>Oxytocin receptor<br>antagonists vs no<br>tocolysis</th><th>Calcium channel<br>blockers vs no<br>tocolysis</th></tr></thead><tbody><tr><td>Survival without moderate to severe neurodevelopmental<br>disabilities at 5.5 y<sup>b</sup></td><td>80.7</td><td>83.7</td><td>82.5</td><td>1.03 (0.57-1.86)</td><td>0.92 (0.52-1.62)</td><td>.77</td></tr><tr><td>Survival without any disabilities at 5.5 y<sup>b</sup></td><td>53.4</td><td>52.9</td><td>51.1</td><td>1.04 (0.61-1.76)</td><td>0.98 (0.61-1.58)</td><td>.82</td></tr><tr><td>Survival at 5.5 y</td><td>92.8</td><td>93.7</td><td>93.1</td><td>1.02 (0.53-1.96)</td><td>0.85 (0.45-1.62)</td><td>.80</td></tr><tr><td>Among survivors at 5.5 y</td><td>n=237</td><td>n=257</td><td>n=181</td><td></td><td></td><td></td></tr><tr><td>Neurodevelopmental disabilities<sup>b</sup></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Severe</td><td>1.8</td><td>1.5</td><td>2.5</td><td>0.69 (0.14-3.28)</td><td>0.80 (0.22-2.91)</td><td>.92</td></tr><tr><td>Moderate</td><td>11.2</td><td>9.1</td><td>8.9</td><td>1.06 (0.57-1.97)</td><td>1.05 (0.57-1.95)</td><td></td></tr><tr><td>Mild</td><td>34.8</td><td>39.7</td><td>42.2</td><td>1.05 (0.72-1.52)</td><td>0.98 (0.69-1.39)</td><td></td></tr><tr><td>None</td><td>52.1</td><td>49.7</td><td>46.4</td><td>Ref</td><td>Ref</td><td></td></tr><tr><td>Cerebral palsy</td><td>6.2</td><td>3.9</td><td>8.6</td><td>0.91 (0.34-2.42)</td><td>0.96 (0.38-2.46)</td><td>.86</td></tr><tr><td>FSIQ score</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (SD)</td><td>97.4 (13.5)</td><td>97 (13.9)</td><td>97 (13.5)</td><td>0.4 (-3.7 to 4.4)</td><td>0.9 (-2.8 to 4.7)</td><td>.68</td></tr><tr><td>&lt;79 (&lt;-2 SD)<sup>c</sup></td><td>9.0</td><td>8.1</td><td>8.1</td><td>1.14 (0.41-3.14)</td><td>1.11 (0.41-2.99)</td><td>.79</td></tr><tr><td>Behavioral difficulties</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Total SDQ score, mean (SD)</td><td>10.5 (5.2)</td><td>11.0 (5.6)</td><td>11.2 (5.1)</td><td>0.2 (-1.3 to 1.6)</td><td>-0.0 (-1.3 to 1.2)</td><td>.82</td></tr><tr><td>Total SDQ score ≥90th percentile<sup>c</sup></td><td>7.8</td><td>11.8</td><td>9.7</td><td>1.63 (0.58-4.57)</td><td>1.22 (0.47-3.14)</td><td>.05</td></tr><tr><td>Developmental Coordination Disorders<sup>d</sup></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Total MABC-2 score, mean (SD)</td><td>10.2 (3.2)</td><td>10.7 (3)</td><td>9.7 (2.9)</td><td>0.0 (-1.0 to 1.1)</td><td>0.9 (-0.0 to 1.8)</td><td>.074</td></tr><tr><td>Total MABC-2 score ≤5th percentile<sup>c</sup></td><td>7.5</td><td>6.0</td><td>7.7</td><td>1.10 (0.36-3.36)</td><td>0.57 (0.21-1.55)</td><td>.32</td></tr></tbody></table>

CI, confidence interval; dB, decibel; FSIQ, Full-Scale Intelligence Quotient; GMFCS, Gross Motor Function Classification System (Ghassabian, 2016); MABC-2, Movement Assessment Battery for Children - Second Edition (Henderson, 2007); MD, mean difference; OR, odd ratios; SD, standard deviation; SDQ, Strengths and Difficulties Questionnaire (Goodman, 1997).

<footnote><sup>a</sup> Weighted to take into account the differences in survey design between gestational age groups; <sup>b</sup> Severe neurodevelopmental disabilities were defined as severe cerebral palsy (GMFCS score of 4 or 5) and/or bilateral binocular visual acuity <1/10 and/or uni- or bilateral hearing loss >70 dB and/or FSIQ score <-3 SDs. Moderate neurodevelopmental disabilities were defined as cerebral palsy with a GMFCS score of 2 or 3 and/or bilateral binocular visual acuity ≥1/10 and <3.2/10 and/or uni- or bilateral hearing loss at 40 to 70 dB and/or FSIQ score between -3 to -2 SDs. Mild neurodevelopmental disabilities were defined as mild cerebral palsy (GMFCS score of 1) and/or visual disability ≥3.2/10 and <5/10 and/or uni- or bilateral hearing loss at <40 dB and/or FSIQ score between -2 and -1 SDs and/or MADC-2 score ≤5th percentile and/or SDQ score ≥90th percentile). Cutoffs of the distribution was related to a reference group born at term; <sup>c</sup> Cutoff of the distribution related to a reference group born at term; <sup>d</sup> Among children without cerebral palsy, severe or moderate sensory disabilities, and with Full-Scale Intelligence Quotient score ≥2 SDs.</footnote>

<footnote>Lorthe. Tocolysis after preterm prelabor rupture of membranes and 5-year neurodevelopment. Am J Obstet Gynecol 2024.</footnote>