# Increased risk of preterm birth in pregnant women exposed to chemotherapy during childhood, adolescence, or young adulthood: A systematic review and a network meta-analysis

E. Fraison, S. Huberlant, M. Cavalieri, A. Gueniffey, J. Riss, C.

Rousset-Jablonski, B. Courbiere

► To cite this version:

E. Fraison, S. Huberlant, M. Cavalieri, A. Gueniffey, J. Riss, et al.. Increased risk of preterm birth in pregnant women exposed to chemotherapy during childhood, adolescence, or young adulthood: A systematic review and a network meta-analysis. European Journal of Obstetrics & Gynecology and Reproductive Biology, 2025, 314, pp.114665. 10.1016/j.ejogrb.2025.114665. hal-05351982

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Review article

# Increased risk of preterm birth in pregnant women exposed to chemotherapy during childhood, adolescence, or young adulthood: A systematic review and a network meta-analysis

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

E. Fraison<sup>a,b,c,*</sup>, S. Huberlant<sup>d,e</sup>, M. Cavalieri<sup>f</sup>, A. Gueniffey<sup>g</sup>, J. Riss<sup>h</sup>, C. Rousset-Jablonski<sup>i,j,k</sup>, B. Courbiere<sup>l,m</sup>

ARTICLE INFO

Keywords:

Chemotherapy

Chemoradiotherapy

Obstetric outcomes

Meta-analysis

Systematic review

Live-birth rate

Preterm birth

ABSTRACT

**Objective:** To assess the long-term impact of chemotherapy exposure on pregnancy outcomes in women treated during childhood, adolescence, or young adulthood (CAYA).

**Data sources:** MEDLINE, Embase, and the Cochrane Library from 1990 to April 2023.

**Methods:** All studies reporting on pregnancy outcomes in adult females who had received chemotherapy or chemoradiotherapy during CAYA (<25 years) were included. The primary outcome was the live-birth rate. One of the secondary outcomes was preterm birth. For each outcome, a random-effect frequentist network meta-analysis (NMA) was carried out to estimate the risk ratios with 95 % confidence intervals. Sensitivity analyses were conducted by excluding studies at high risk of bias and the leave-one-out method.

**Results:** Eight studies were included in the meta-analysis on live-birth rates: 3,997 females became pregnant, leading to 2,878 live births. The NMA showed moderate heterogeneity or inconsistency ($\tau^2$ = 0.012, I² = 58 % [11 %; 80 %]) and did not show any significant impact of treatments on live-birth rate. Six studies reported a total of 125 preterm births out of 1,976 started pregnancies and were included in the NMA ($\tau^2$ = 0.07, I² = 19 % [0 %; 62 %]). Chemoradiotherapy was significantly associated with a higher risk of preterm birth when compared to the control group (3.44 [1.94; 6.09]) and the chemotherapy group (1.93 [1.19; 3.15]). Chemotherapy alone was associated with a statistically higher risk of preterm birth compared to the control group (1.78 [1.01; 3.13]).

**Conclusion:** Although live-birth rate was similar in pregnant women with a history of CAYA chemotherapy or chemoradiotherapy, preterm birth was significantly increased.

Introduction

The survival rate in patients treated for cancer in childhood or in

adolescence and the young adult period has improved to 81 % and 87 %, respectively [1]. Consequently, the impact of anti-cancer treatment on long-term reproductive function has become an important issue for

<footnote><sup>a</sup> Department of Gynecology-Obstetric and Reproductive Medicine, University Hospital of Lyon, Lyon, France</footnote>

<footnote><sup>b</sup> UMR, CNRS 5558, LBBE, Villeurbanne, France</footnote>

<footnote><sup>c</sup> Claude Bernard University, Lyon, France</footnote>

<footnote><sup>d</sup> University Hospital of Nîmes, Department of Gynecology-Obstetric and Reproductive Medicine, Nîmes, France</footnote>

<footnote><sup>e</sup> University of Montpellier, IBMM, CNRS, ENSCM, Polymers for Health and Biomaterials, Montpellier, France</footnote>

<footnote><sup>f</sup> Department of Gynecology-Obstetric and Reproductive Medicine, University Hospital François Mitterrand, Dijon, France</footnote>

<footnote><sup>g</sup> Clinique Belledonne, 83 Avenue Gabriel Péri, 38400 Saint-Martin-d'Hères, France</footnote>

<footnote><sup>h</sup> Department of Gynecology-Obstetric and Reproductive Medicine, University Hospital of Strasbourg, Strasbourg, France</footnote>

<footnote><sup>i</sup> Centre Léon Bérard, Oncologique and Surgery Department, Lyon, France</footnote>

<footnote><sup>j</sup> Department of Gynecology-Obstetric, Hôpital Femme Mère Enfant, Bron, Lyon, France</footnote>

<footnote><sup>k</sup> University of Lyon, EA 7425 HESPER - Health Services and Performance Research, F-69003 Lyon, France</footnote>

<footnote><sup>l</sup> AP-HM, Hôpital La Conception Department of Gynecology-Obstetric and Reproductive Medicine, Marseille, France</footnote>

<footnote><sup>m</sup> IMBE, Aix-Marseille University, Avignon University, CNRS, IRD, Marseille, France</footnote>

<footnote>* Corresponding author at: Department of Gynecology-Obstetric and Reproductive Medicine, University Hospital of Lyon, 69 boulevard Pinel 69500, Bron, France.
E-mail address: eloise.fraison@chu-lyon.fr (E. Fraison).</footnote>
women's long-term quality of life. Young women clearly express their feelings about their loss of fertility being almost as devastating as the diagnosis of cancer [2]. From birth, the ovarian reserve is definitive for the entire reproductive life, and ovaries are extremely sensitive to exogenous insults. The damaging impact on ovarian reserve of both radiotherapy and gonadotoxic chemotherapy is already well established, with a decreased reproductive lifespan [3]. The obstetrical consequences of previous uterine irradiation have been widely described. Initially, only total body irradiation (TBI) and pelvic radiotherapy were found to have an obstetrical impact, with a higher risk of miscarriages and prematurity [4]. However, some recent studies have also underlined the potential negative effects of chemotherapy on the uterus. Indeed, three studies have reported that adult women previously treated with hematopoietic stem cell transplantation (HSCT) during childhood had reduced uterine volume, both after TBI-based conditioning and after alkylating agent-based conditioning [5-7]. Pregnancy outcomes depend partly on uterine volume and on vascularization. The review by Griffiths et al. reported all the potential deleterious impacts of chemotherapy on the uterus and consequently on obstetrical outcomes and especially underlined the role of alkylating agents [3]. The last systematic review and meta-analysis by Gerstl et al. did not include these recent data [1].

The objective of this systematic review and meta-analysis was to assess the long-term impact of chemotherapy exposure on pregnancy outcomes in women treated during the CAYA period.

## Material and methods

### Literature search strategy and eligibility criteria

The protocol was prospectively registered in PROSPERO (CRD42023440219). The reporting of this systematic review and meta-analysis was guided by PRISMA-NMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses for network meta-analysis) guidelines. We included comparative studies, published as full-text papers, involving female cancer survivors or females who underwent stem cells transplantation for non-oncological indications, aged over 18 years, and who received chemotherapy and/or radiotherapy during childhood (<15 years), adolescence and young adulthood (15-25 years). Studies were included if they reported live birth outcome and compared two or more of the following groups: chemotherapy alone, radiotherapy, chemoradiotherapy, control groups. Radiotherapy was defined as total body or pelvic irradiation. We excluded animal studies, as well as studies involving females treated after the age of 25, or studies with a median age at treatment exceeding 20 years. Additionally, studies including radical trachelectomy only for cervical cancer, anti-cancer treatment involving hysterectomy, or chemotherapy for gestational trophoblastic neoplasia were systematically excluded.

The primary outcome was the live-birth rate (defined by the number of deliveries that resulted in at least 1 live born baby divided by the total number of started pregnancies). The secondary outcomes included the rates of preterm birth, pregnancy loss, stillbirth, small weight for gestational age (SGA) fetus, obstetrical complications, and cesarean delivery.

Searches were performed in the Cochrane Library, Embase and PubMed from inception until April 30, 2023. The search strategy was limited to articles published in English or French. We used a combination of Medical Subject Headings terms and text words in 'cancer survivors', 'bone marrow transplantation', 'chemotherapy', 'radiotherapy', 'pregnancy outcome', 'pregnancy complications', 'preterm birth', 'pregnancy loss'. The full search strategy for each database is described in detail in the Appendix. Furthermore, relevant reviews identified through the search were screened to check for additional relevant cited articles.

### Selection process and data collection

Two independent reviewers (EF and SH), unaware of authors, institutions, journal titles, and study results, conducted an initial screening of the titles and abstracts of all articles. Full texts of potentially relevant articles were then retrieved and independently assessed for inclusion by two reviewers. The reasons for excluding ineligible studies were documented. Methodological validity was also assessed before inclusion in the review using the adapted Newcastle-Ottawa Quality Assessment Scale for cohort studies and case-control studies [8]. Any discrepancies or uncertainties were resolved through discussion among the reviewers to reach a consensus.

Pairs of reviewers extracted data from the included articles independently using a data extraction form designed by the authors. The following study details were collected for all included studies: country, study design, study type, inclusion and exclusion criteria, study period, cancer and treatment characteristics, age at main treatment, follow-up duration, age at examination, parity, comorbidity, outcomes.

### Risk of bias and assessment of study quality

The methodological quality of the selected studies was assessed by six independent reviewers (E.F., S.H., M.C., A.G., J.R. and C.R.J.) using the Cochrane Handbook methods and the adapted Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies [8]. Risks of bias were assessed using the ROBINS-I tool [9].

### Data analysis

All qualified studies with quantitative data on the primary outcome comparing 2 or more groups were included in the meta-analysis. The meta-analysis was performed only if 3 or more studies could be included. No replacement of missing data was done. Each outcome was analyzed independently.

The 'netmeta' version 2.8.2 of R-4.3.1 software was used to perform frequentist (a Graph Theoretical Model) network meta-analyses (NMA) (11). For each dichotomous outcome, a NMA was carried out to estimate risk ratios (RR) with their 95 % 2-sided confidence intervals (CI). Random effects models were fitted with the Restricted maximum likelihood (REML) method. Pooled effect sizes were deemed statistically significant at p < 0.05.

In a first step, the network structure was determined as the number of networks and whether a given network was fully connected. The network geometry was visualized using a network graph in order to show which therapies have been compared directly in the qualified articles and which can only be informed indirectly. Effect modifiers used for the assumption of transitivity were chronological age at time of evaluation, chronological age at treatment, percentage of women with comorbidity (tobacco and obesity), gestational diabetes and parity at time of evaluation.

Common heterogeneity was assumed to act as only few articles per direct comparison were expected. In addition to the estimation of between-study variance (τ²), the Q chi-square test was used to test the heterogeneity between the studies. The inconsistency in the network and in pairwise meta-analyses was quantified using I² statistics and interpreted following the Cochrane Collaboration guide. Inconsistency (i.e., the possible disagreement between different pieces of evidence) was assessed both globally (decomposition of Cochran's Q statistic) and locally (by comparing direct and indirect estimates). Additionally, to evaluate the global inconsistency in the random effects models, the between-design inconsistency Q statistic under the assumption of a full design-by-treatment interaction random effects model was calculated as the p value.

Then pairwise meta-analyses of all directly compared therapies was carried out so that the statistical heterogeneity of studies within each comparison can be evaluated.
The control group of females with a history of cancer treated without chemotherapy nor radiotherapy and the cancer-free control group were merged into a single control group, as none of them had exposure to chemotherapy or uterine radiotherapy. If the control group was unavailable for a particular outcome, chemotherapy alone was used as the reference. In studies with no recorded event in at least one group, a fixed value of 0.5 was added.

Subgroup analyses were planned in the protocol by study type, age at treatment and alkylating agents' exposure. Sensitivity analyses were conducted by excluding studies judged to be at serious or critical risk of bias and using the leave-one-out method.

Potential publication bias was assessed visually on funnel plots.

The quality of evidence for each outcome was judged using the Grading of Recommendations Assessment, Development and Evaluation working group methodology.

## Results

Our search strategy revealed 2847 reports, 158 reports were potentially eligible and retrieved in full text. Eight articles presented live-birth rates [6,10–16]. One study was added for secondary outcomes only, preterm delivery and pregnancy loss, small for gestational age [7]. All studies were published in English. The included studies appeared to be sufficiently similar with respect to the distribution of effect modifiers.

The main characteristics of the included studies are presented in Table 1.

### Risk of bias in the included studies

Most studies were classified as having a low to moderate risk of bias. Regarding participant selection bias, three studies had a moderate risk of bias because there was no accurate information about the patient selection process [12,16] or because multiple pregnancies were excluded [11]). For intervention classification, two studies had a moderate risk of bias because chemotherapy protocols were insufficiently detailed [6,13]. Only one study had a serious risk of bias because the treatment types (chemotherapy alone, radiotherapy alone, or chemoradiotherapy) were not detailed [16]. For missing data, two studies had moderate risk of bias because the results were not presented according to the parity [13] or the pregnancy was not the main objective; therefore, some of them could have been missing [10]. Finally, concerning the measurement of outcomes, three studies had moderate risk because they were based on self-administered questionnaires [13,14,16].

### Synthesis of results

#### Primary outcome

**LBR.** Eight studies were included in the meta-analysis for live-birth rates in pregnant women. In total, 3,997 females became pregnant, leading to 2,878 live births. Three studies compared live-birth rates between women who had chemotherapy versus a control group [11,12,16] two compared a chemoradiotherapy group versus a control group [11,16] and seven articles compared a chemoradiotherapy versus chemotherapy group [6,10,11,13–16].

The NMA was performed and showed moderate heterogeneity or inconsistency ($\tau^2 = 0.012$, $I^2 = 58\%$ [11%; 80%]) and did not show any significant impact of treatments on live-birth rate (chemotherapy versus control group: 0.96 [0.84; 1.11], chemoradiotherapy versus control group: 0.88 [0.75; 1.04], and chemotherapy versus chemoradiotherapy: 0.91 [0.78; 1.07]) (Fig. 1).

Sensitivity analyses led to the same conclusions.

### Secondary outcomes

**Preterm birth.** Six studies were included in the meta-analysis of preterm birth risk. A total of 1,976 pregnancies were started with 125 preterm births. Three studies compared preterm birth risks between women who had chemotherapy versus a control group [10,14,16], three articles compared a chemoradiotherapy group versus a control group [7,10,14] and six compared a chemoradiotherapy group versus a chemotherapy group [6,7,10,12–14].

The NMA was performed and showed low heterogeneity or inconsistency ($\tau^2 = 0.07$, $I^2 = 19\%$ [0%; 62%]).

Chemoradiotherapy was significantly associated with a higher risk of preterm birth compared to the control group (3.44 [1.94; 6.09]) and chemotherapy group (1.93 [1.19; 3.15]). Compared to the control group, pregnant women with only exposure to chemotherapy had a statistically higher risk of preterm birth than the control group (1.78 [1.01; 3.13]) (Fig. 2).

**Pregnancy loss.** Because few articles made this distinction, in our study, pregnancy loss included early pregnancy loss (spontaneous ending of pregnancy before 12 weeks of gestation) and late pregnancy loss (spontaneous ending of pregnancy between 12 and 19 weeks of gestation).

Eight studies were included in the meta-analysis of pregnancy loss. A total of 3653 pregnancies were started, with 606 pregnancy losses. Three studies compared pregnancy loss between women who had chemotherapy versus a control group [7,12,16], two articles compared a chemoradiotherapy group versus a control group [7,16], and seven compared a chemoradiotherapy group versus a chemotherapy group [6,7,10,13–16].

The NMA was performed and showed low heterogeneity or inconsistency ($\tau^2 = 0$, $I^2 = 0\%$ [0%; 65%]).

Chemoradiotherapy was associated with a significantly higher risk of pregnancy loss compared to the control group (1.80 [1.34; 2.43]) and chemotherapy group (1.68 [1.26; 2.25]). No statistical difference was shown in the risk of pregnancy loss between the chemotherapy and control groups (1.07 [0.87; 1.32]) (Figs. 3, 4).

**Stillbirth and small for gestational age (SGA).** There were no significant differences for these outcomes.

### Quality of evidence based on GRADE

Evidence was judged to be “low quality” for the primary outcome of live-birth rate. Regarding secondary outcomes, preterm birth, pregnancy loss, and SGA, the evidence was judged to be “low quality.” Concerning the secondary outcome of stillbirth, the quality of the evidence was downgraded because there were very few studies included in the meta-analysis and was judged to be “very low quality.”

## Discussion

Spontaneous fertility is strongly decreased after pelvic or total body irradiation and after high doses of gonadotoxic chemotherapy [17,18]. However, in this study, despite a history of CAYA chemotherapy or chemoradiotherapy exposure, a woman starting a pregnancy had the same chance of giving birth as a control woman. The major adverse outcome was the risk of prematurity.

Indeed, this meta-analysis did not find any significant difference in live-birth rates between the chemotherapy, chemoradiotherapy, and control groups. It should be emphasized that only women who had started a pregnancy were included in this study, therefore our results could underestimate the true impact of chemotherapy and chemoradiotherapy on reproductive outcomes. Infertile cancer survivors who did not become pregnant probably would have had the poorest
<table><caption>**Table 1**
Main characteristics of studies included in the systematic review and network meta-analysis.</caption><thead><tr><th>First author, year</th><th>Country</th><th>Type of study</th><th>Study design</th><th>Study population<br>Inclusion/ exclusion criteria</th><th>Study control<br>Inclusion/ Exclusion criteria</th><th>Recruitment period<br>Treatment/<br>Assessment</th></tr></thead><tbody><tr><td>Sanders, 1996</td><td>USA</td><td>Non<br>matched<br>exposed/<br>non exposed</td><td>Prospective</td><td><strong>Inclusion criteria:</strong> pregnant survivors free following bone marrow transplant for non-malignant or malignant hematological disease.<br>Consecutive female &gt;12 years old.<br><strong>Exclusion criteria:</strong> N/A</td><td>N/A</td><td><strong>Treatment:</strong> August 1971-January 1992</td></tr><tr><td>Chiarelli, 2000</td><td>USA</td><td>Cohort study</td><td>Retrospective</td><td><strong>Inclusion criteria:</strong> females diagnosed with any histologically confirmed malignancy before age 20; resident of Ontario at time of diagnosis; survived at least 5 years after diagnosis; at least 18 years of age at start date; and still alive.<br><strong>Exclusion criteria:</strong> women who had sterilizing surgery, had a second primary cancer before starting menstruation, never had a menstrual period, became menopausal before or during treatment, or were of unknown menopausal status at the end of treatment.</td><td>N/A</td><td><strong>Treatment:</strong><br>1964-1988<br><strong>Assessment:</strong><br>November 1993-December1994</td></tr><tr><td>Green, 2002</td><td>USA</td><td>Matched<br>exposed/<br>non-exposed</td><td>Retrospective</td><td><strong>Inclusion criteria:</strong> females &lt; 21 years old diagnosed with cancer.<br><strong>Exclusion criteria:</strong> N/A</td><td>N/A</td><td><strong>Treatment:</strong> January 1970-December 1986<br><strong>Assessment:</strong><br>Questionnaire February 2000</td></tr><tr><td>Larsen, 2004</td><td>Denmark</td><td>Cohort study</td><td>Prospective</td><td><strong>Inclusion criteria:</strong> female survivors diagnosed and treated for a noncentral nervous system childhood cancer (malignant hematological disease, solid tumor); &le; 15 years old at the time of diagnosis, treated with radiotherapy and/or chemotherapy; off treatment for at least 1 year at study inclusion; in complete remission, &ge; 18 years old at study inclusion.<br><strong>Exclusion criteria:</strong> lost to follow up, previous hysterectomy, institutionalized mental disorders</td><td>N/A</td><td><strong>Treatment:</strong> January 1970-December 1996</td></tr><tr><td>Sudour 2010</td><td>France</td><td>Non<br>matched<br>exposed/<br>non exposed</td><td>Retrospective</td><td><strong>Inclusion criteria:</strong> alive women treated with radiotherapy for cancer (lymphoma, solid tumor); &lt; 18 years old, no surgery, no cranial irradiation.<br><strong>Exclusion criteria:</strong> N/A</td><td>N/A</td><td><strong>Treatment:</strong> between January 1975-December 2004</td></tr><tr><td>van de Loo,<br>2019*Secondary<br>outcomes only</td><td>The<br>Netherlands</td><td>Cohort study</td><td>Retrospective</td><td><strong>Inclusion criteria:</strong> adult women treated for a cancer before the age of 18 years who survived for at least five years after diagnosis and were at least 18 years old at study entry with two inclusion criteria:<br>— they had a transvaginal ultrasound scan performed and a blood sample taken<br>— their former childhood cancer treatment included external beam RT to a field that certainly (total body irradiation and pelvic RT) or most likely (low-abdominal and lower spinal RT) involved part of the uterus<br><strong>Exclusion criteria:</strong><br>— Childhood cancer survivors without a uterus or with uterine fibroids<br>— Childhood cancer survivors without ultrasonographic data not stored</td><td>N/A</td><td><strong>Treatment:</strong> 1963 and 2002<br><strong>Assessment:</strong> January 2008-July 2014</td></tr><tr><td>van Djik, 2020</td><td>The<br>Netherlands</td><td>Cohort study</td><td>Retrospective</td><td><strong>Inclusion criteria:</strong> adult women, treated for cancer &lt; 18 years old who survived for at least five years after diagnosis.<br><strong>Exclusion criteria:</strong> virgins and women who never tried to become pregnant.</td><td>Sisters from participating women; never been diagnosed with cancer</td><td><strong>Treatment:</strong> 1963-2002</td></tr><tr><td>Chabut, 2023</td><td>France</td><td>Cohort study</td><td>Retrospective</td><td><strong>Inclusion criteria:</strong> women treated for acute leukemia after 1980 in one of the participating LEA cohort centers; &lt; 18</td><td>N/A</td><td>2004-2020</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>First author, year</th><th>Country</th><th>Type of study</th><th>Study design</th><th>Study population<br>Inclusion/ exclusion criteria</th><th>Study control<br>Inclusion/ Exclusion criteria</th><th>Recrutment period<br>Treatment/ Assessment</th></tr></thead><tbody><tr><td>Courbiere, 2023</td><td>France</td><td>Cohort study</td><td>Prospective</td><td>years old at diagnosis.<br><i>Exclusion criteria:</i> &gt; 2 HSCT.<br><i>Inclusion criteria:</i> Women &gt; 18 years old participating in the LEA cohort; those who underwent HSCT during childhood or adolescence for acute leukemia and after an MAC regimen including either TBI or an alkylating agent-based regimen; who agreed with undergoing pelvic magnetic resonance imaging (MRI) to assess their uterine volume.<br><i>Exclusion criteria:</i> N/A</td><td><i>Inclusion criteria:</i> omen enrolled in the radiology department of the principal investigator for pelvic MRI during the study period, aged between 18 and 40 years, without any uterine pathology who underwent pelvic MRI during the study period.<br><i>Exclusion criteria:</i> controls were excluded in case of uterine pathology, such as adenomyosis or fibroids</td><td>November 2017-June 2021</td></tr></tbody></table>

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** *Live birth rate:* Forest plot of direct, indirect and network meta-analysis comparing Chemotherapy versus Control Group and Radiotherapy + Chemotherapy versus Control Group using a random effect model. No statistical differences were observed.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** *Preterm birth:* Forest plot of direct, indirect and network meta-analysis comparing Chemotherapy versus Control Group and Radiotherapy + Chemotherapy versus Control Group using a random effect model. Chemotherapy and Radiotherapy + Chemotherapy were significantly associated with a higher risk of preterm birth compared to the Control Group.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Global pregnancy loss: Forest plot of direct, indirect and network meta-analysis comparing Chemotherapy versus Control Group and Radiotherapy + Chemotherapy versus Control Group using a random effect model. Radiotherapy + Chemotherapy was significantly associated with a higher risk of global pregnancy loss compared to the Control Group.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Global pregnancy loss: Forest plot of direct, indirect and network meta-analysis comparing Control Group versus Chemotherapy and Radiotherapy + Chemotherapy versus Chemotherapy using a random effect model. Radiotherapy + Chemotherapy was significantly associated with a higher risk of global pregnancy loss compared to Chemotherapy.</figcaption></figure>

obstetrical prognosis, with a strongly damaged uterus and no possibility of implantation. Therefore, the impact of chemotherapy and chemo-radiotherapy on the live-birth rate was probably underestimated. Regarding secondary outcomes, preterm birth was significantly increased in the chemo- and chemoradiotherapy-exposed women and pregnancy loss was significantly increased only in the chemo-radiotherapy group. Even though the results were not significant, the risk of having a stillbirth or an SGA baby increased after chemo or chemoradiotherapy compared to the control group. Regarding these results, obstetricians may consider the risk for prematurity when there is a history of CAYA chemotherapy.

The last systematic review with Gerstl et al.'s meta-analysis on reproductive outcomes after a CAYA cancer diagnosis dates back to 2018 and included all types of studies (population-based studies, cohort studies, retrospective review studies, and survey studies), while our meta-analysis included only comparative studies [1]. Gerstl et al. reported a lower live-birth rate in CAYA cancer survivors; however, they did not have comparative groups and the heterogeneity was high, making the results difficult to interpret. Nevertheless, in the subgroup

studying live births in three matched studies, they observed a significantly decreased live-birth rate following chemotherapy alone (0.18, 95% CI: 0.16–0,18) [1]. Moreover, since then, three high-interest studies raising the potential impact of high doses of chemotherapy alone on the uterus have been published [5–7]. Most studies have focused on the impact of radiotherapy on obstetric outcomes and did not look at the impact of chemotherapy. Although the differences were not statistically significant, Van de loo *et al.* observed an increased risk of obstetrical complications, miscarriages, preterm births, and SGA in the chemo-therapy group compared to the control group [7]. In a cohort of HSCT childhood survivors, Courbiere et al. reported a live-birth rate of 11% in women exposed during childhood to TBI and 60% in women exposed during childhood to high doses of alkylating agents [6]. These live-birth rates were much lower than in the general population. Furthermore, a recent publication of Sunguc et al. found a decreased live-birth rate in a nationwide cohort of female survivors of adolescent and young adult cancer. They also found a risk of prematurity in some specific types of cancer like cervical cancer. Nevertheless, they did not have a control group and did not differentiate the treatment received by patients, e.g.
chemotherapy, radiotherapy or chemoradiotherapy [19]. This study is,
therefore, in line with the recent literature that hypothesizes a long-term
impact of high-dose chemotherapy on the uterus and obstetrical
outcomes.

The major strength of this study was its rigorous methodology, with a
strict selection of included studies. Heterogeneity was low, and the risk
of assessment bias was based on the Cochrane RoB tool. Pairwise com-
parisons were coherent with the NMA, providing strength and confi-
dence to the results. A sensitive analysis was performed for all outcomes.
Regarding our primary outcome, live-birth rate, the number of included
studies for meta-analysis was enough to draw a robust conclusion. The
studied population was homogeneous in age because we chose to select
studies that focused only on adolescents and young adults. There was
probably a majority of nulliparous patients. Finally, all the results were
consistent with the clinical observations.

On the other hand, some limitations must be underlined. First, the
search in the Cochrane Library, Embase, and PubMed was not exhaus-
tive on the secondary outcomes, such as pregnancy loss, SGA, and
obstetrical complications, because the study selection for the systematic
review was focused on live-birth rate. This meta-analysis did not include
randomized controlled trials, and the quality of the evidence was judged
to be low for the primary outcome, preterm birth, pregnancy loss, SGA
and very low for stillbirth. Therefore, results need to be interpreted with
caution. Then, in the studies included in this systematic review, infor-
mation on the onset of chemotherapy, before or after puberty, was not
always described. However, regarding the physiopathological aspects,
the prepubertal uterus is more sensitive to radiotherapy, with a dramatic
decreased uterine volume after pelvic radiotherapy or TBI [20]. It could
be the same for the impact of chemotherapy. Concerning pregnancy loss,
we could not differentiate between early and late pregnancy loss
because the data were unavailable in most studies. Differentiating be-
tween these two outcomes would be interesting because the etiologies of
pregnancy losses are probably not the same; especially since etiologies
were also lacking. The same goes for finding the accurate delivery term,
and the definition for SGA which were heterogeneous, depending on the
authors. Besides, a recent publication by Feng et al. demonstrated a
significant lack and variability of pregnancy and obstetrics outcomes
definitions in scientific literature [21]. Moreover, data regarding the
reason for prematurity were also lacking. Indeed, we could not deter-
mine if the prematurity was “spontaneous” after premature labor or if
prematurity was secondary to obstetrical reasons, e.g., SGA or prema-
ture rupture of membranes. Finally, adjustment on other important
confounding variables, such as the type of initial pathology, parity, or
history of hormonal replacement therapy (HRT), could not be performed
because of a lack of data. Subgroup analysis on the type of chemotherapy
(with potential differential impact of different molecules) and on cu-
mulative doses was not possible either.

To conclude, results of this meta-analysis confirmed concerns about
the impact of CAYA chemotherapy and chemoradiotherapy exposure on
pregnancy outcomes, with a higher risk of prematurity. Regarding
physiopathology, the negative impact of chemotherapy on endometrial
epithelium receptivity and on the myometrium itself with a decreased
myometrial mass have only been studied in mice [22-24]. The impact on
uterine vasculature has not been investigated; however, there is good
evidence in other tissues suggesting that it could also damage vessels
[25]. Therefore, the following physiopathology must be further inves-
tigated: Is specific damage of high doses of chemotherapy or indirect
consequences of a hypoestrogenic state on the uterus anatomy due to
post-chemotherapy ovarian endocrine dysfunction? Until we have more
accurate data in this population, obstetricians must consider that a
history of CAYA chemotherapy is a risk factor for prematurity and must
set up appropriate monitoring and prevention measures for pregnant
women who are CAYA cancer survivors.

CRediT authorship contribution statement

**E. Fraison**: Writing – original draft, Investigation, Formal analysis, Data curation, Conceptualization. **S. Huberlant**: Validation, Formal analysis, Data curation, Conceptualization. **M. Cavalieri**: Validation, Formal analysis, Data curation. **A. Gueniffey**: Validation, Formal analysis, Data curation. **J. Riss**: Validation, Formal analysis, Data curation. **C. Rousset-Jablonski**: Writing – review & editing, Validation, Supervision, Formal analysis, Data curation. **B. Courbiere**: Writing – review & editing, Writing – original draft, Supervision, Conceptualization.

Funding

This research was sponsored by an unrestricted grant from GEDEON
RICHTER France. The funder had no role in the design or conduct of the
study; collection, management, analysis, or interpretation of the data;
preparation, review, or approval of the manuscript; or the decision to
submit the manuscript for publication.

Declaration of competing interest

The authors declare the following financial interests/personal re-
lationships which may be considered as potential competing interests:
FRAISON Eloise reports financial support was provided by Gedeon
Richter France. If there are other authors, they declare that they have no
known competing financial interests or personal relationships that could
have appeared to influence the work reported in this paper.

Acknowledgments

The authors would like to thank Mathilde Chabut and Alina Zgardau
for providing additional data about their initial publications: "Ovarian
Function and Spontaneous Pregnancy After Hematopoietic Stem Cell
Transplantation for Leukemia Before Puberty: An L.E.A. Cohort Study"
and "Obstetrical and Perinatal Outcomes in Female Survivors of Child-
hood and Adolescent Cancer: A Population-Based Cohort Study,"
respectively.

The authors also thank Solène Languille (Monitoring Force Group, Maison-Laffitte), who developed the search strategy, and Dr Bernadette Darné (Monitoring Force Group, Maison-Laffitte), who provided statistical expertise.

Registration

This systematic review and meta-analysis were registered in the In-
ternational Prospective Register of Systematic Reviews (PROSPERO
CRD42023440219) on July 10, 2023.

**Appendix A. Supplementary data**

Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ejogrb.2025.114665.

Data availability

The data underlying this article will be shared on reasonable request
to the corresponding author.

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