A Study of Outcomes and Events of Interest in Pregnant Women, Neonates and Infants and of RSV Surveillance

Study Overview
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Brief Summary
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The purpose of this study is to assess pregnancy outcomes, and maternal, as well as neonatal events of interest in healthy pregnant women and their new-borns. The study will also determine incidence of lower respiratory tract illness (LRTI) caused by respiratory syncytial virus (RSV) in the new-borns during their first year of life.

Official Title
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A Prospective Epidemiological Study of Pregnancy Outcomes and of Events of Interest in Pregnant Women, Neonates and Infants (PEPNI)

Conditions
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Respiratory Syncytial Virus Infections

Intervention / Treatment
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* Procedure: Blood sample collection
* Procedure: Cord blood sample collection
* Other: Maternal Diary Card
* Procedure: Nasal Swab collection
* Other: Infant Diary Card


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy pregnant women 18-45years of age who are ≥ 24 0/7 weeks GA at screening and ≤ 27 6/7 weeks GA at Visit 1, as established by ultrasound examination and/or last menstrual period (LMP) date Women with pre-pregnancy body mass index (BMI) ≥18.5 and ≤ 39.9 kg/m2. Women whose pregnancy is considered low risk, based on medical history, obstetric history, and clinical findings during the current pregnancy Women who had no significant findings (such as abnormal fetal morphology, amniotic fluid levels, placenta, or umbilical cord) observed during a Level 2 ultrasound (fetal morphology assessment). Human Immunodeficiency Virus (HIV) uninfected women who have been tested within the past year and have documented HIV negative test results. Individuals who give written or witnessed/thumb printed informed consent after the study has been explained according to local regulatory requirements. The informed consent given at screening should either include consent for both the mother's participation and participation of the infant after the infant's birth (if consistent with local regulations/guidelines), or consent for the mother's participation and expressed willingness to consider permitting the infant to take part after the infant has been born (if local regulations/guidelines require parent(s) to provide an additional informed consent after the infant's birth). Both mother and father should consent if local regulations/guidelines require it. Individuals who consent to have cord blood collected at delivery for the purpose of the study; Individuals who plan to reside in the study area for at least one year after delivery. Individuals who are in good health as determined by the outcome of medical history, physical examination and clinical judgment of the investigator; Individuals who, in the opinion of the investigator can and will comprehend and comply with all study procedures Infants who were in utero at the time maternal (and paternal, if required) informed consent was given, and who are live-born. If local law requires it: Written or witnessed/thumb printed informed consent for study participation of the infant obtained from parent(s)/Legally Accepted Representative [LAR(s)] within 21 days of birth. Exclusion Criteria: Individuals determined to have one of the following conditions associated with increased risk for a serious obstetrical complication Gestational hypertension; Gestational diabetes uncontrolled by diet and exercise; Pre-eclampsia or eclampsia; Multiple pregnancy; Intrauterine growth restriction; Placenta previa; Polyhydramnios; Oligohydramnios; Individuals determined to have (during the current pregnancy) one of the following infections or conditions associated with risk of adverse outcome: Known or suspected: Syphilis infection, Parvovirus B19, Rubella infection, primary herpes simplex infection, primary cytomegalovirus infection, varicella infection, Zika infection, Active tuberculosis infection, Incompetent cervix or cerclage Individuals who have any underlying condition or infection that would predispose them to increased risk for a serious obstetrical complication that is not mentioned above Individuals who have behavioural or cognitive impairment or psychiatric disease that, in the opinion of the investigator, could interfere with the subject's ability to participate in the study; Individuals who have known or suspected impairment of the immune system, an active autoimmune disorder that is not well-controlled, or who are receiving systemic immunosuppressive therapy; Individuals participating in any concurrent clinical trial during the current pregnancy; Individuals pregnant with a fetus with a confirmed or suspected major congenital anomaly at the time of enrolment. Child in care

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Single Group Assignment is selected because this is a low-interventional, epidemiological study. As such, the study does not have multiple groups/treatment arms that will be compared against one another statistically in the way two study arms would be compared against each other in a clinical trial. Instead, the study will longitudinally follow pregnant women through a 42-day post-delivery period and will also follow the infants born to these women. It should be noted that these are the two populations listed in the protocol, but these are not two groups that will compared against one another. Statistical analyses will be conducted within each group and some analyses will be done across the two groups. However, these two groups should not be considered equivalent to two study arms. This explains why a single group assignment is appropriate while two study groups (mothers and infants) will be examined.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Pregnant Women/Mothers Group<br>Subjects, 18 to 45 years of age enrolled in the study in view of determining pregnancy outcomes and related events of interest, as well as the occurrence of lower respiratory tract illness (LRTI) associated with respiratory syncytial virus (RSV). | Procedure: Blood sample collection<br>* Venous blood samples will be collected from the maternal subjects at Day 1 and Day 56 of the study and at delivery.<br>Procedure: Cord blood sample collection<br>* Collection of cord blood samples from maternal subjects will occur, at delivery<br>Other: Maternal Diary Card<br>* Completion of Diary Card about health by pregnant woman/ mother, from enrolment through week 6 post delivery.<br>|
| Other: Neonates/Infants Group<br>Infants born to mothers aged 18-45 years old, enrolled for the collection of infant events of interest, nasal swabs and the incidence of RSV LRTI and RSV hospitalization. | Procedure: Nasal Swab collection<br>* Collection of nasal swabs from infants with potential LRTIs, from birth to 12 months of age.<br>Other: Infant Diary Card<br>* Completion of Diary Card about health of infant from birth to 12 months of age.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Maternal Subjects With Pregnancy Outcomes | Pregnancy outcomes included: live birth with no congenital anomalies, live birth with congenital anomalies, fetal death/stillbirth loss at or after 22 weeks of gestation (antepartum stillbirth, Intrapartum stillbirth) with no congenital anomalies, fetal death/still birth loss at or after 22 weeks of gestation (antepartum stillbirth, Intrapartum stillbirth) with congenital anomalies, elective/therapeutic termination with no congenital anomalies, elective/therapeutic termination with congenital anomalies. | From Day 1 up to Day 42 post delivery | 
| Number of Maternal Subjects With Pregnancy Related Events of Interest | Pregnancy related events of interest included: maternal death, hypertensive disorders of pregnancy including gestational hypertension, pre-eclampsia and pre-eclampsia with severe features (including eclampsia), antenatal bleeding (morbidly adherent placenta, placental abruption, Caesarean scar pregnancy, uterine rupture), postpartum haemorrhage, fetal growth restriction, dysfunctional labor (first stage of labor, second stage of labor), gestational diabetes mellitus, non-reassuring fetal status, pathways to preterm birth including premature preterm rupture of membranes, preterm labour, and provider initiated preterm birth, chorioamnionitis, oligohydramnios, polyhydramnios, gestational liver disease (intrahepatic cholestasis of pregnancy [ICP], acute fatty liver of pregnancy), and maternal sepsis. | From Day 1 up to Day 42 post-delivery | 
| Number of Infant Subjects With Neonatal Events of Interest | Neonatal events of interest included: small for gestational age, low birth weight including very low birth weight, neonatal encephalopathy, congenital microcephaly (postnatally diagnosed, prenatally diagnosed), congenital anomalies [CA] (major external structural defects, internal structural defects, functional defects), neonatal death (neonatal death in a preterm live birth [gestational age greater than or equal to (≥) 28 to less than (<) 37 weeks], neonatal death in a term live birth), neonatal infections, (blood stream infections, meningitis, respiratory infection), respiratory distress in the neonate, preterm birth, failure to thrive, large for gestational age, macrosomia, any other neonatal event considered by the investigator to be of concern (e.g. neurodevelopmental delay). | From birth up to Day 28 post-birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Maternal Subjects With Pregnancy Related Events of Interest for Each Global Alignment of Immunization Safety Assessment (GAIA) Level of Diagnostic Certainty | Pregnancy related events of interest by GAIA level (Lv.) of diagnostic certainty (where applicable/feasible) range from Level 1 to Level 2 or 3 (Highest level of diagnostic certainty (1) to lowest level of diagnostic certainty (2 or 3)): maternal death, hypertensive disorders of pregnancy including gestational hypertension, pre-eclampsia and Pre-eclampsia with severe features (including eclampsia), antenatal bleeding (morbidly adherent placenta, placental abruption, Cesarean scar pregnancy, uterine rupture), postpartum haemorrhage, fetal growth restriction, dysfunctional labor, (first stage of labor, second stage of labor), gestational diabetes mellitus, non-reassuring fetal status, pathways to preterm birth including premature preterm rupture of membranes, preterm labour, and provider initiated preterm birth. | From Day 1 up to Day 42 post-delivery | 
| Number of Infant Subjects With Neonatal Events of Interest for Each GAIA Level of Diagnostic Certainty | Neonatal events of interest by GAIA level (Lv.) of diagnostic certainty, range from Level 1 to Level 4 or 5 (Highest level of diagnostic certainty (1) to lowest level of diagnostic certainty (4 or 5 based on the neonatal events)): small for gestational age, low birth weight including very low birth weight, neonatal encephalopathy, congenital microcephaly (postnatally diagnosed, prenatally diagnosed), congenital anomalies [CA] (major external structural defects, internal structural defects, functional defects), neonatal death (neonatal death in a preterm live birth [gestational age ≥ 28 to <37 weeks], neonatal death in a term live birth), neonatal infections (blood stream infections, meningitis, respiratory infection, respiratory distress in the neonate, preterm birth, failure to thrive, large for gestational age, macrosomia, any other neonatal event considered by the investigator to be of concern (e.g. neurodevelopmental delay). | From birth through Day 28 of life | 
| Respiratory Syncytial Virus Type A (RSV-A) Neutralizing Antibody Titers in Maternal Blood | Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were expressed Geometric Mean Titers (GMT) with 95% Confidence Interval (CI) in Estimated Dilution 60 (ED60) and were measured on blood samples collected from vaccinated maternal subjects. | At delivery | 
| RSV-A Neutralizing Antibodies Titers in Cord Blood | Serological assays for the determination of antibodies against RSV-A were performed by neutralization assay. The corresponding antibody titers were presented as GMTs, expressed in ED60. The antibodies were measured on the cord blood sample collected at delivery. | At delivery | 
| Incidence Rates of RSV Lower Respiratory Tract Infection (LRTI) or Severe LRTI or Very Severe LRTI for Infant Subjects as Defined by the LRTI Case Definition | The incidence rate was calculated by dividing the number of infant subjects reporting first episodes over the follow-up period, to the total person-years. LRTI Case definition by WHO (Modjarrad, 2016): LRTI is diagnosed when infant has history of cough OR difficulty in breathing AND SpO2 < 95%, OR RR increase AND Confirmed RSV infection. Severe LRTI is diagnosed when an infant with RSV LRTI has oxygen saturation <93% or lower chest wall drawing. Very severe LRTI is diagnosed when an infant with RSV LRTI has oxygen saturation <90%, OR inability to feed OR failure to respond / unconscious. | From birth up to 1 year of age | 
| Incidence Rates of Infant Subjects With RSV Hospitalizations | The incidence rate was calculated by dividing the number of subjects reporting first episodes over the follow-up period to the total person-years. RSV hospitalizations definition by WHO (Modjarrad, 2015): Infant has confirmed RSV infection AND hospitalized for acute medical condition. | From birth up to 1 year of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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third trimester, Respiratory Syncytial Virus (RSV) illness, Pregnancy, Maternal Immunization, Pregnant Women, Neonates, Respiratory Tract Illness