6-year Outcomes in Children After Nifedipine vs Placebo for Preterm Prelabor Rupture of Membranes at 22-33 Weeks

Official title

6-year Follow-up of Children Born to Mothers Exposed to Nifedipine vs Placebo After Preterm Prelabor Rupture of Membranes at 22 to 33 Weeks of Gestation

Overview

The purpose of this study is to evaluate the neurodevelopment at age 6 of children born to women with preterm prelabor rupture of membranes at 22 to 33 weeks of gestation, after antenatal exposure to nifedipine vs placebo.

Detailed description

Preterm prelabor rupture of membranes (PPROM) complicates 3% of pregnancies and accounts for one-third of preterm births. It is a leading cause of neonatal mortality and morbidity and increases the risk of maternal infectious morbidity. In cases of early PPROM (22 to 33 completed weeks' gestation), expectant management is recommended in the absence of labor, chorioamnionitis or fetal distress. Antenatal steroids and antibiotics administration are recommended by international guidelines. However, there is no recommendation regarding tocolysis administration in the setting of PPROM. In theory, reducing uterine contractility should delay delivery and reduce the risks of prematurity and neonatal adverse consequences. Likewise, a prolongation of gestation may allow administering a corticosteroids complete course that is associated with a two-fold reduction of morbidity and mortality. However, tocolysis may prolong fetal exposure to inflammation and be associated with higher risk of materno-fetal infection, potentially associated with neonatal death or long-term sequelae, including cerebral palsy.

The investigators implemented the TOCOPROM randomized clinical trial to assess whether short-term (48 hr) tocolysis reduces perinatal morti-morbidity in cases of PPROM at 22-33 weeks. However, both short- and long-term outcomes should be taken into account to define the optimal treatment strategy. There are currently no data allowing to evaluate the impact of a short course of nifedipine versus placebo on neurodevelopmental outcomes in school-aged children born after PPROM. Therefore, following-up children born to mothers enrolled in the TOCOPROM trial, through a new study, the TOCOKIDS cohort, is a unique and timely opportunity to advance scientific knowledge and adapt clinical practices in France and worldwide.

The assessment at 6 years of age will consist in:

* A self-administered parental questionnaire, completed online or on paper * Data collected from the health book, in particular the 6-year consultation * A short psychological assessment (45 minutes), performed remotely by a psychologist through video conference.

Interventions

• Other Self-administered parental questionnaire
  A self-administered parental questionnaire, completed online or on paper, to assess different dimension of neurodevelopment
• Other A short psychological assessment performed online
  NEMI-3: an intelligence test administered by a psychologist measuring a fluid and crystallised intelligence. The test consists of 117 spoken and visual questions, for a total administration time of 45 min. Results are expressed in the form of standard indices (mean 100, standard deviation 15) that facilitate comparisons with the results obtained on other intelligence scales. Results will be classified as normal, mild delay (between 1 and \<2 standard deviation \[SD\] below the mean) or severe d

Primary outcome measures

• Cerebral palsy at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Developmental Coordination Disorder at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Language at 6 years of age [Time frame: Up to 6 months after inclusion.]
• Behavior at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Executive functions at 6 years of age. [Time frame: Up to 6 months after inclusion.]

Secondary outcome measures (12)

• Vital status at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Neurodevelopmental impairment. [Time frame: Up to 6 months after inclusion.]
• Survival without any neurodevelopmental impairment at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Survival without moderate-to-severe neurodevelopmental impairment at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Growth at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Growth at 6 years of age [Time frame: Up to 6 months after inclusion]
• Health at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Health at 6 years of age [Time frame: Up to 6 months after inclusion]
• Health at 6 years of age [Time frame: Up to 6 months after inclusion]
• Vision at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Hearing at 6 years of age. [Time frame: Up to 6 months after inclusion.]
• Development at 6 years of age. [Time frame: Up to 6 months after inclusion.]

Eligibility criteria

Inclusion criteria

• All children born to mothers enrolled in the TOCOPROM trial who consented to participate in the 2-year follow-up and who agreed to be contacted for the 6-year follow-up
• Alive at 6 years
• Internet access, including access to a good-quality video-conference system (only for the psychological evaluation)
• Non opposition of the holders of the exercise of parental authority

Exclusion criteria

• Major malformations and/or chromosomal aberrations evidenced after birth
• Impossibility to contact the family
• Opposition to participate in the follow-up

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

France · 1 center

• Trousseau University Hospital — Paris

Publications

• Houtzager BA, Hogendoorn SM, Papatsonis DN, Samsom JF, van Geijn HP, Bleker OP, van Wassenaer AG. Long-term follow up of children exposed in utero to nifedipine or ritodrine for the management of preterm labour. BJOG. 2006 Mar;113(3):324-31. doi: 10.1111/j.1471-0528.2006.00851.x. PMID 16487205
• 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(3):340-5. doi: 10.1080/00016340801913189. PMID 18307075
• van Vliet E, Seinen L, Roos C, Schuit E, Scheepers H, Bloemenkamp K, Duvekot JJ, van Eyck J, Kok JH, Lotgering FK, van Baar A, van Wassenaer-Leemhuis AG, Franssen MT, Porath MM, van der Post J, Franx A, Mol B, Oudijk MA. Maintenance tocolysis with nifedipine in threatened preterm labour: 2-year follow up of the offspring in the APOSTEL II trial. BJOG. 2016 Jun;123(7):1107-14. doi: 10.1111/1471-052 PMID 26330379
• van Winden T, Klumper J, Kleinrouweler CE, Tichelaar MA, Naaktgeboren CA, Nijman TA, van Baar AL, van Wassenaer-Leemhuis AG, Roseboom TJ, Van't Hooft J, Roos C, Mol BW, Pajkrt E, Oudijk MA. Effects of tocolysis with nifedipine or atosiban on child outcome: follow-up of the APOSTEL III trial. BJOG. 2020 Aug;127(9):1129-1137. doi: 10.1111/1471-0528.16186. Epub 2020 Mar 29. PMID 32124520
• Wilson A, Hodgetts-Morton VA, Marson EJ, Markland AD, Larkai E, Papadopoulou A, Coomarasamy A, Tobias A, Chou D, Oladapo OT, Price MJ, Morris K, Gallos ID. Tocolytics for delaying preterm birth: a network meta-analysis (0924). Cochrane Database Syst Rev. 2022 Aug 10;8(8):CD014978. doi: 10.1002/14651858.CD014978.pub2. PMID 35947046
• Lorthe E, Kayem G; TOCOPROM Study Group and the GROG (Groupe de Recherche en Obstetrique et Gynecologie). Tocolysis in the management of preterm prelabor 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 Sep 8;21(1):614. doi: 10.1186/s12884-021-04 PMID 34496799

Identifiers

NCT: NCT07146451 · APHP230846

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗