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| Name | Class |
|---|---|
| URC-CIC Paris Descartes Necker Cochin | OTHER |
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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.
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nifedipine | Exposure during pregnancy to Oral Nifedipine 20 mg LP (between 22 to 33 weeks of gestation): Loading dose at T0 and T0.5 (i.e. 30 min), total=2x20 mg Maintenance dose: Oral Nifedipine 20 mg LP at T3, then 1 pill every 8 hours for 48 hours (i.e. T11, T19, T27, T35 and T43, total=6x20 mg) |
| |
| Placebo | Exposure during pregnancy to oral placebo of nifedipine (between 22 to 33 weeks of gestation) at T0, T0.5, T3, T11, T19, T27, T35 and T43 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Self-administered parental questionnaire | Other | A self-administered parental questionnaire, completed online or on paper, to assess different dimension of neurodevelopment |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cerebral palsy at 6 years of age. | Cerebral palsy assessed using the Gross Motor Function Classification System (GMFCS), a five-level classification based on the child's current gross motor abilities, limitations in gross motor function, and need for assistive technology and wheeled mobility. Severe/moderate cerebral palsy (GMFCS≥2). Mild cerebral palsy (GMFCS-1). | Up to 6 months after inclusion. |
| Developmental Coordination Disorder at 6 years of age. | Measured using the Developmental Coordination Disorder Questionnaire - European French (DCDQ-FE), a brief parent questionnaire (15 items) designed to screen for gross and fine motor skills and coordination disorders in children, aged 5 to 15 years. Total score=15-56: indication of a risk of DCD or suspected of a risk of DCD. Total score=57-75: probably no DCD. | Up to 6 months after inclusion. |
| Language at 6 years of age | Language assessed using the verbal communication subscale (4 items) of the 5-15R scale, covering comprehension, expressive language skills and verbal communication, with an extra question on the impact of language and communication difficulties on daily activities. Mean (SD). Reference to cut-off scores in relation to the 90 and 98 percentiles (%). | Up to 6 months after inclusion. |
| Behavior at 6 years of age. | Behavior assessed using the Strengths and Difficulties Questionnaire (SDQ), a brief behavioral screening questionnaire (25 items), designed to screen for symptoms of hyperactivity inattention, emotional, conduct, and peer problems among 2-17 year olds. Mean (SD). Abnormal: >90th percentile. Mildly abnormal: 80-90 percentile. | Up to 6 months after inclusion. |
| Executive functions at 6 years of age. | Executive functions measured using the Childhood Executive Functioning Inventory (CHEXI), a rating instrument (24 items) for parents that was developed for measuring executive functioning in children age 4-12. It includes four different subscales tapping working memory, planning, regulation and inhibition, combined into two global scales: working memory (working memory and planning subscales) and inhibition (inhibition and regulation subscales). Normative data are not yet available. Abnormality will be defined considering a cut-off or deviation compared to the mean score, depending on the literature. |
| Measure | Description | Time Frame |
|---|---|---|
| Vital status at 6 years of age. | Whether the child is alive or not at years of age. | Up to 6 months after inclusion. |
| Neurodevelopmental impairment. | Moderate-to-severe impairment (severe/moderate cerebral palsy, and/or abnormal SDQ score, and/or NEMI-3 ≥2 SD below the mean, and/or blindness, and/or deafness), mild impairment (mildly abnormal scores or mild impairment) vs no neurodevelopmental impairment. |
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Inclusion Criteria:
Exclusion Criteria:
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Children born to women enrolled in the TOCOPROM trial reaching the age of 6 years
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Gilles KAYEM, MD,PhD | Contact | 01 44 73 51 18 | +33 | gilles.kayem@aphp.fr |
| Nelly Briand, PhD | Contact | 01 44 38 18 62 | +33 | nelly.briand@aphp.fr |
| Name | Affiliation | Role |
|---|---|---|
| Gilles KAYEM, MD,PhD | Université Paris Cité and Université Sorbonne Paris Nord, Paris, France. DHU Risks in Pregnancy, Paris Descartes University, Trousseau University Hospital | Principal Investigator |
| Elsa LORTHE, RM,PhD | Université Paris Cité and Université Sorbonne Paris Nord, Paris, France. |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Trousseau University Hospital | Recruiting | Paris | France | 75012 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 16487205 | Background | 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. | |
| 18307075 | Background | 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. |
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| A short psychological assessment performed online | Other | 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 delay (≥2 SD). |
|
| Up to 6 months after inclusion. |
| Up to 6 months after inclusion. |
| Survival without any neurodevelopmental impairment at 6 years of age. | Survival without any neurodevelopmental impairment (as defined in the primary endpoint, and then including also cognitive impairment). | Up to 6 months after inclusion. |
| Survival without moderate-to-severe neurodevelopmental impairment at 6 years of age. | Survival without moderate-to-severe neurodevelopmental impairment (i.e. severe/moderate cerebral palsy, and/or abnormal SDQ score, and/or NEMI-3 ≥2 SD below the mean, and/or blindness, and/or deafness). | Up to 6 months after inclusion. |
| Growth at 6 years of age. | Height compulsory examination in the sixth year, reported in the health book. | Up to 6 months after inclusion. |
| Growth at 6 years of age | Weight. Compulsory examination in the sixth year, reported in the health book | Up to 6 months after inclusion |
| Health at 6 years of age. | Arterial pressure. Compulsory examination in the sixth year, reported in the health book. | Up to 6 months after inclusion. |
| Health at 6 years of age | chronic diseases, compulsory examination in the sixth year, reported in the health book | Up to 6 months after inclusion |
| Health at 6 years of age | oral health. Compulsory examination in the sixth year, reported in the health book | Up to 6 months after inclusion |
| Vision at 6 years of age. | Visual acuity, any vision problem mentioned. Compulsory examination in the sixth year, reported in the health book. | Up to 6 months after inclusion. |
| Hearing at 6 years of age. | Hearing test. Compulsory examination in the sixth year, reported in the health book. | Up to 6 months after inclusion. |
| Development at 6 years of age. | Data reported in the health book during the compulsory examination in the sixth year. | Up to 6 months after inclusion. |
| Language at 6 years of age. | Language test. Compulsory examination in the sixth year, reported in the health book. | Up to 6 months after inclusion. |
| Behaviour at 6 years of age. | Data reported in the health book during the compulsory examination in the sixth year. | Up to 6 months after inclusion. |
| Cognition at 6 years of age. | 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 delay (≥2 SD). | Up to 6 months after inclusion. |
| Feasibility of performing an online psychological evaluation. | Acceptability E-Scale (adapted - 3 items), participation and completion rates, technical difficulties. | Up to 6 months after inclusion. |
| Parent-reported health and development. | Self-reported. Perceived health and development of the child, parental concerns about health and development, and professional diagnoses of health conditions (e.g., asthma, respiratory problems, etc.). | Up to 6 months after inclusion. |
| Parent-reported Health-Related Quality of Life. | PedsQL Short Form - 15 items. All items will be added up and linearly transformed on a scale between 0 and 100, a higher score indicating a better HRQoL. Physical and psychosocial functioning will be further assessed using the corresponding subscales. Poor HRQoL, physical or psychosocial functioning will be defined using thresholds compatible with a severe health condition. | Up to 6 months after inclusion. |
| Parent-reported school difficulties | Ad-hoc questions | Up to 6 months after inclusion |
| Maternal self-perceived health | Minimum European Health Module - 1 item | Up to 6 months after inclusion |
| Maternal mental health | PHQ-4 (anxiety and depression) - 4 items | Up to 6 months after inclusion |
| Maternal well-being | WHO-5 Well-Being Index - 5 items | Up to 6 months after inclusion |
| Maternal quality of life | WHOQOL bref FR - 1 item | Up to 6 months after inclusion |
| Study Director |
| 26330379 | Background | 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: 10.1111/1471-0528.13586. Epub 2015 Aug 27. |
| 32124520 | Background | 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. |
| 35947046 | Background | 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. |
| 34496799 | Background | 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/s12884-021-04047-2. |
| ID | Term |
|---|---|
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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