Advertisement

Neurodevelopment at 5 years of age for preterm-born children according to mode of conception: a cohort study

  • Caroline Verhaeghe
    Affiliations
    Université Paris Cité, Centre of Research in Epidemiology and Statistics, Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Institut National de la Sante et de la Recherche Medicale, French National Research Institute for Agriculture, Food, and the Environment, Paris, France
    Search for articles by this author
  • Laetitia Marchand-Martin
    Affiliations
    Université Paris Cité, Centre of Research in Epidemiology and Statistics, Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Institut National de la Sante et de la Recherche Medicale, French National Research Institute for Agriculture, Food, and the Environment, Paris, France
    Search for articles by this author
  • Monique Kaminski
    Affiliations
    Université Paris Cité, Centre of Research in Epidemiology and Statistics, Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Institut National de la Sante et de la Recherche Medicale, French National Research Institute for Agriculture, Food, and the Environment, Paris, France
    Search for articles by this author
  • Géraldine Gascoin
    Affiliations
    Department of Neonatology, Hôpital des Enfants, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
    Search for articles by this author
  • Laurence Foix-L’Helias
    Affiliations
    Université Paris Cité, Centre of Research in Epidemiology and Statistics, Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Institut National de la Sante et de la Recherche Medicale, French National Research Institute for Agriculture, Food, and the Environment, Paris, France

    Department of Neonatal Pediatrics, Armand-Trousseau Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
    Search for articles by this author
  • Pierre-Yves Ancel
    Affiliations
    Université Paris Cité, Centre of Research in Epidemiology and Statistics, Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Institut National de la Sante et de la Recherche Medicale, French National Research Institute for Agriculture, Food, and the Environment, Paris, France

    Clinical Investigation Center P1419, Assistance Publique – Hôpitaux de Paris, Paris, France
    Search for articles by this author
  • Pierre-Emmanuel Bouet
    Affiliations
    Service de gynécologie-obstétrique, Centre Hospitalier Universitaire d’Angers, Angers, France
    Search for articles by this author
  • Andrei S. Morgan
    Correspondence
    Corresponding author: Andrei S. Morgan, FRCPCH, PhD.
    Affiliations
    Université Paris Cité, Centre of Research in Epidemiology and Statistics, Obstetrical Perinatal and Pediatric Epidemiology Research Team (EPOPé), Institut National de la Sante et de la Recherche Medicale, French National Research Institute for Agriculture, Food, and the Environment, Paris, France

    Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, United Kingdom

    Department of Neonatology, Port Royal Maternity Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
    Search for articles by this author
Open AccessPublished:June 04, 2022DOI:https://doi.org/10.1016/j.ajog.2022.05.062

      Background

      Preterm delivery is a risk factor for suboptimal neurodevelopment. Pregnancies conceived after medically assisted reproduction—which includes in vitro fertilization, with or without intracytoplasmic insemination, and induction of ovulation followed by intrauterine insemination or timed intercourse—have a higher risk of preterm delivery. Few studies have evaluated the outcome at >2 years of age of such preterm-born children.

      Objective

      To evaluate neurodevelopmental outcome at 5½ years of age of children born preterm according to the mode of conception (spontaneous vs medically assisted reproduction).

      Study Design

      A total of 4349 children born between 24 and 34 weeks of gestation who survived to 5½ years of age in the 2011 French prospective national cohort study “EPIPAGE-2” were included: 814 in the medically assisted reproduction group (433 by in vitro fertilization, with or without intracytoplasmic insemination, and 381 by induction of ovulation) and 3535 in the spontaneously conceived group. The studied neurodevelopmental outcomes were sensory (hearing and vision) impairments, cerebral palsy, cognition, and developmental coordination disorders. Multivariate analyses were performed with generalized estimating equation models adjusted for gestational age, antenatal steroids, and social characteristics. All analyses were performed following multiple imputation. Sensitivity analyses were performed with the populations of singletons and cases with complete data.

      Results

      No differences in cerebral palsy (adjusted odds ratio, 1.00; 95% confidence interval, 0.67–1.49), neurodevelopmental impairment (adjusted odds ratio, 1.09; 95% confidence interval, 0.82–1.45), or developmental coordination disorders (adjusted odds ratio, 0.75; 95% confidence interval, 0.50–1.12) were found between children born following medically assisted reproduction and children born following spontaneous conception after adjustment for sociodemographic factors. For proportions of children with an intelligence quotient below 1 and 2 standard deviations, there were no differences between those born after medically assisted reproduction and those born after spontaneous pregnancy (respectively, adjusted odds ratio, 0.99; 95% confidence interval, 0.80–1.23 and adjusted odds ratio, 1.14; 95% confidence interval, 0.83–1.56). In subgroup analyses, no differences were observed between children born following induction of ovulation or in vitro fertilization and those conceived spontaneously. Sensitivity analyses were consistent with the main results.

      Conclusion

      In this cohort of preterm-born children, there was no evidence of an impact of the mode of conception on neurodevelopmental outcomes at 5½ years of age.

      Key words

      Why was this study conducted?

      Some studies have suggested that children born preterm following medically assisted reproduction (MAR) are at additional risk for neurodevelopmental impairments. These have mostly focused on outcomes at up to 2 years of age, but evidence at older ages is lacking.

      Key findings

      In this prospective cohort, there were no differences in neurodevelopmental outcomes—including cognition, cerebral palsy, combined neurosensory impairment, and developmental coordination disorders—at 5½ years of age between children born preterm after MAR and those conceived naturally when results were fully adjusted for sociodemographic factors.

      What does this add to what is known?

      MAR is not associated with additional long-term neurodevelopmental impairments at up to 5½ years of age for children born preterm.

      Introduction

      Infertility, defined as inability to conceive after 1 year of regular, unprotected sexual intercourse,
      • Zegers-Hochschild F.
      • Adamson G.D.
      • Dyer S.
      • et al.
      The international glossary on infertility and fertility care, 2017.
      affects approximately 15% of couples.
      • Oakley L.
      • Doyle P.
      • Maconochie N.
      Lifetime prevalence of infertility and infertility treatment in the UK: results from a population-based survey of reproduction.
      This has many consequences, including sexual dysfunction, social stigmatization, and relationship breakdown.
      • Schmidt L.
      Social and psychological consequences of infertility and assisted reproduction - what are the research priorities?.
      • Peterson B.D.
      • Pirritano M.
      • Christensen U.
      • Boivin J.
      • Block J.
      • Schmidt L.
      The longitudinal impact of partner coping in couples following 5 years of unsuccessful fertility treatments.
      • Volgsten H.
      • Skoog Svanberg A.
      • Ekselius L.
      • Lundkvist O.
      • Sundström Poromaa I.
      Prevalence of psychiatric disorders in infertile women and men undergoing in vitro fertilization treatment.
      • Chachamovich J.R.
      • Chachamovich E.
      • Ezer H.
      • Fleck M.P.
      • Knauth D.
      • Passos E.P.
      Investigating quality of life and health-related quality of life in infertility: a systematic review.
      • Facchin F.
      • Somigliana E.
      • Busnelli A.
      • Catavorello A.
      • Barbara G.
      • Vercellini P.
      Infertility-related distress and female sexual function during assisted reproduction.
      • Gabr A.A.
      • Omran E.F.
      • Abdallah A.A.
      • et al.
      Prevalence of sexual dysfunction in infertile versus fertile couples.
      Since the birth of the first child conceived through in vitro fertilization (IVF) in 1978, the use of assisted reproductive technologies (ARTs) has increased substantially, such that 3% to 4% of births are now from pregnancies conceived through ART.
      • Goisis A.
      • Håberg S.E.
      • Hanevik H.I.
      • Magnus M.C.
      • Kravdal Ø.
      The demographics of assisted reproductive technology births in a Nordic country.
      ,
      • De Geyter C.
      • Calhaz-Jorge C.
      • Kupka M.S.
      • et al.
      ART in Europe, 2015: results generated from European registries by ESHRE.
      However, ART includes only the in vitro handling of oocytes and sperm, or of embryos, thus including IVF and IVF with intracytoplasmic sperm injection (ICSI) but not intrauterine insemination (IUI) following induction of ovulation (IO) or timed intercourse (TIC) following IO.
      • Zegers-Hochschild F.
      • Adamson G.D.
      • Dyer S.
      • et al.
      The international glossary on infertility and fertility care, 2017.
      These techniques, which fall under the broader term of “medically-assisted reproduction” (MAR),
      • Zegers-Hochschild F.
      • Adamson G.D.
      • Dyer S.
      • et al.
      The international glossary on infertility and fertility care, 2017.
      also expose women and fetuses to exogenous hormones.
      A major concern for women undergoing MAR and their partners is long-term neurodevelopmental outcome of the offspring. Problems potentially arise because genes subject to parental imprinting may be affected by epigenetic modifications relating to MAR (hormonal IO, manipulation of male gametes, IVF, or embryo transfer), thus negatively affecting the offspring.
      • Mani S.
      • Ghosh J.
      • Coutifaris C.
      • Sapienza C.
      • Mainigi M.
      Epigenetic changes and assisted reproductive technologies.
      MAR is also associated with both an increased risk of preterm birth (at <37 weeks of gestational age [GA]), including very preterm birth (at <32 weeks’ GA),
      • Berntsen S.
      • Söderström-Anttila V.
      • Wennerholm U.B.
      • et al.
      The health of children conceived by ART: ‘the chicken or the egg?’.
      and with multiple pregnancy (particularly following multifollicular stimulation or multiple embryo transfers), which is itself associated with preterm birth.
      • De Geyter C.
      • Calhaz-Jorge C.
      • Kupka M.S.
      • et al.
      ART in Europe, 2015: results generated from European registries by ESHRE.
      Preterm birth is in turn associated with a risk of poorer neurodevelopmental outcomes.
      • Wolke D.
      • Johnson S.
      • Mendonça M.
      The life course consequences of very preterm birth.
      • Doyle L.W.
      • Spittle A.
      • Anderson P.J.
      • Cheong J.L.Y.
      School-aged neurodevelopmental outcomes for children born extremely preterm.
      • Morgan A.S.
      • Mendonça M.
      • Thiele N.
      • David A.L.
      Management and outcomes of extreme preterm birth.
      To date, however, data concerning the neurodevelopment of children born following MAR have been inconsistent, with studies finding outcomes in children conceived following MAR compared with children conceived naturally to be poorer,
      • Strömberg B.
      • Dahlquist G.
      • Ericson A.
      • Finnström O.
      • Köster M.
      • Stjernqvist K.
      Neurological sequelae in children born after in-vitro fertilisation: a population-based study.
      better,
      • Hashimoto K.
      • Ogawa K.
      • Horikawa R.
      • et al.
      Gross motor function and general development of babies born after assisted reproductive technology.
      ,
      • Roychoudhury S.
      • Lodha A.
      • Synnes A.
      • et al.
      Neurodevelopmental outcomes of preterm infants conceived by assisted reproductive technology.
      or the same.
      • Berntsen S.
      • Söderström-Anttila V.
      • Wennerholm U.B.
      • et al.
      The health of children conceived by ART: ‘the chicken or the egg?’.
      ,
      • Balayla J.
      • Sheehy O.
      • Fraser W.D.
      • et al.
      Neurodevelopmental outcomes after assisted reproductive technologies.
      Such discrepancies arise because of differences in neurodevelopmental domains studied and age at follow-up, and methodological differences between the studies
      • Torchin H.
      • Morgan A.S.
      • Ancel P.Y.
      International comparisons of neurodevelopmental outcomes in infants born very preterm.
      ; the true impact of MAR therefore remains unclear.
      • Berntsen S.
      • Söderström-Anttila V.
      • Wennerholm U.B.
      • et al.
      The health of children conceived by ART: ‘the chicken or the egg?’.
      When looking more specifically at neurodevelopment in children born preterm following MAR, few data are available. Two retrospective population-based studies of births before 29 weeks’ GA assessed at 18 to 24 months found conflicting results,
      • Roychoudhury S.
      • Lodha A.
      • Synnes A.
      • et al.
      Neurodevelopmental outcomes of preterm infants conceived by assisted reproductive technology.
      ,
      • Abdel-Latif M.E.
      • Bajuk B.
      • Ward M.
      • Oei J.L.
      • Badawi N.
      NSW and ACT Neonatal Intensive Care Units Audit Group. Neurodevelopmental outcomes of extremely premature infants conceived after assisted conception: a population based cohort study.
      whereas a single-center study of births before 34 weeks found a reduced probability of poor neurodevelopment at 2 years of age.
      • Molines L.
      • Nusinovici S.
      • Moreau M.
      • et al.
      Impact of mode of conception on neonatal and neurodevelopmental outcomes in preterm infants.
      Only 1 study has examined outcomes after at least 5 years of age—and only in relation to cerebral palsy—and found no differences by mode of conception.
      • Hvidtjørn D.
      • Grove J.
      • Schendel D.
      • et al.
      Multiplicity and early gestational age contribute to an increased risk of cerebral palsy from assisted conception: a population-based cohort study.
      However, neurodevelopment is dynamic and evolves over time: motor deficits become apparent first, with cognitive deficits appearing later. By age 5, more subtle defects are detectable, thus multiple dimensions of development should be studied. We sought to evaluate the impact of mode of conception on neurodevelopment at 5½ years of age in children born at <35 weeks’ GA. Our primary objective was to assess whether any effect on neurodevelopment was evident using all MAR techniques combined. Different techniques may also have different effects: IVF or IVF-ICSI techniques, such as multifollicular stimulation, gamete manipulation, embryo culture, and embryo transfer, might cause epigenetic disturbances; these might also be observed following hormonal stimulation (IO with TIC, or IUI).
      • Mani S.
      • Ghosh J.
      • Coutifaris C.
      • Sapienza C.
      • Mainigi M.
      Epigenetic changes and assisted reproductive technologies.
      We therefore studied subgroups of children born following the use of these techniques in comparison with those born after spontaneous conception. We hypothesized that there would be no differences once social factors were accounted for.

      Materials and Methods

      Setting and data collection

      The French prospective, national cohort study “EPIPAGE-2” collected information about all births at <35 weeks’ GA in 546 maternity hospitals in France in 2011.
      • Ancel P.Y.
      • Goffinet F.
      EPIPAGE 2 Writing Group
      EPIPAGE 2: a preterm birth cohort in France in 2011.
      ,
      • Lorthe E.
      • Benhammou V.
      • Marchand-Martin L.
      • et al.
      Cohort profile: the Etude Epidemiologique sur les Petits Ages Gestationnels-2 (EPIPAGE-2) preterm birth cohort.
      Children born at <27 weeks’ GA were recruited over 8 months (equivalent to 35 weeks), those born between 27 and 31 completed weeks of GA over 6 months (equivalent to 26 weeks), and those between 32- and 34-weeks’ GA over 5 weeks. At birth, maternal, obstetrical, and neonatal data were obtained from medical records, and during the child’s hospital stay, mothers were interviewed to obtain information on their social characteristics and pregnancy. Surviving children were seen by trained investigators at 5½ years of age: this included a medical examination and neuropsychological assessment, and parents completed a questionnaire.

      Population

      Only children born between 24- and 34-weeks’ GA were included because the 1 child born at <24 weeks who survived was lost to follow-up at 5½ years. We excluded children for whom mode of conception or, if born following MAR, type of infertility treatment were unknown.

      Exposure

      Birth following MAR was compared with that following spontaneous conception. Information about MAR was collected at birth from medical notes and postnatal interview; the use of hormonal stimulation (IO with TIC, or IUI) or IVF (alone or with ICSI) were accepted as evidence of an MAR-conceived pregnancy. The subgroups of IO with TIC or IUI, and IVF or IVF-ICSI were also examined separately.

      Main outcomes

      We studied cerebral palsy, sensory (hearing and vision) and cognitive impairments, and developmental coordination disorders. Cerebral palsy was diagnosed clinically using the Surveillance of Cerebral Palsy in Europe network criteria and classified according to the Gross Motor Function Classification System (GMFCS). Visual impairment was defined as binocular visual acuity <3.2/10, and hearing impairment was defined as uni- or bilateral hearing loss >40 dB not corrected or only partially corrected with hearing aids. Cognitive ability was measured using the full-scale intelligence quotient (FSIQ) from the Wechsler Preschool and Primary Scale of Intelligence—Fourth Edition (WPPSI-IV, French version); this composite score is obtained from 5 domains: verbal comprehension, visuospatial indices, fluid reasoning, working memory, and processing speed. We studied mean intelligence quotient (IQ) and proportions of children with scores both 1 and 2 standard deviations (SDs) below the mean of a reference group of children born at term (37–41 weeks’ GA). The reference group, weighted to be representative of the French population, was selected from a contemporaneous birth cohort, with children undergoing the same follow-up as those in EPIPAGE-2.
      • Pierrat V.
      • Marchand-Martin L.
      • Marret S.
      • et al.
      Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study.
      Moderate to severe impairment was defined as having at least 1 sensory impairment, cerebral palsy GMFCS level 2 or higher, or FSIQ >2 SDs below the mean of the reference group. Finally, developmental coordination disorders were assessed in children without moderate or severe impairment using the Movement Assessment Battery for Children, Second Edition. We studied both total scores and using a cutoff score below the fifth percentile (relative to the reference group).

      Other studied factors

      Maternal characteristics available from delivery were: maternal age (years), level of education (less than high school, high school, 1–2 years or >2 years of graduate study), currently employed (yes/no), birth country (France or elsewhere), cohabitation status, smoking during pregnancy (yes/no), and household socioeconomic status defined according to the highest status of the mother and partner, or mother only if she lived alone (executive, intermediate, administration, service and trade, manual worker, and unemployed). Obstetrical variables were: parity (nulliparous or not), singleton or multiple pregnancy, induced or spontaneous labor, delivery mode (vaginal or cesarean), receipt of antenatal steroids and tocolysis, and neonatal unit level at delivery hospital. Neonatal characteristics were: GA at delivery (completed weeks), sex, small for GA (using French reference curves
      • Ego A.
      • Prunet C.
      • Lebreton E.
      • et al.
      [Customized and non-customized French intrauterine growth curves. I - methodology].
      ), and severe malformations (yes/no).

      Statistical analysis

      Population characteristics were described using means and SDs for continuous variables, with groups compared using Student or Wilcoxon tests. For categorical variables, we described proportions and used chi square or Fisher exact tests. Mortality rates between birth and follow-up were assessed to determine whether there were differences in survival between children conceived following MAR and those conceived spontaneously. Regression analyses were performed among survivors aged 5½ years. For binary outcomes, odds ratios were estimated with logistic regression, and for continuous outcomes, linear regression was used; both used generalized estimating equations (GEE) to account for nonindependence of multiple children born to the same mother. We first estimated crude associations, then added GA at birth and antenatal steroids to explore any potential mediating impact from these factors, and finally, in the fully adjusted model, included sociodemographic variables that were considered a priori to be potential confounders. These were: maternal age, parity, birth country, level of education, employment, smoking during pregnancy, cohabitation, and socioeconomic status. A P value <.05 was considered statistically significant; results are presented with 95% confidence intervals (CIs).
      Data were weighted according to GA group by a factor of 1.34 (35/26) for children born at 27 to 31 weeks and by a factor of 7 (35/5) for those born at 32 to 34 weeks to account for the differing recruitment periods, and multiple imputation was performed using chained equations to account for missing outcome data; imputation models included variables potentially predicting nonresponse or the outcome (Supplemental Table 1). Estimates were combined using Rubin’s rules.
      • Rubin D.B.
      Multiple Imputation for non response in surveys.
      All investigations were conducted using R, version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). GEE models were performed using the R package “geepack”
      • Højsgaard S.
      • Halekoh U.
      • Yan J.
      The R package geepack for Generalized Estimating Equations.
      and multiple imputation with the package “mice.”
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: multivariate Imputation by Chained Equations in R.

      Sensitivity analyses

      We did not adjust for multiple pregnancy status because this potentially lies on the causal pathway between MAR and later outcome. Instead, we repeated analyses using singleton births only. We also performed sensitivity analyses of all models on the population of children with complete data.

      Ethical approvals

      Data were collected with permission from the Commission Nationale de l’Informatique et des Libertés (National Data Protection Authority—reference: 911009) and from the relevant ethics committees (Consultative Committee on the Treatment of Data on Personal Health for Research Purposes—reference: 10.626; Committee for the Protection of People Participating in Biomedical Research—reference: CPP SC-2873). Mothers gave verbal consent to provide data following delivery, and written consent was obtained for follow-up.

      Results

      Study population

      At 24 to 34 completed weeks’ GA, 5022 children were born alive; mode of conception, including type of infertility treatment, was known for 4907. Of these, 558 children died before reaching 5½ years of age (4.6% in the MAR and 6.0% in the non-MAR group, P=.025). Among the 4349 survivors, complete information was available for 641 of 814 children born following MAR and 2390 of 3535 children born following spontaneous pregnancy. More children were lost to follow-up from spontaneous and singleton pregnancies and from families of lower socioeconomic status, and their mothers were more often younger, multiparous, single, smokers, and born outside of France (Figure; Supplemental Tables 2 and 3).
      Figure thumbnail gr1
      FigureFlowchart
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically assisted reproduction. Am J Obstet Gynecol 2022.

      Baseline characteristics

      MAR was used by 532 mothers; at delivery, these mothers were older, more highly educated, more often employed, of higher socioprofessional category, and less frequently smokers than women with spontaneous pregnancies (Table 1). Their children were more often from multiple pregnancies, small for GA, exposed to antenatal steroids, and born following spontaneous labor, with noncephalic presentation, and in hospitals with level 3 neonatal intensive care units. There were no differences in terms of GA, sex, presence of severe malformations, or mode of delivery (Table 2).
      Table 1Characteristics of the 3667 mothers with children in the EPIPAGE-2 cohort surviving to 5½ years of age according to mode of conception, after multiple imputation
      CharacteristicSpontaneousMAR
      MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      IO or IUIIVF or IVF-ICSI
      N mothers=3135N mothers=532N mothers=254N mothers=278
      Age, mean (95% confidence interval)29.4 (29.2–29.7)32.0 (31.5–32.6)31.4 (30.4–32.3)32.6 (32.0–33.2)
      Primiparous49.9 (47.5–52.3)77.0 (72.3–81.8)74.8 (67.8–81.7)79.0 (72.4–85.6)
      Born in France78.8 (76.9–80.7)84.8 (81.0–88.6)85.5 (80.3–90.8)84.1 (78.6–89.6)
      Smoked during pregnancy23.5 (21.5–25.5)8.8 (5.5–12.1)9.2 (4.5–14.0)8.4 (3.8–13.0)
      Level of education
       Less than high school36.7 (34.4–39.0)22.1 (17.3–27.0)25.7 (18.1–33.3)19.0 (12.8–25.2)
       High school23.3 (21.3–25.4)15.9 (11.7–20.1)15.4 (9.7–21.1)16.3 (10.3–22.3)
       1–2 y of graduate studies17.9 (16.0–19.8)21.0 (16.3–25.6)23.7 (16.4–31.0)18.6 (12.8–24.4)
       ≥3 y of graduate studies22.0 (20.0–24.1)41.0 (35.3–46.8)35.2 (27.0–43.4)46.1 (38.1–54.0)
      Occupational activity during pregnancy61.7 (59.4–64.0)80.1 (75.5–84.6)74.7 (67.3–82.0)84.8 (79.2–90.3)
      Cohabiting with partner at delivery88.9 (87.4–90.4)97.3 (95.4–99.2)96.5 (93.4–99.5)98.1 (95.8–100)
      Parents’ socioeconomic status
      Defined as the highest occupational status between occupations of the mother and the father, or mother only if living alone.
       Executive18.7 (16.8–20.6)34.8 (29.2–40.3)28.8 (21–36.6)40.0 (32.2–47.8)
       Intermediate19.9 (18.0–21.9)27.6 (22.3–33.0)31.6 (23.5–39.8)24.1 (17.1–31.2)
       Administration28.9 (26.8–31.1)24 (19.0–29.0)23.3 (16.1–30.6)24.6 (17.7–31.5)
       Service, trade15.8 (14.0–17.5)7.1 (4.2–10.0)7.5 (3.1–12.0)6.7 (2.9–10.5)
       Worker12.8 (11.2–14.3)5.8 (3.2–8.3)7.3 (3.0–11.5)4.5 (1.6–7.4)
       Unemployed3.9 (3.0–4.8)0.8 (0.0–1.8)1.5 (0.0–3.6)0.2 (0.0–0.8)
      Data are percentage (95% confidence interval) unless otherwise noted. Results are given after multiple imputation and are weighted to take into account the differences in survey design between gestational age groups; proportions are not exactly n/N because of the weighting.
      ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; IUI, intrauterine insemination; IVF, in vitro fertilization; MAR, medically assisted reproduction.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      b Defined as the highest occupational status between occupations of the mother and the father, or mother only if living alone.
      Table 2Pregnancy and childbirth outcomes for 4349 children from the EPIPAGE-2 cohort surviving at 5½ years of age according to mode of conception, after multiple imputation
      OutcomesSpontaneousMAR
      MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      IO or IUIIVF or IVF-ICSI
      N children=3535N children=814N children=381N children=433
      Multiple pregnancy status
       Singleton74.2 (72.2–76.1)24.3 (20.5–28.1)31.4 (25.1–37.7)18.7 (14.2–23.3)
       Twin24.7 (22.8–26.6)68.7 (64.6–72.9)58.2 (51.5–64.9)77.1 (72.1–82.0)
       Triplet1.1 (0.7–1.6)6.7 (4.5–9.0)9.9 (5.9–13.9)4.2 (1.8–6.7)
       Quadruplet0.00.2 (0.0–0.4)0.5 (0.1–0.9)0.0
      Antenatal steroids75.6 (73.6–77.6)85.5 (82.1–89.0)79.4 (73.5–85.4)90.3 (86.5–94.1)
      Tocolysis47.0 (44.8–49.2)55.8 (51.2–60.4)50.6 (43.7–57.5)59.9 (53.7–66.1)
      Spontaneous preterm delivery51.7 (49.4–53.9)44.7 (40.1–49.4)49.8 (42.8–56.7)40.8 (34.6–47.0)
      Cephalic presentation74.7 (72.8–76.6)63.4 (59.0–67.8)62.1 (55.5–68.6)64.4 (58.5–70.4)
      Cesarean delivery58.6 (56.3–60.8)60.8 (56.3–65.4)62.3 (55.5–69.0)59.7(51.3–68.1)
      Maternity level III61.9 (59.7–64.2)66.8 (62.2–71.5)63.6 (56.7–70.6)69.3 (63.2–75.5)
      Week of gestation, mean (95% confidence interval)31.8 (31.7–31.9)31.8 (31.6–31.9)31.6 (31.4–31.9)31.9 (31.6–32.1)
       24–26 wk4.1 (3.7–4.5)5.4 (4.4–6.5)6.0 (4.4–7.7)5.0 (3.7–6.3)
       27–31 wk30.0 (28.4–31.5)26.5 (23.6–29.5)29.3 (24.6–34.0)24.3 (20.5–28.1)
       32–34 wk65.9 (64.2–67.6)68.0 (64.7–71.4)64.7 (59.3–70.0)70.7 (66.5–75.0)
      Male sex53.6 (51.3–55.8)51.1 (46.5–55.7)49.0 (42.2–55.8)52.8 (46.6–59.1)
      Small for gestational age
      Small-for-gestational-age was defined as birthweight <10th percentile for gestational age and sex on the basis of French intrauterine growth curves.28
      32.8 (30.7–34.9)36.7 (32.2–41.2)41.5 (34.7–48.3)32.9 (27.0–38.8)
      Severe malformations6.7 (5.6–7.8)6.5 (4.3–8.7)10.0 (5.9–14.2)3.7 (1.7–5.7)
      Data are percentage (95% confidence interval) unless otherwise noted. Results are given after multiple imputation and are weighted to take into account the differences in survey design between gestational age groups; proportions are not exactly n/N because of the weighting.
      ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; IUI, intrauterine insemination; IVF, in vitro fertilization; MAR, medically assisted reproduction.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      b Small-for-gestational-age was defined as birthweight <10th percentile for gestational age and sex on the basis of French intrauterine growth curves.
      • Ego A.
      • Prunet C.
      • Lebreton E.
      • et al.
      [Customized and non-customized French intrauterine growth curves. I - methodology].

      Outcomes at 5½ years of age

      At 5½ years of age, before adjustment, there were better outcomes for cognition among children born following MAR than among those from spontaneous pregnancies (Table 3). These differences disappeared following adjustment with sociodemographic variables (Table 4). Similar results were observed for the composite measure of moderate to severe neurodevelopmental impairment. There were no differences in unadjusted or adjusted analyses for cerebral palsy, nor in proportions of sensory deficiencies, between children born following MAR and children from spontaneous pregnancy (Table 3), nor were any differences identified for developmental coordination disorders (Tables 3 and 4).
      Table 3Neurodevelopmental outcome measures for 4349 children from the EPIPAGE-2 cohort surviving at 5½ years according to mode of conception, after multiple imputation
      OutcomeSpontaneousMAR
      MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      P value
      Chi square test P value, estimated with the generalized estimating equations (GEE) approach to take into account correlation between twins or triplets, compared with spontaneous pregnancy
      IO or IUIP value
      Chi square test P value, estimated with the generalized estimating equations (GEE) approach to take into account correlation between twins or triplets, compared with spontaneous pregnancy
      IVF or IVF-ICSIP value
      Chi square test P value, estimated with the generalized estimating equations (GEE) approach to take into account correlation between twins or triplets, compared with spontaneous pregnancy
      N=3535N=814N=381N=433
      Cerebral palsy5.1 (4.0–6.2)4.5 (2.4–6.6).626.3 (2.5–10.0).523.1 (0.9–5.2).16
      Visual impairment
      Severe and moderate impairment
      Blindness or binocular corrected visual acuity <3.2/10
      1.3 (0.7–2.0)0.9 (0.0–2.0).481.3 (0.0–3.3).940.5 (0.0–1.7).27
      Hearing impairment
      Severe and moderate impairment
      Deafness, hearing loss >40 dB not corrected or partially corrected with hearing aid
      1.1 (0.5–1.7)1.5 (0.2–2.8).510.6 (0.0–2.0).422.2 (0.2–4.3).18
      FSIQ
      Full-scale intelligence quotient, measured by the Wechsler Preschool and Primary Scale of Intelligence—Fourth Edition26
      Mean (SD)95.8 (15.7)100.1 (15.5)<.00199.4 (15.5).011100.6 (15.6)<.001
      <1 SD (<93)
      Cutoff of the distribution related to a reference group born at term27
      40.1 (37.4–42.8)29.0 (24.6–33.5)<.00128.8 (22.0–35.7).00829.1 (23.2–35.1).003
      <2 SD (<79)
      Cutoff of the distribution related to a reference group born at term27
      13.4 (11.5–15.3)8.6 (5.9–11.4).0109.3 (5.2–13.4).138.1 (4.5–11.7).024
      Neurodevelopmental impairment
      Severe and moderate impairment
      Severe or moderate cerebral palsy, severe or moderate sensory impairments, or FSIQ <2 SDs below the mean of a reference population
      16.0 (14.0–17.9)11.2 (8.0–14.4).02012.1 (7.3–16.9).1810.4 (6.3–14.5).036
      Developmental coordination disorders
      Among children without cerebral palsy or severe or moderate sensory impairments, and with full-scale intelligence quotients ≥2 SDs below the mean of a reference population.
      Total MABC-2 score, mean (SD)10.2 (3.1)10.5 (2.9).2710.4 (3.1).5210.5 (2.7).32
      Total MABC-2 score <5th percentile
      Cutoff of the distribution related to a reference group born at term27
      5.9 (4.6–7.2)4.4 (2.2–6.6).295.7 (1.9–9.4).903.4 (0.7–6.1).16
      Data are percentage (95% confidence interval) unless otherwise noted. Results are given after multiple imputation and are weighted to take into account the differences in survey design between gestational age groups; proportions are not exactly n/N because of the weighting.
      FSIQ, full-scale intelligence quotient; ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; IUI, intrauterine insemination; IVF, in vitro fertilization; MABC-2, Movement Assessment Battery for Children, Second Edition (Henderson, 2007); MAR, medically assisted reproduction; SD, standard deviation.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      b Chi square test P value, estimated with the generalized estimating equations (GEE) approach to take into account correlation between twins or triplets, compared with spontaneous pregnancy
      c Blindness or binocular corrected visual acuity <3.2/10
      d Deafness, hearing loss >40 dB not corrected or partially corrected with hearing aid
      e Full-scale intelligence quotient, measured by the Wechsler Preschool and Primary Scale of Intelligence—Fourth Edition
      f Cutoff of the distribution related to a reference group born at term
      • Pierrat V.
      • Marchand-Martin L.
      • Marret S.
      • et al.
      Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study.
      g Severe or moderate cerebral palsy, severe or moderate sensory impairments, or FSIQ <2 SDs below the mean of a reference population
      h Among children without cerebral palsy or severe or moderate sensory impairments, and with full-scale intelligence quotients ≥2 SDs below the mean of a reference population.
      Table 4Association between mode of conception and neurodevelopmental outcome measures for 4349 children from the EPIPAGE-2 cohort surviving at 5½ years—multivariate analysis after multiple imputation
      Outcome (Model)MAR
      MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      (N children=814)
      IO or IUI (N children=381)IVF or IVF-ICSI (N children=433)
      vs spontaneous conception (N children=3535)
      OR or mean difference (95% CI)
      The reported measures of association are odds ratios, except for FSIQ and total MABC-2 scores, where mean differences are reported. The generalized estimating equations approach was used to take into account correlation between twins or triplets
      P valueOR or mean difference (95% CI)
      The reported measures of association are odds ratios, except for FSIQ and total MABC-2 scores, where mean differences are reported. The generalized estimating equations approach was used to take into account correlation between twins or triplets
      P valueOR or mean difference (95% CI)
      The reported measures of association are odds ratios, except for FSIQ and total MABC-2 scores, where mean differences are reported. The generalized estimating equations approach was used to take into account correlation between twins or triplets
      P value
      Cerebral palsy
       Adjusted for GA and antenatal steroids0.85 (0.59–1.24).410.89 (0.53–1.50).670.81 (0.49–1.35).42
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.00 (0.67–1.49).990.99 (0.59–1.69).991.00 (0.58–1.72).99
      FSIQ
      Full-scale intelligence quotient, measured by the Wechsler Preschool and Primary Scale of Intelligence—Fourth Edition26
      Mean difference (95% CI)
       Adjusted for GA and antenatal steroids3.8 (2.4–5.3)<.0013.3 (1.3–5.3).0024.3 (2.4–6.3)<.001
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      −0.3 (−1.7 to 1.1).660.0 (−1.9 to 1.9).99−0.6 (−2.5 to 1.3).52
      <1 SD (<93)
      Cutoff of the distribution related to a reference group born at term27
       Adjusted for GA and antenatal steroids0.64 (0.53–0.77)<.0010.61 (0.46–0.80)<.0010.66 (0.52–0.85).001
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.99 (0.80–1.23).940.84 (0.62–1.15).281.15 (0.87–1.52).32
      < 2 SD (<79)
      Cutoff of the distribution related to a reference group born at term27
       Adjusted for GA and antenatal steroids0.67 (0.51–0.88).0040.69 (0.47–1.02).0600.64 (0.44–0.94).023
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.14 (0.83–1.56).421.04 (0.69–1.57).861.26 (0.82–1.93).30
      Severe and moderate neurodevelopmental impairment
      Severe or moderate cerebral palsy, severe or moderate sensory impairment, or FSIQ <2 SDs below the mean of a reference population
       Adjusted for GA and antenatal steroids0.68 (0.53–0.88).0030.72 (0.51–1.02).0660.64 (0.45–0.91).013
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.09 (0.82–1.45).561.04 (0.72–1.51).831.14 (0.77–1.68).51
      Developmental coordination disorders
      Among children without cerebral palsy or severe or moderate sensory impairment, and with FSIQ ≥2 SDs below the mean of a reference population.
      Total MABC-2 score, mean difference (95% CI)
       Adjusted for GA and antenatal steroids0.2 (−0.1 to 0.5).280.1 (−0.3 to 0.5).670.2 (−0.2 to 0.6).25
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.1 (−0.3 to 0.4).740.0 (−0.4 to 0.5).920.1 (−0.3 to 0.5).69
      Total MABC-2 score <fifth percentile
      Cutoff of the distribution related to a reference group born at term27
       Adjusted for GA and antenatal steroids0.76 (0.51–1.11).160.77 (0.45–1.31).340.74 (0.43–1.28).28
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.75 (0.50–1.12).160.77 (0.45–1.31).330.73 (0.41–1.29).28
      CI, confidence interval; FSIQ, full-scale intelligence quotient; GA, gestational age; ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; IUI, intrauterine insemination; IVF, in vitro fertilization; MABC-2, Movement Assessment Battery for Children, Second Edition (Henderson, 2007); MAR, medically assisted reproduction; OR, odds ratio; SD, standard deviation.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques, that is, IO, IUI, IVF, and IVF-ICSI
      b The reported measures of association are odds ratios, except for FSIQ and total MABC-2 scores, where mean differences are reported. The generalized estimating equations approach was used to take into account correlation between twins or triplets
      c Sociodemographic factors adjusted for are: maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      d Full-scale intelligence quotient, measured by the Wechsler Preschool and Primary Scale of Intelligence—Fourth Edition
      e Cutoff of the distribution related to a reference group born at term
      • Pierrat V.
      • Marchand-Martin L.
      • Marret S.
      • et al.
      Neurodevelopmental outcomes at age 5 among children born preterm: EPIPAGE-2 cohort study.
      f Severe or moderate cerebral palsy, severe or moderate sensory impairment, or FSIQ <2 SDs below the mean of a reference population
      g Among children without cerebral palsy or severe or moderate sensory impairment, and with FSIQ ≥2 SDs below the mean of a reference population.

      Subgroup analyses

      For both the children born following IO or IUI and those born following IVF or IVF-ICSI, similar patterns to those observed in the main analysis were noted. In both groups, the mean IQ before adjustment was higher than that of children born from spontaneous pregnancies, and fewer children had an IQ <1 SD (Table 3); the proportion of children with an IQ <2 SDs was also lower in the IVF/IVF-ICSI group but not in the IO/IUI group. Again, after adjustment for sociodemographic factors, no differences persisted (Table 4).

      Sensitivity analyses

      Results for singleton analyses were consistent for all outcomes among the entire population (Supplemental Table 4). In subgroup analyses, the odds ratio for having an FSIQ <1 SD below the mean was lower among those born following IO or IUI than among those born after spontaneous conception, but all other results were nonsignificant after adjustment for sociodemographic factors and consistent with analyses of the full population. Results from the IVF/IVF-ICSI group were also consistent with the main results (Supplemental Table 4), with no differences seen in complete case analyses (Supplemental Tables 5 and 6).

      Comment

      Principal findings

      In this prospective cohort study of preterm-born children followed-up at 5½ years of age, we found no evidence of an association between mode of conception and moderate to severe neurodevelopmental impairment following adjustment for sociodemographic factors, nor with cerebral palsy, sensory impairments, cognition, or developmental coordination disorders. Results were the same regardless of whether outcomes were analyzed as continuous scores or in binary categories representing potentially serious impairment. Sensitivity analyses using singletons and complete cases were also consistent.

      Results in the context of what is known

      Previous studies have identified differences in neurodevelopment related to mode of conception among children born preterm, particularly for cerebral palsy. One study that found an increased risk of cerebral palsy following IVF included children born between 1982 and 1995; however, evaluation was done at 2 years of age and results were only adjusted for the child’s sex, year of birth, and maternal age
      • Strömberg B.
      • Dahlquist G.
      • Ericson A.
      • Finnström O.
      • Köster M.
      • Stjernqvist K.
      Neurological sequelae in children born after in-vitro fertilisation: a population-based study.
      ; moreover, IVF techniques have evolved since then.
      • Berntsen S.
      • Söderström-Anttila V.
      • Wennerholm U.B.
      • et al.
      The health of children conceived by ART: ‘the chicken or the egg?’.
      Increased risk of cerebral palsy was identified for children born at <32 weeks’ GA in a whole-population Australian study, but CIs were wide because few very preterm children were included.
      • Goldsmith S.
      • Mcintyre S.
      • Badawi N.
      • Hansen M.
      Cerebral palsy after assisted reproductive technology: a cohort study.
      A different, prospective Australian cohort had similar findings, with an increased risk of moderate to severe neurodevelopmental impairment at 2 to 3 years of age for children born between 1998 and 2004 at 22 to 26 weeks’ GA following MAR. However, in subgroup analysis this applied only to births following IVF or IVF-ICSI and not to those following IO or IUI. This study only adjusted for year of birth, maternal age, and parity.
      • Abdel-Latif M.E.
      • Bajuk B.
      • Ward M.
      • Oei J.L.
      • Badawi N.
      NSW and ACT Neonatal Intensive Care Units Audit Group. Neurodevelopmental outcomes of extremely premature infants conceived after assisted conception: a population based cohort study.
      A more recent prospective study evaluating neurodevelopment at 2 years of age in preterm infants born following MAR found a decreased risk of poor neurodevelopmental outcomes after adjusting for socioeconomic level
      • Molines L.
      • Nusinovici S.
      • Moreau M.
      • et al.
      Impact of mode of conception on neonatal and neurodevelopmental outcomes in preterm infants.
      ; similar results were found in a retrospective study adjusting for maternal education.
      • Roychoudhury S.
      • Lodha A.
      • Synnes A.
      • et al.
      Neurodevelopmental outcomes of preterm infants conceived by assisted reproductive technology.
      However, neither study accounted for missing data, and the results are thus difficult to interpret. Other studies were also restricted to complete-case analyses.
      • Strömberg B.
      • Dahlquist G.
      • Ericson A.
      • Finnström O.
      • Köster M.
      • Stjernqvist K.
      Neurological sequelae in children born after in-vitro fertilisation: a population-based study.
      ,
      • Goldsmith S.
      • Mcintyre S.
      • Badawi N.
      • Hansen M.
      Cerebral palsy after assisted reproductive technology: a cohort study.
      Not only did we use multiple imputation and perform sensitivity analyses on complete cases, but we also adjusted for multiple social factors, and found that any initially perceived differences in outcome following MAR disappeared following this adjustment.

      Clinical implications

      The finding that there are no differences in neurodevelopmental outcomes according to mode of conception in this prospectively collected French national cohort of very and moderately preterm children is highly likely to apply also in other countries. External validity may be limited because French perinatal care was less active than that of some other countries for neonates born extremely preterm (at <27 weeks’ GA), but it was not dissimilar to that of other European countries
      • Edstedt Bonamy A.K.
      • Zeitlin J.
      • Piedvache A.
      • et al.
      Wide variation in severe neonatal morbidity among very preterm infants in European regions.
      ; furthermore, these children represented only approximately 5% of the births included in this study. Of greater concern might be that MAR techniques have changed: methods for both freezing embryos and the media in which they were subsequently cultured were different in 2011, and the transfer of several embryos was also more frequent and usually occurred at day 2 or 3.
      • De Geyter C.
      • Calhaz-Jorge C.
      • Kupka M.S.
      • et al.
      ART in Europe, 2015: results generated from European registries by ESHRE.
      However, evolution of practice has occurred internationally, not just within France, and longer-term follow-up necessarily requires that practices are from the past, thus implying that they are likely to have evolved in the interim period. Consequently, this study should be reassuring for health professionals and parents or parents-to-be of children born preterm following MAR because it indicates that any developmental consequences arise from preterm birth rather than the mode of conception itself conveying an additional risk.

      Research implications

      Although EPIPAGE-2 contains a wealth of follow-up and social data, information was limited about the MAR techniques. We did not have details about which drugs were used and at what dose, or whether embryos were transferred fresh or frozen, nor could we identify children born from donated gametes. This leaves questions about the impact of more specific fertility treatments for future research.

      Strengths and limitations

      This study evaluated multiple dimensions of longer-term neurodevelopment among children born preterm according to the mode of conception. Using a large, prospectively collected national cohort with comprehensive data covering a range of medical and sociodemographic characteristics
      • Ancel P.Y.
      • Goffinet F.
      EPIPAGE 2 Writing Group
      EPIPAGE 2: a preterm birth cohort in France in 2011.
      ,
      • Lorthe E.
      • Benhammou V.
      • Marchand-Martin L.
      • et al.
      Cohort profile: the Etude Epidemiologique sur les Petits Ages Gestationnels-2 (EPIPAGE-2) preterm birth cohort.
      allowed us to study several neurodevelopmental outcomes while taking into consideration important confounding factors with sufficient power to detect potential differences, particularly for the most frequent outcomes (cognitive impairment, developmental coordination disorder, and cerebral palsy). The quality of the used sociodemographic information is a further strength: most previous studies had only medical data with minimal additional information, and given that the social environment is a major predictor of child development, residual confounding may have been an issue. The main difficulty in prospective cohort studies is loss to follow-up.
      • Wolke D.
      • Söhne B.
      • Ohrt B.
      • Riegel K.
      Follow-up of preterm children: important to document dropouts.
      Data we had available covered pregnancy, the neonatal hospitalization, and subsequent course of the children, thus allowing us to use these data in imputation models, thereby increasing the likelihood of the “missing at random” assumption being met.
      • van Buuren S.
      • Groothuis-Oudshoorn K.
      mice: multivariate Imputation by Chained Equations in R.
      This is important because missing data may have impact in ways that are difficult to determine.
      • Wolke D.
      • Söhne B.
      • Ohrt B.
      • Riegel K.
      Follow-up of preterm children: important to document dropouts.
      We were further reassured by the very similar results found in analyses using complete cases. We were also able to examine the implication of broader MAR techniques both together and separated into ART and non-ART techniques, although more detailed information about specific techniques was not available; previous studies in the preterm population have predominantly focused on children born either after IVF/IVF-ICSI
      • Strömberg B.
      • Dahlquist G.
      • Ericson A.
      • Finnström O.
      • Köster M.
      • Stjernqvist K.
      Neurological sequelae in children born after in-vitro fertilisation: a population-based study.
      ,
      • Hvidtjørn D.
      • Grove J.
      • Schendel D.E.
      • et al.
      Cerebral palsy among children born after in vitro fertilization: the role of preterm delivery–a population-based, cohort study.
      or after all types of MAR combined.
      • Roychoudhury S.
      • Lodha A.
      • Synnes A.
      • et al.
      Neurodevelopmental outcomes of preterm infants conceived by assisted reproductive technology.
      ,
      • Abdel-Latif M.E.
      • Bajuk B.
      • Ward M.
      • Oei J.L.
      • Badawi N.
      NSW and ACT Neonatal Intensive Care Units Audit Group. Neurodevelopmental outcomes of extremely premature infants conceived after assisted conception: a population based cohort study.
      ,
      • Molines L.
      • Nusinovici S.
      • Moreau M.
      • et al.
      Impact of mode of conception on neonatal and neurodevelopmental outcomes in preterm infants.
      Only 1 other study separated ART and non-ART techniques, but it only examined the relationship with cerebral palsy and was restricted in the sociodemographic variables available for inclusion because the data were obtained from national registers.
      • Hvidtjørn D.
      • Grove J.
      • Schendel D.
      • et al.
      Multiplicity and early gestational age contribute to an increased risk of cerebral palsy from assisted conception: a population-based cohort study.
      Our study was also limited by its restriction to preterm-born children; we are therefore only able to state that there was no increased risk of neurodevelopmental impairment according to mode of conception in this population, but it is also important to remember that there are increased risks of multiple pregnancy and preterm birth with the use of MAR.
      • De Geyter C.
      • Calhaz-Jorge C.
      • Kupka M.S.
      • et al.
      ART in Europe, 2015: results generated from European registries by ESHRE.
      ,
      • Berntsen S.
      • Söderström-Anttila V.
      • Wennerholm U.B.
      • et al.
      The health of children conceived by ART: ‘the chicken or the egg?’.

      Conclusion

      In summary, we assessed neurodevelopmental outcomes at 5½ years of age for children born preterm following MAR, and after adjusting for social characteristics, found no differences from children born following spontaneously conceived pregnancies. These are important insights for obstetricians, pediatricians, and other healthcare professionals working with women and their families. Our study provides further evidence for health professionals to reassure parents or parents-to-be when a child conceived from MAR is born preterm.

      Acknowledgments

      The authors wish to thank everyone involved in the EPIPAGE-2 Study Groups.

      Members of the EPIPAGE-2 Obstetric Writing Group

      P.YA., MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 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 (Department of Gynecology and Obstetrics, CIC, University hospital of Nantes, Nantes, France), Julie Blanc, MD (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, MSc (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 Paris, France, Department of Obstetrics and Gynecology, Cochin, Broca, Hôtel Dieu 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, MSc (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 Paris, France), Caroline Diguisto, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 Paris, France, Maternité Olympe de Gouges, University Francois Rabelais, Tours, France), Laurence Foix-L’Helias, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 Paris, France, Department of Neonatal Pediatrics, Trousseau Hospital, AP-HP, Paris, France), Aurélie Garbi, MD (Department of Neonatology, Assistance Publique Hopitaux de Marseille, Marseille, France), Géraldine Gascoin, MD, PhD (Department of Neonatal Medicine, Angers University Hospital, Angers, 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, INRA, F-75006 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, Armand-Trousseau Hospital, Sorbonne University, Paris, France, Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 Paris, France), Gilles Kayem, MD, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 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, MSc (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 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, INRA, F-75006 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, INRA, F-75006 Paris, France), Andrei Scott Morgan, MBChB, FRCPCH, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 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, INRA, F-75006 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, INRA, F-75006 Paris, France, Neonatal Medicine and Resuscitation Service in 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 Vayssière, 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, INRA, UMR 1280 Physiologie des adaptations nutritionnelles, Nantes, France), Jennifer Zeitlin, PhD (Université Paris Cité, Epidemiology and Statistics Research Center/CRESS, INSERM, INRA, F-75006 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.

      EPIPAGE-2 Study group–2 year follow-up

      Alsace: D Astruc, P Kuhn, B Langer, J Matis, C Ramousset; Aquitaine: X Hernandorena, P Chabanier, L Joly-Pedespan, MJ Costedoat, A Leguen; Auvergne: B Lecomte, D Lemery, F Vendittelli; Basse-Normandie: G Beucher, M Dreyfus, B Guillois, Y Toure; Bourgogne: A Burguet, S Couvreur, JB Gouyon, P Sagot, N Colas; Bretagne: J Sizun, A Beuchée, P Pladys, F Rouget, RP Dupuy, D Soupre, F Charlot, S Roudaut; Centre: A Favreau, E Saliba, L Reboul; Champagne-Ardenne: N Bednarek, P Morville, V Verrière; Franche-Comté: G Thiriez, C Balamou; Haute-Normandie: L Marpeau, S Marret, C Barbier; Ile-de-France: G Kayem, X Durrmeyer, M Granier, M Ayoubi, O Baud, B Carbonne, L Foix-L’Helias, F Goffinet, PH Jarreau, D Mitanchez, P Boileau, C Duffaut, E Lorthe, L Cornu, R Moras; Languedoc-Roussillon: P Boulot, G Cambonie, H Daudé, A Badessi, N Tsaoussis; Limousin: A Bédu, F Mons, C Bahans; Lorraine: MH Binet, J Fresson, JM Hascoët, A Milton, O Morel, R Vieux, L Hilpert; Midi-Pyrénées: C Alberge, C Arnaud, C Vayssière, M Baron; Nord-Pas-de-Calais: ML Charkaluk, V Pierrat, D Subtil, P Truffert, S Akowanou; PACA et Corse: C D’Ercole, C Gire, U Simeoni, A Bongain, M Deschamps; Pays de Loire: B Branger, JC Rozé, N Winer, V Rouger, C Dupont; Picardie: J Gondry, G Krim, B Baby; Rhône-Alpes: M Debeir, O Claris, JC Picaud, S Rubio-Gurung, C Cans, A Ego, T Debillon, H Patural, A Rannaud; Guadeloupe: E Janky, A Poulichet, JM Rosenthal, E Coliné; Guyane: A Favre, N Joly; Martinique: S Châlons, J Pignol, PL Laurence; La Réunion : PY Robillard, S Samperiz, D Ramful.
      Inserm UMR 1153: PY Ancel, V Benhammou, B Blondel, M Bonet, A Brinis, A Coquelin, M Durox, M Kaminski, K Khemache, B Khoshnood, C Lebeaux, L Marchand-Martin, J Rousseau, MJ Saurel-Cubizolles, D Tran, J Zeitlin.

      EPIPAGE-2 Study group – 5 year follow-up

      Alsace: D Astruc, P Kuhn, B Langer, J Matis, C Ramousset; Aquitaine: X Hernandorena, P Chabanier, L Joly-Pedespan, M Rebola, MJ Costedoat, A Leguen, C Martin; Auvergne: B Lecomte, D Lemery, F Vendittelli, E Rochette; Basse-Normandie: G Beucher, M Dreyfus, B Guillois, V. Datin-Dorrière, Y Toure, D Rots; Bourgogne: A Burguet, S Couvreur, JB Gouyon, P Sagot, N Colas, A Franzin; Bretagne: J Sizun, A Beuchée, P Pladys, F Rouget, RP Dupuy, D Soupre, F Charlot, S Roudaut; Centre: A Favreau, E Saliba, L Reboul, E Aoustin; Champagne-Ardenne: N Bednarek, P Morville, V Verrière; Franche-Comté: G Thiriez, C Balamou, C Ratajczak; Haute-Normandie: L Marpeau, S Marret, C Barbier, N Mestre; Ile-de-France: G Kayem, X Durrmeyer, M Granier, M Ayoubi, O Baud, B Carbonne, L Foix-L’Helias, F Goffinet, PH Jarreau, D Mitanchez, P Boileau, C Duffaut, E Lorthe, L Cornu, R Moras, D Salomon, S Medjahed, K Ahmed; Languedoc-Roussillon: P Boulot, G Cambonie, H Daudé, A Badessi, N Tsaoussis, M Poujol; Limousin: A Bédu, F Mons, C Bahans; Lorraine: MH Binet, J Fresson, JM Hascoët, A Milton, O Morel, R Vieux, L Hilpert; Midi-Pyrénées: C Alberge, C Arnaud, C Vayssière, M Baron; Nord-Pas-de-Calais: ML Charkaluk, V Pierrat, D Subtil, P Truffert, S Akowanou, D Roche, M Thibaut; PACA et Corse: C D’Ercole, C Gire, U Simeoni, A Bongain, M Deschamps, M Zahed; Pays de Loire: B Branger, JC Rozé, N Winer, V Rouger, C Dupont, H Martin; Picardie: J Gondry, G Krim, B Baby, I Popov; Rhône-Alpes: M Debeir, O Claris, JC Picaud, S Rubio-Gurung, C Cans, A Ego, T Debillon, H Patural, A Rannaud; Guadeloupe: E Janky, A Poulichet, JM Rosenthal, E Coliné, C Cabrera; Guyane: A Favre, N Joly, Stouvenel A; Martinique: S Châlons, J Pignol, PL Laurence, V Lochelongue; La Réunion : PY Robillard, S Samperiz, D Ramful.
      Inserm UMR 1153: PY Ancel, H Asadullah, V Benhammou, B Blondel, A Brinis, ML Charkaluk, A Coquelin, V Delormel, M Durox, M Fériaud, L Foix-L’Helias, F Goffinet, M Kaminski, G Kayem, K Khemache, B Khoshnood, C Lebeaux, E Lorthe, L Marchand-Martin, AS Morgan, L Onestas, V Pierrat, J Rousseau, MJ Saurel-Cubizolles, D Tran, D Sylla, L Vasante-Annamale, J Zeitlin.

      Appendix

      Supplemental Table 1Type of variables, model used to predict missing data, and percentages of values missing for each variable included in the imputation model (N=4349 live children at 5.5 years)
      VariableType of variableModel used to predict missing dataPercentage of missing values among survivors at 5.5 y
      Perinatal characteristics
      Mode of conception (spontaneous, IO, IUI, IVF, IVF-ICSI)Categorical (5 categories)No missing data0%
      GA by weekCategorical (11 categories)No missing data0%
      Birth countryCategorical (5 categories)Multinomial regression1%
      Maternal age at deliveryContinuousNo missing data0%
      PrimiparityBinaryLogistic regression1%
      Parents’ socioeconomic status
      Defined as the highest occupational status among occupations of the mother and the father or mother only if living alone
      Categorical (6 categories)Multinomial regression5%
      Maternal level of educationCategorical (4 categories)Multinomial regression7%
      Smoking during pregnancyBinaryLogistic regression3%
      Occupational activity during pregnancyBinaryLogistic regression6%
      Living with partner at deliveryBinaryLogistic regression5%
      Antenatal steroidsBinaryLogistic regression2%
      TocolysisBinaryLogistic regression<1%
      Pregnancy type (singleton or twins)Categorical (4 categories)Multinomial regression0%
      Spontaneous preterm deliveryBinaryLogistic regression3%
      Cephalic presentationBinaryLogistic regression3%
      Maternity levelBinaryNo missing data0%
      Caesarean deliveryBinaryLogistic regression1%
      SexBinaryNo missing data0%
      SGA
      SGA was defined as a birthweight of <10th percentile for GA and sex based on the French intrauterine growth curves.28
      BinaryLogistic regression<1%
      Severe congenital malformationsBinaryNo missing data0%
      SurfactantBinaryLogistic regression1%
      Severe cerebral lesionsBinaryLogistic regression1%
      Severe bronchopulmonary dysplasiaBinaryLogistic regression3%
      Severe necrotizing enterocolitisBinaryLogistic regression2%
      Suspected early-onset neonatal sepsisBinaryLogistic regression4%
      Late-onset neonatal sepsisBinaryLogistic regression1%
      At 2 y
      Cerebral palsyCategorical (5 categories)Multinomial regression19%
      Hearing impairmentCategorical (3 categories)Multinomial regression21%
      Visual impairmentCategorical (3 categories)Multinomial regression23%
      ASQ communication scoreContinuousPredictive mean matching18%
      ASQ gross motor scoreContinuousPredictive mean matching20%
      ASQ fine motor scoreContinuousPredictive mean matching21%
      ASQ problem-solving scoreContinuousPredictive mean matching21%
      ASQ personal-social scoreContinuousPredictive mean matching21%
      At 5 y
      Support at school or special schoolingCategorical (3 categories)Multinomial regression33%
      Cerebral palsyCategorical (5 categories)Multinomial regression31%
      Hearing impairmentCategorical (4 categories)Multinomial regression32%
      Visual impairmentCategorical (4 categories)Multinomial regression40%
      WPPSI-IV Verbal Comprehension Index scoreContinuousPredictive mean matching40%
      WPPSI-IV Visual-Spatial Index scoreContinuousPredictive mean matching40%
      WPPSI-IV Fluid Reasoning Index scoreContinuousPredictive mean matching40%
      WPPSI-IV Working Memory Index scoreContinuousPredictive mean matching40%
      WPPSI-IV Processing Speed Index scoreContinuousPredictive mean matching40%
      WPPSI-IV Full Scale IQ scoreContinuousPredictive mean matching40%
      MABC-2 total scoreContinuousPredictive mean matching42%
      SDQ total scoreContinuousPredictive mean matching40%
      All variables were included as a predictor in all imputation models.
      ASQ, Ages and Stages Questionnaire (Squire, 2009); GA, gestational age; ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; MABC-2, Movement Assessment Battery for Children-Second Edition (Henderson, 2007); SDQ, Strengths and Difficulties Questionnaire (Goodman, 1997); MAR, medically assisted reproduction; IUI, intrauterine insemination; IVF, in vitro fertilization; SGA, small for gestational age; WPPSI, Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (Wechsler, 2014).
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically-assisted reproduction. Am J Obstet Gynecol 2022.
      a Defined as the highest occupational status among occupations of the mother and the father or mother only if living alone
      b SGA was defined as a birthweight of <10th percentile for GA and sex based on the French intrauterine growth curves.28
      Supplemental Table 2Comparison of children participating and nonparticipating in follow-up (N=4349 live children at 5.5 years)
      VariableParticipating children at 5.5 yearsNon-participating children at 5.5 yearsChi-squared P value
      n=3031n=1318
      Mode of conception
       Spontaneous2390/303178.11145/131886.7<.001
       MAR
      MAR corresponds to the whole range of MAR techniques (ie, IO, IUI, IVF, and IVF-ICSI)
      641/303121.9173/131813.3
       IO or IUI299/30319.682/13186.0
       IVF or IVF-ICSI342/303112.391/13187.3
      Maternal characteristics at birth
      Maternal age, mean (SD)303130.5 (5.5)131828.9 (6.0)<.001
      Primiparous1699/300456.5652/129851.7.031
      Born in France2477/302585.0891/128471.2<.001
      Smoked during pregnancy564/294917.9344/128525.2<.001
      Maternal level of education
       Less than high school835/293827.1486/109842.4<.001
       High school605/293820.4268/109824.6
       1–2 y of graduate studies622/293821.7156/109813.9
       ≥3 y of graduate studies876/293830.8188/109819.1
      Occupational activity during pregnancy1976/284171.3640/123655.7<.001
      Cohabiting with partner at delivery2686/288494.01067/124684.6<.001
      Parents’ socioeconomic status
      Defined as the highest occupational status among occupations of the mother and the father or mother only if living alone
       Executive742/292126.3168/121515.3<.001
       Intermediate696/292125.0176/121515.6
       Administration761/292125.6375/121531.9
       Service, trade360/292111.9228/121517.6
       Worker308/29219.4184/121513.8
       Unemployed54/29211.784/12155.8
      Obstetrical and neonatal factors
      Multiple pregnancy status
       Singleton1967/303162.7916/131868.6<.001
       Twins991/303134.8372/131829.6
       Triplets68/30312.430/13181.8
       Quadruplets5/30310.10/13180.0
      Antenatal steroids2466/298678.61024/129575.1.068
      Tocolysis1595/301248.7700/131148.8.98
      Spontaneous preterm delivery1422/291648.9684/128553.4.046
      Cephalic presentation1975/293771.6887/127174.4.313
      Cesarean delivery1960/301960.8782/130655.7.019
      Maternity level III2373/303164.7974/131859.0<.001
      GA at birth (wk), mean (SD)303131.7 (2.4)131832.0 (2.3)
       24–26375/30314.6159/13184.0<.001
       27–311900/303131.1759/131825.7
       32–34756/303164.3400/131870.3
      Male gender1605/303154.6683/131850.1.040
      SGA
      SGA was defined as a birthweight of <10th percentile for GA and sex based on French intrauterine growth curves.28
      1053/303034.3437/131832.0.31
      Severe malformations223/30317.392/13185.4.069
      Data are presented as number of events/number in groups or percentages, unless otherwise indicated. For observed data, denominators vary according to the number of missing data for each variable. Results are weighted to consider the differences in survey design among GA groups. Proportions are not exactly number/total number because of weighting.
      GA, gestational age; ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; IUI, intrauterine insemination; IVF, in vitro fertilization; MAR, medically assisted reproduction; SD, standard deviation; SGA, small for gestational age.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically-assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques (ie, IO, IUI, IVF, and IVF-ICSI)
      b Defined as the highest occupational status among occupations of the mother and the father or mother only if living alone
      c SGA was defined as a birthweight of <10th percentile for GA and sex based on French intrauterine growth curves.28
      Supplemental Table 3Survival at 5.5 years according to mode of conception (N=4907 live births included)
      VariableSpontaneousMAR
      MAR corresponds to the whole range of MAR techniques (ie, OI, IUI, IVF, and IVF-ICSI)
      P value
      Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy.
      IO or IUIP value
      Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy.
      IVF or IVF-ICSIP value
      Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy.
      No. of children = 4004No. of children = 903No. of children = 421No. of children = 482
      Survival.025.15.60
       Deaths in delivery room1241.4181.080.8101.2
       Neonatal deaths3214.0703.4313.7393.2
       Deaths after discharge240.610.110.100.0
       Survival at 5.5 years353594.081495.538195.443395.6
      Data are presented as number of events and percentages. Denominators vary according to the number of missing data for each variable. Results are weighted to consider the differences in survey design among gestational age groups. Proportions are not exactly number/total number because of weighting.
      ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; IUI, intrauterine insemination; IVF, in vitro fertilization; MAR, medically assisted reproduction.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically-assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques (ie, OI, IUI, IVF, and IVF-ICSI)
      b Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy.
      Supplemental Table 4Association between mode of conception and neurodevelopmental outcome measures at 5.5 years, multivariate analysis after multiple imputation, among singleton pregnancies
      VariableMAR
      MAR corresponds to the whole range of MAR techniques (ie, OI, IUI, IVF, and IVF-ICSI)
      (no. of children = 231)
      IO or IUI (no. of children = 123)IVF or IVF-ICSI (no. of children = 108)
      vs
      Spontaneous conception (no. of children = 2652)
      OR or MD (95% CI)
      The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported
      P valueOR or MD (95% CI)
      The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported
      P valueOR or MD (95% CI)
      The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported
      P value
      Cerebral palsy
       Adjusted for GA and antenatal steroids1.04 (0.58–1.86).901.04 (0.46–2.32).931.02 (0.45–2.33).95
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.26 (0.69–2.31).451.24 (0.55–2.79).611.27 (0.54–2.99).58
      Full Scale IQ
      Full Scale IQ, measured using the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition26
       MD (95% CI)
      Adjusted for GA and antenatal steroids4.6 (2.3–6.9)<.0013.6 (0.6–6.6).0205.8 (2.4–9.2)<.001
      Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.2 (−1.0 to 3.3).290.9 (−1.9 to 3.7).531.5 (−1.7 to 4.7).36
       <1 SD (<93)
      Cutoff of the distribution related to a reference group born at term27
      Adjusted for GA and antenatal steroids0.52 (0.38–0.73)<.0010.48 (0.31–0.75).0010.57 (0.36–0.92).022
      Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.72 (0.49–1.04).0790.59 (0.36–0.96).0350.89 (0.53–1.51).67
       <2 SD (<79)
      Cutoff of the distribution related to a reference group born at term27
      Adjusted for GA and antenatal steroids0.64 (0.40–1.03).0680.67 (0.36–1.24).200.61 (0.30–1.24).17
      Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.99 (0.59–1.66).970.92 (0.47–1.79).811.08 (0.50–2.32).85
      Severe and moderate neurodevelopmental impairment
      Severe or moderate cerebral palsy, severe or moderate sensory disabilities, or Full Scale IQ <2 SDs below the mean of a reference population
       Adjusted for GA and antenatal steroids0.63 (0.40–1.00).050.64 (0.36–1.17).150.61 (0.31–1.19).14
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.93 (0.56–1.53).770.86 (0.46–1.62).651.01 (0.49–2.06).98
      Developmental coordination disorders
      Among children without cerebral palsy, without severe or moderate sensory disabilities, and with Full Scale IQ ≥2 SDs below the mean of a reference population.
       Total MABC-2 score, MD (95% CI)
      Adjusted for GA and antenatal steroids0.2 (−0.4 to 0.7).530.2 (−0.6 to 0.9).670.2 (−0.6 to 0.9).63
      Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.1 (−0.5 to 0.6).790.1 (−0.6 to 0.8).810.1 (−0.7 to 0.8).89
       Total MABC-2 score<5th percentile
      Cutoff of the distribution related to a reference group born at term27
      Adjusted for GA and antenatal steroids0.75 (0.39–1.43).390.83 (0.36–1.91).660.66 (0.24–1.78).41
      Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.76 (0.39–1.46).400.84 (0.36–1.94).680.66 (0.24–1.79).41
      CI, confidence interval; GA, gestational age; ICSI, intracytoplasmic sperm injection; IQ, intelligence quotient; IUI, intrauterine insemination; IVF, in vitro fertilization; MABC-2, Movement Assessment Battery for Children-Second Edition (Henderson, 2007); MAR, medically assisted reproduction; MD, mean difference; OI, ovulation induction; OR, odds ratio; SD, standard deviation.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically-assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques (ie, OI, IUI, IVF, and IVF-ICSI)
      b The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported
      c Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      d Full Scale IQ, measured using the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition26
      e Cutoff of the distribution related to a reference group born at term27
      f Severe or moderate cerebral palsy, severe or moderate sensory disabilities, or Full Scale IQ <2 SDs below the mean of a reference population
      g Among children without cerebral palsy, without severe or moderate sensory disabilities, and with Full Scale IQ ≥2 SDs below the mean of a reference population.
      Supplemental Table 5Neurodevelopmental outcome measures at 5.5 years according to mode of conception (complete case analysis)
      VariablesSpontaneousMAR
      MAR corresponds to the whole range of MAR techniques (ie IO, IUI, IVF, and IVF-ICSI)
      P value
      Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy
      IO or IUIP value
      Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy
      IVF or IVF-ICSIP value
      Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy
      Cerebral palsy116/23683.432/6384.0.5415/2985.9.1217/3402.6.43
      Visual impairment
      Severe and moderate impairment
      Blindness or binocular corrected visual acuity of <3.2/10
      12/20490.53/5700.6.812/2591.2.341/3110.1.27
      Hearing impairment
      Severe and moderate impairment
      Deafness, hearing loss of >40 dB not corrected or partially corrected with hearing aid
      18/23120.69/6271.6.102/2920.3.247/3352.6.014
      Full Scale IQ
      Full Scale IQ, measured by the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition26
      Mean (SD)203797.9 (14.4)552101.2 (14.9)<.001251100.7 (14.6).051301101.7 (15.1).003
      <1 SD (<93)
      Cutoff of the distribution related to a reference group born at term27
      757/203734.0168/55225.6.02972/25124.5.02696/30126.4.048
      <2 SD (<79)
      Cutoff of the distribution related to a reference group born at term27
      225/20378.755/5526.6.1427/2516.9.3328/3016.4.22
      Neurodevelopmental impairment
      Severe and moderate impairment
      Severe or moderate cerebral palsy, severe or moderate sensory impairment, or Full Scale IQ quotient <2 SDs below the mean of a reference group
      283/205910.570/5569.2.4136/22510.1.8134/3018.4.36
      Developmental coordination disorders
      Among children without cerebral palsy, without severe or moderate sensory impairment, and with Full Scale IQ ≥2 SDs below the mean of a reference group.
      Total MABC-2 score, mean (SD)171310.3 (3.0)47010.5 (2.8).3421310.4 (3.2).7225710.6 (2.5).27
      Total MABC-2 score<5th percentile
      Cutoff of the distribution related to a reference group born at term27
      134/17135.128/4703.7.2514/2135.8.7414/2572.1.005
      Data are presented as number of events/number in groups or percentages, unless otherwise indicated. Denominators vary according to the number of missing data for each variable. Results are weighted to consider the differences in survey design among gestational age groups. Proportions are not exactly number/total number because of the weighting.
      ICSI, intracytoplasmic sperm injection; IO, induction of ovulation; IQ, intelligence quotient; IUI, intrauterine insemination; IVF, in vitro fertilization; MABC-2, Movement Assessment Battery for Children-Second Edition (Henderson, 2007); MAR, medically assisted reproduction; SD, standard deviation.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically-assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques (ie IO, IUI, IVF, and IVF-ICSI)
      b Chi-squared test P value, estimated with generalized estimating equations approach to consider the correlation between twins and triplets, compared to spontaneous pregnancy
      c Blindness or binocular corrected visual acuity of <3.2/10
      d Deafness, hearing loss of >40 dB not corrected or partially corrected with hearing aid
      e Full Scale IQ, measured by the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition26
      f Cutoff of the distribution related to a reference group born at term27
      g Severe or moderate cerebral palsy, severe or moderate sensory impairment, or Full Scale IQ quotient <2 SDs below the mean of a reference group
      h Among children without cerebral palsy, without severe or moderate sensory impairment, and with Full Scale IQ ≥2 SDs below the mean of a reference group.
      Supplemental Table 6Association between mode of conception and neurodevelopmental outcome measures at 5.5 years (multivariate complete case analysis)
      VariableMAR
      MAR corresponds to the whole range of MAR techniques (ie IO, IUI, IVF, and IVF-ICSI)
      IO or IUIIVF or IVF-ICSI
      vs
      Spontaneous conception
      OR or MD (95% CI)
      The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported. The generalized estimating equations approach is used to consider the correlation between twins or triplets
      P valueOR or MD (95% CI)
      The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported. The generalized estimating equations approach is used to consider the correlation between twins or triplets
      P valueOR or MD (95% CI)
      The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported. The generalized estimating equations approach is used to consider the correlation between twins or triplets
      P value
      Cerebral palsy
       Adjusted for GA and antenatal steroids1.03 (0.67–1.58).900.95 (0.52–1.72).861.11 (0.64–1.93).71
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.17 (0.67–2.03).580.90 (0.43–1.92).791.48 (0.75–2.89).26
      Full Scale IQ,
      Full Scale IQ, measured by the Wechsler Preschool and Primary Scale of Intelligence-Fourth edition26
      MD (95% CI)
       Adjusted for GA and antenatal steroids2.6 (1.0–4.3).0022.2 (−0.1 to 4.4).0573.0 (0.8–5.2).007
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.1 (−1.5 to 1.8).860.9 (−1.2 to 3.0).40−0.6 (−2.9 to 1.7).63
      <1 SD (<93)
      Cutoff of the distribution related to a reference group born at term27
       Adjusted for GA and antenatal steroids0.72 (0.57–0.90).0040.63 (0.45–0.88).0070.79 (0.60–1.06).110
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.99 (0.74–1.32).950.76 (0.51–1.13).181.26 (0.88–1.80).20
      <2 SD (<79)
      Cutoff of the distribution related to a reference group born at term27
       Adjusted for GA and antenatal steroids0.91 (0.64–1.30).610.94 (0.59–1.51).800.88 (0.54–1.45).62
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.29 (0.82–2.01).271.04 (0.59–1.85).881.62 (0.88–2.96).12
      Severe and moderate neurodevelopmental impairment
      Severe or moderate cerebral palsy, severe or moderate sensory disabilities, or Full scale IQ <2 SDs below the mean of a reference population
       Adjusted for GA and antenatal steroids0.95 (0.69–1.29).731.01 (0.68–1.51).950.88 (0.57–1.37).57
       Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      1.33 (0.90–1.96).151.19 (0.73–1.93).491.51 (0.89–2.54).12
      Developmental coordination disorders
      Among children without cerebral palsy, without severe or moderate sensory disabilities, and with Full Scale IQ ≥2 SDs below the mean of a reference population.
       Total MABC-2 score, MD (95% CI)
      Adjusted for GA and antenatal steroids0.2 (−0.2 to 0.5).36−0.0 (−0.5 to 0.5).890.3 (−0.1 to 0.8).13
      Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      -0.0 (-0.4–0.4).99−0.1 (−0.6 to 0.5).770.1 (−0.4 to 0.6).74
       Total MABC-2 score<5th percentile
      Cutoff of the distribution related to a reference group born at term27
      Adjusted for GA and antenatal steroids0.66 (0.42–1.05).0800.68 (0.36–1.27).230.65 (0.35–1.20).17
      Adjusted for GA, antenatal steroids, and sociodemographic variables
      Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      0.76 (0.44–1.31).320.78 (0.39–1.59).500.73 (0.36–1.49).39
      CI, confidence interval; GA, gestational age; ICSI, intracytoplasmic sperm injection; IQ, intelligence quotient; IUI, intrauterine insemination; IVF, in vitro fertilization; MABC-2, Movement Assessment Battery for Children-Second Edition (Henderson, 2007); MAR, medically assisted reproduction; MD, mean difference; OI, ovulation induction; OR, odds ratio; SD, standard deviation.
      Verhaeghe. Neurodevelopment at age 5 for preterm children born following medically-assisted reproduction. Am J Obstet Gynecol 2022.
      a MAR corresponds to the whole range of MAR techniques (ie IO, IUI, IVF, and IVF-ICSI)
      b The reported measures of association are OR, except for Full Scale IQ and total MABC-2 score where MDs are reported. The generalized estimating equations approach is used to consider the correlation between twins or triplets
      c Sociodemographic factors adjusted for were maternal age, parity, education level, employment status, living with a partner, smoking during pregnancy, country of birth, and parents’ socioeconomic status
      d Full Scale IQ, measured by the Wechsler Preschool and Primary Scale of Intelligence-Fourth edition26
      e Cutoff of the distribution related to a reference group born at term27
      f Severe or moderate cerebral palsy, severe or moderate sensory disabilities, or Full scale IQ <2 SDs below the mean of a reference population
      g Among children without cerebral palsy, without severe or moderate sensory disabilities, and with Full Scale IQ ≥2 SDs below the mean of a reference population.

      References

        • Zegers-Hochschild F.
        • Adamson G.D.
        • Dyer S.
        • et al.
        The international glossary on infertility and fertility care, 2017.
        Hum Reprod. 2017; 32: 1786-1801
        • Oakley L.
        • Doyle P.
        • Maconochie N.
        Lifetime prevalence of infertility and infertility treatment in the UK: results from a population-based survey of reproduction.
        Hum Reprod. 2008; 23: 447-450
        • Schmidt L.
        Social and psychological consequences of infertility and assisted reproduction - what are the research priorities?.
        Hum Fertil (Camb). 2009; 12: 14-20
        • Peterson B.D.
        • Pirritano M.
        • Christensen U.
        • Boivin J.
        • Block J.
        • Schmidt L.
        The longitudinal impact of partner coping in couples following 5 years of unsuccessful fertility treatments.
        Hum Reprod. 2009; 24: 1656-1664
        • Volgsten H.
        • Skoog Svanberg A.
        • Ekselius L.
        • Lundkvist O.
        • Sundström Poromaa I.
        Prevalence of psychiatric disorders in infertile women and men undergoing in vitro fertilization treatment.
        Hum Reprod. 2008; 23: 2056-2063
        • Chachamovich J.R.
        • Chachamovich E.
        • Ezer H.
        • Fleck M.P.
        • Knauth D.
        • Passos E.P.
        Investigating quality of life and health-related quality of life in infertility: a systematic review.
        J Psychosom Obstet Gynaecol. 2010; 31: 101-110
        • Facchin F.
        • Somigliana E.
        • Busnelli A.
        • Catavorello A.
        • Barbara G.
        • Vercellini P.
        Infertility-related distress and female sexual function during assisted reproduction.
        Hum Reprod. 2019; 34: 1065-1073
        • Gabr A.A.
        • Omran E.F.
        • Abdallah A.A.
        • et al.
        Prevalence of sexual dysfunction in infertile versus fertile couples.
        Eur J Obstet Gynecol Reprod Biol. 2017; 217: 38-43
        • Goisis A.
        • Håberg S.E.
        • Hanevik H.I.
        • Magnus M.C.
        • Kravdal Ø.
        The demographics of assisted reproductive technology births in a Nordic country.
        Hum Reprod. 2020; 35: 1441-1450
        • De Geyter C.
        • Calhaz-Jorge C.
        • Kupka M.S.
        • et al.
        ART in Europe, 2015: results generated from European registries by ESHRE.
        Hum Reprod Open. 2020; 2020: hoz038
        • Mani S.
        • Ghosh J.
        • Coutifaris C.
        • Sapienza C.
        • Mainigi M.
        Epigenetic changes and assisted reproductive technologies.
        Epigenetics. 2020; 15: 12-25
        • Berntsen S.
        • Söderström-Anttila V.
        • Wennerholm U.B.
        • et al.
        The health of children conceived by ART: ‘the chicken or the egg?’.
        Hum Reprod Update. 2019; 25: 137-158
        • Wolke D.
        • Johnson S.
        • Mendonça M.
        The life course consequences of very preterm birth.
        Annu Rev Dev Psychol. 2019; 1: 69-92
        • Doyle L.W.
        • Spittle A.
        • Anderson P.J.
        • Cheong J.L.Y.
        School-aged neurodevelopmental outcomes for children born extremely preterm.
        Arch Dis Child. 2021; 106: 834-838
        • Morgan A.S.
        • Mendonça M.
        • Thiele N.
        • David A.L.
        Management and outcomes of extreme preterm birth.
        BMJ (Clin Res Ed). 2022; 376e055924
        • Strömberg B.
        • Dahlquist G.
        • Ericson A.
        • Finnström O.
        • Köster M.
        • Stjernqvist K.
        Neurological sequelae in children born after in-vitro fertilisation: a population-based study.
        Lancet. 2002; 359: 461-465
        • Hashimoto K.
        • Ogawa K.
        • Horikawa R.
        • et al.
        Gross motor function and general development of babies born after assisted reproductive technology.
        J Obstet Gynaecol Res. 2016; 42: 266-272
        • Roychoudhury S.
        • Lodha A.
        • Synnes A.
        • et al.
        Neurodevelopmental outcomes of preterm infants conceived by assisted reproductive technology.
        Am J Obstet Gynecol. 2021; 225: 276.e1-276.e9
        • Balayla J.
        • Sheehy O.
        • Fraser W.D.
        • et al.
        Neurodevelopmental outcomes after assisted reproductive technologies.
        Obstet Gynecol. 2017; 129: 265-272
        • Torchin H.
        • Morgan A.S.
        • Ancel P.Y.
        International comparisons of neurodevelopmental outcomes in infants born very preterm.
        Semin Fetal Neonatal Med. 2020; 25101109
        • Abdel-Latif M.E.
        • Bajuk B.
        • Ward M.
        • Oei J.L.
        • Badawi N.
        NSW and ACT Neonatal Intensive Care Units Audit Group. Neurodevelopmental outcomes of extremely premature infants conceived after assisted conception: a population based cohort study.
        Arch Dis Child Fetal Neonatal Ed. 2013; 98: F205-F211
        • Molines L.
        • Nusinovici S.
        • Moreau M.
        • et al.
        Impact of mode of conception on neonatal and neurodevelopmental outcomes in preterm infants.
        Hum Reprod. 2019; 34: 356-364
        • Hvidtjørn D.
        • Grove J.
        • Schendel D.
        • et al.
        Multiplicity and early gestational age contribute to an increased risk of cerebral palsy from assisted conception: a population-based cohort study.
        Hum Reprod. 2010; 25: 2115-2123
        • Ancel P.Y.
        • Goffinet F.
        • EPIPAGE 2 Writing Group
        EPIPAGE 2: a preterm birth cohort in France in 2011.
        BMC Pediatr. 2014; 14: 97
        • Lorthe E.
        • Benhammou V.
        • Marchand-Martin L.
        • et al.
        Cohort profile: the Etude Epidemiologique sur les Petits Ages Gestationnels-2 (EPIPAGE-2) preterm birth cohort.
        Int J Epidemiol. 2021; 50: 1428-1429m
      1. Wechsler D. Pearson clinical & talent assessment. WPPSI-IV – échelle d’intelligence de Wechsler pour enfants. 4ème édition. Published online; 2014. Available at: https://nam12.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.pearsonclinical.fr%2Fwppsi-iv&data=05%7C01%7CS.Devarajan%40elsevier.com%7C74521eadbdef41dca8ed08da56983b99%7C9274ee3f94254109a27f9fb15c10675d%7C0%7C0%7C637917509079069870%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=g2ZfN0ETohxPJjU8bnC65N%2FiQl%2B71f0J6g1pGavdC%2BI%3D&reserved=0. Accessed June 23, 2022

        • 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
        • Ego A.
        • Prunet C.
        • Lebreton E.
        • et al.
        [Customized and non-customized French intrauterine growth curves. I - methodology].
        J Gynecol Obstet Biol Reprod (Paris). 2016; 45: 155-164
        • Rubin D.B.
        Multiple Imputation for non response in surveys.
        1st ed. John Wiley & Sons, Inc, Chichester1987
      2. R Core Team. R: A language and environment for statistical computing. Version 4.0.4 (2021-02-15) -- “Lost Library Book”. R Foundation for Statistical Computing: Vienna, Austria. 2021 Available at: https://nam12.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.r-project.org%2F&data=05%7C01%7CS.Devarajan%40elsevier.com%7C74521eadbdef41dca8ed08da56983b99%7C9274ee3f94254109a27f9fb15c10675d%7C0%7C0%7C637917509079069870%7CUnknown%7CTWFpbGZsb3d8eyJWIoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=ksO8JZ1pYdp4LlKSc5PWsSYBQgE8NQTkpV70FTGduao%3D&reserved=0.

        • Højsgaard S.
        • Halekoh U.
        • Yan J.
        The R package geepack for Generalized Estimating Equations.
        J Stat Softw. 2005; 15: 1-11
        • van Buuren S.
        • Groothuis-Oudshoorn K.
        mice: multivariate Imputation by Chained Equations in R.
        J Stat Soft. 2011; 45: 1-67
        • Goldsmith S.
        • Mcintyre S.
        • Badawi N.
        • Hansen M.
        Cerebral palsy after assisted reproductive technology: a cohort study.
        Dev Med Child Neurol. 2018; 60: 73-80
        • Edstedt Bonamy A.K.
        • Zeitlin J.
        • Piedvache A.
        • et al.
        Wide variation in severe neonatal morbidity among very preterm infants in European regions.
        Arch Dis Child Fetal Neonatal Ed. 2019; 104: F36-F45
        • Wolke D.
        • Söhne B.
        • Ohrt B.
        • Riegel K.
        Follow-up of preterm children: important to document dropouts.
        Lancet. 1995; 345: 447
        • Hvidtjørn D.
        • Grove J.
        • Schendel D.E.
        • et al.
        Cerebral palsy among children born after in vitro fertilization: the role of preterm delivery–a population-based, cohort study.
        Pediatrics. 2006; 118: 475-482