Articles
Long-term effects of selective fetal growth restriction (LEMON): a cohort study of neurodevelopmental outcome in growth discordant identical twins in the Netherlands

https://doi.org/10.1016/S2352-4642(22)00159-6Get rights and content

Summary

Background

Singletons born after fetal growth restriction (FGR) are at increased risk of poor neurodevelopmental outcomes. Studies of singletons with FGR usually compare outcomes with those without FGR, a comparison that is inherently biased by obstetrical, parental, and genetic factors. We aim to compare neurodevelopmental outcomes between the smaller and larger twin in a population of discordant identical twins who shared a single placenta (monochorionic diamniotic), naturally eliminating these confounders.

Methods

This study is part of the cohort study LEMON of monochorionic diamniotic twins with selective FGR. All monochorionic diamniotic twins with selective FGR who were born in Leiden University Medical Center (Leiden, Netherlands) between March 1, 2002, and Dec 31, 2017, were eligible for inclusion. Twin pregnancies that were complicated by twin–twin transfusion syndrome, twin anaemia polycythaemia sequence, or monoamnionicity were excluded. Cognitive performance was evaluated with two standardised psychometric age-appropriate tests, producing a full-scale intelligence quotient (FSIQ). Motor functioning was assessed with a standardised neurological examination. A composite outcome of neurodevelopmental impairment (NDI) was used, subdivided into mild NDI (defined as FSIQ <85, minor neurological dysfunction or cerebral palsy grade 1, or mild visual or hearing impairment) and severe NDI (defined as FSIQ <70, severe neurological dysfunction, or severe visual or hearing impairment).

Findings

Between Jan 25, 2021, and March 15, 2022, 47 twin pairs were enrolled in the study and underwent neurodevelopmental assessment. The median gestational age at birth was 33·9 weeks (IQR 31·3–36·0) for the 47 included twin pairs, with median birthweights of 1400 g (1111–1875) in the smaller twin and 2003 g (1600–2680) in the larger twin. The median age at neurodevelopmental assessment was 11 years (8–13). Median FSIQ was 94 (86–101) for the smaller twin and 100 (92–108) for the larger twin (p<0·0001). More smaller twins had mild NDI (17 [36%] of 47) than did the larger twins (five [11%] of 47; odds ratio 4·8 [95% CI 1·6–14·1]; p=0·0049). There was no difference in the proportion of children with severe NDI (two [4%] of 47 in both groups, p=1·0).

Interpretation

As mild NDI can impede children in their daily functioning, we recommend standardised long-term follow-up, including neurodevelopmental testing, for monochorionic diamniotic twins with selective FGR to facilitate early identification of children at risk.

Funding

The Dutch Heart Foundation.

Introduction

The intrauterine environment sets the foundation for lifelong health. Unfavourable intrauterine circumstances, such as fetal growth restriction (FGR), in which the fetus does not reach its growth potential, are associated with health disadvantages.1 High rates of perinatal morbidity and substantial long-term neurodevelopmental impairment (NDI), with poor cognitive performance and neurological dysfunction, have been reported for singletons with FGR.2, 3 In these studies, however, singletons with FGR are primarily compared with singletons without FGR. This comparison is inherently biased by obstetrical, parental, and genetic factors, impeding a proper risk assessment. A study population of identical twins who are discordant for fetal growth naturally eliminates these confounders.

Monochorionic diamniotic (MCDA) twins are genetically identical and share a single placenta. In 15% of MCDA twins, this placenta is unequally shared: one twin has a much smaller placental share than their co-twin, causing FGR for the twin with the smaller share, which is termed selective FGR (sFGR).4, 5 Similar to FGR in singletons, the severity of sFGR in twins is classified according to the umbilical artery Doppler flow pattern in the smaller twin, as proposed by Gratacós and colleagues, with poorer outcomes in children from pregnancies with persistent (type II) or intermittent (type III) absent or reversed end-diastolic flow (A/REDF) than in children from pregnancies with positive end-diastolic flow (type I).6 Assessment of MCDA twins with sFGR can be considered a unique natural experiment in which a twin with restricted growth can be compared with its genetically identical co-twin without growth restriction, allowing evaluation of the true effect of FGR on neurodevelopmental outcomes. Little is known about the long-term outcomes of these twins at present.

Research in context

Evidence before this study

Fetal growth restriction (FGR) is associated with an increased risk of neurodevelopmental problems in childhood, with lower cognitive test scores and higher rates of impairment across different domains than for children without FGR. We searched PubMed on March 7, 2022, with the search terms “fetal growth restriction” and “neurodevelopment”, with no date or language restrictions. We found that current evidence is primarily based on studies in which singletons with FGR are compared with singletons without FGR, a comparison that is inherently biased by obstetrical, parental, and genetic factors.

Added value of this study

Identical twins discordant for fetal growth are a unique population for studying the actual effect of FGR as they share their genetic make-up, sex, age, and family environment and, apart from the factors that led to discordant growth, had the same in utero conditions and the same gestational age at birth. Our study presents extensive long-term neurodevelopmental follow-up, including age-appropriate cognitive testing and standardised neurological examinations, in a cohort of discordant monochorionic diamniotic twins for whom comprehensive perinatal data are available.

Implications of all the available evidence

Consistent with previous studies, our identical twin study shows a strong association between FGR and neurodevelopmental impairment. Standardised long-term follow-up is essential for the early identification of children at risk of neurodevelopmental impairment. The next step in research on neurodevelopmental outcomes in monochorionic diamniotic twins with selective FGR is to perform MRI studies to identify any changes in structural brain development that underlie the observed functional consequences.

Neonatal neurological outcomes of MCDA twins with sFGR have been widely reported, with a high incidence of cerebral injury (ie, up to 33%) and an overall restriction in brain growth for the smaller twin on cerebral ultrasound.7, 8 Yet, well designed studies of long-term neurodevelopmental outcomes are scarce. The existing studies are underpowered; differ extensively in methodology, timing, and type of neurodevelopmental evaluation; and do not give detailed perinatal information.9 The aim of this study is to compare neurodevelopmental outcomes between the smaller and larger twin in MCDA twin pairs with sFGR.

Section snippets

Study design and participants

This study is part of the LEMON study (Long-Term Effects of selective fetal growth restriction in MONochorionic twins), which is a cohort study, including all MCDA twin pairs with sFGR born in the Leiden University Medical Center (LUMC), Leiden, Netherlands, the national referral centre for complications specific to monochorionic twins, such as twin–twin transfusion syndrome, twin anaemia polycythaemia sequence, and sFGR. The LEMON study was reviewed and approved by the ethics committee of the

Results

Between March 1, 2002, and Dec 31, 2017, 806 MCDA twin pairs were born in the LUMC, of which 73 were eligible for inclusion in the LEMON study. Of these twin pairs, 12 (16%) did not want to participate in the study, 13 (18%) were lost to follow-up (five twin pairs moved abroad and eight pairs could not be reached for inclusion), and one (1%) twin pair participated only in the questionnaire assessment of the LEMON study, leaving 47 twin pairs to be included in the neurodevelopmental follow-up

Discussion

In MCDA twins with sFGR, the smaller twin presents with a lower intelligence quotient across all indexes and an increased rate of mild NDI compared with the larger co-twin. To our knowledge, we are the first to show that FGR poses a substantial risk for long-term neurodevelopment in this unique identical twin model controlling for maternal, obstetrical, and genetic factors.

We report that the prevalence of mild NDI in smaller twins with sFGR (36%) was more than double that of the general

Data sharing

Individual participant data (including data dictionaries) that underlie the results reported in this article (text, tables, figures, and appendices) and the study protocol will be available beginning 3 months and ending 10 years after publication. Data will be shared with researchers who provide a methodologically sound proposal and whose proposed use of the data has been approved by an independent review committee (learned intermediary) identified for this purpose and the medical ethical

Declaration of interests

We declare no competing interests.

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