It is estimated that 2%–6% of all births are conceived through assisted reproductive technology (ART) (1). Although reproductive medicine techniques have been used for more than 40 years and are generally considered to be safe, some studies nevertheless suggested a slight increase in congenital comorbidities, pregnancy complications, and neonatal morbidity, as well as an increase in epigenetic abnormalities in children born through in vitro fertilization (IVF) with poorly understood etiological mechanisms (2).

Prematurity, defined by live birth before 37 weeks of gestational age (GA), is a major and growing health issue of concern. It is associated with an increased risk of congenital malformation, mortality and neonatal morbidities, and long-term complications such as neurodevelopmental sequelae. In 2010, prematurity concerned 15 million births worldwide (11% of the total birth) (3). The increasing rate of prematurity has been partly linked to the increased use of ART worldwide (4). Indeed, several studies, including some meta-analyses, reported an increased risk of prematurity and low birth weight after ART, regardless of multiple pregnancy status (5).

Some studies analyzed the neurodevelopmental outcomes in children conceived through ART. Their results were compiled and summarized in systematic reviews, which concluded to the absence of significant difference in the neurodevelopmental wellbeing between children born after ART and children who are naturally conceived (2). Although motor and cognitive development does not appear to be affected by the method of conception, the parental educational level and maternal age might be confounding factors, as they play a key role in cognitive development (2, 6). Available scientific data are therefore mostly reassuring.

Relatively few studies have specifically analyzed neonatal outcomes in preterm infants born after ART, without reporting significant differences with the naturally conceived ones (7–9). Interestingly, only four studies compared the neurodevelopmental outcome of preterm infants born after ART with preterm infants who were spontaneously conceived (10–13). Abdel-Latif et al. focused on extreme prematurity (<29 weeks GA) and on functional disability at 2–3 years defined by developmental delay, cerebral palsy, or sensorial impairment. ART conceptions were associated with adverse neurodevelopmental outcome only among high-risk infants born at 22–26 weeks GA (10). Molines et al. reported a lower probability of non-optimal neurodevelopment at 2 years [using the age and stage questionnaire (ASQ) or development quotient of Brunet–Lezine test] after ART than after spontaneous pregnancy in a cohort of preterm children born before 34 weeks GA (11). The third one concluded to a similar neurodevelopmental outcome at 24–36 months of age, using Gross Motor Function Classification System and Denver II, in 125 preterm infants born between 24 and 36 weeks GA either after ART or after spontaneous multiple pregnancy (12). Recently, Roychoudhury et al. reported a lower risk of neurodevelopmental impairment at 18–24 months of preterm infants born before 29 weeks GA after ART. They also emphasized the importance of carrying out a long-term follow-up study to explore learning disabilities and cognitive impairment (13).

Among the tools that explore general child development, the ASQ is a widely recommended general development assessment tool, gathering the observation of the parents of child skills (14). Furthermore, ASQ is currently being used in large national cohorts of preterm infants as a screening tool for developmental delays, as well as in large longitudinal studies of children born through ART such as the Upstate KIDS study (15). It is composed of an age-specific questionnaire, from 4 to 60 months. To date and to the best of our knowledge, no data are available in the literature on neurodevelopment or the need for referral to therapy services at age 4 for children born prematurely after ART. Comparing such data with those obtained in the spontaneously conceived preterm children would be relevant to help health professionals provide reliable information to parents.

The main objective of this study was to evaluate the impact of ART on the neurodevelopmental outcomes at 4 years in preterm infants born before 34 weeks GA compared with preterm infants who were spontaneously conceived. The secondary objective was to assess the need for therapy services at the same age.

In this study conducted in a large cohort of preterm children born before 34 weeks GA, the neurodevelopmental outcomes at 4 years were not found to be negatively impacted by ART conception. Actually, the mean ASQ score at 4 years was even significantly higher, and the frequency of non-optimal neurodevelopment illustrated by a difficulty in at least two domains was significantly reduced in ART-conceived preterm children compared with the naturally conceived ones. ART-conceived preterm children also did not require significantly more therapy services than the naturally conceived ones.

As widely described in the field of ART, we also reported a significant increase in the rate of multiple pregnancies and a higher maternal age in ART-conceived children as compared with natural conceptions (18). Previously, Farhi et al. already published similar long-term cognitive achievement outcome at school age between children born at term after ART and those spontaneously conceived. Our results are consistent with well-known neonatal characteristics of preterm children associated with poor neurodevelopmental outcomes (20), such as earlier weeks GA at birth, lower socio-economic status, and male gender (birth weight < −1 z-score is significant for ASQ ≥1 domain in difficulty). Our results obtained at 4 years confirm and reinforce those previously reported in preterm children evaluated at 2 years (10–12), showing that preterm children conceived by ART have reduced risk of non-optimal neurodevelopment as compared with the naturally conceived ones. Consistently with the literature, we found that women who underwent ART had a higher SES, which is a protective factor against neurodevelopmental disorders (21). However, we confirmed that preterm children born after ART still had fewer neurodevelopmental disorders than those conceived naturally, even after adjusting for SES, thus highlighting the specificity of ART-conceived preterm children. This is also illustrated in our study by the lower (although not significant) referral to therapy services in the ART preterm group, while the literature reported that women with high SES were more likely to refer children to therapy services (22).

Long-term developmental outcomes in preterm twins vs. singletons have been extensively discussed in the literature before (23). In addition, there is a risk of neurodevelopmental disorders associated with monochorionic pregnancies; in our cohort, the number of children born from a monochorionic pregnancy is not different in the ART vs. the naturally conceived group (11.9% vs. 11.4%, respectively). Higher maternal age has been suggested to stimulate infant neurodevelopment (24). These two factors have therefore been considered here as confounding factors. After adjustment in multivariate analysis, we observed that ART conception remained independently associated with a reduction in the risk of non-optimal neurodevelopment. Other factors stemming from the mother may be implicated in preterm neurodevelopmental outcomes. Parental factors that support neurodevelopment in ART situations are complex to explain. Nevertheless, sending of positive signals and repeated interaction attempts have been reported to be specific characteristics of the behavior of ART mothers (25). It can thus be speculated that these better mother–baby interactions support and enhance child neurodevelopment (26).

The main strength of this study is the large number of preterm children monitored at 4 years. Multicentric inclusion also allowed a short inclusion period, ensuring consistency of care. Multivariate analysis that allowed controlling for main confounding factors, missing data imputation analysis, and GEE modeling reinforced the results. Finally, ASQ is a well-known and validated tool, especially in preterm children (17). Nevertheless, the continuous ASQ score as a cognitive predictive tool have a limited specificity and should be used with caution. As proposed by Sices et al., using the criteria of difficulty in at least one or two domains of development enhanced specificity (96% for difficulty in at least two domains vs. 84% for difficulty in at least one domain) (27).

We also acknowledge that our study has some limitations. The comparison of study and lost to follow-up populations showed that ART-conceived preterm children were more closely monitored than the spontaneously conceived ones, probably because of the higher socio-economic status and parental investment in this group. However, this limitation was partly overcome by missing data imputation.

In conclusion, long-term neurodevelopment of preterm children born after ART is very similar, or even better than that of the spontaneously conceived children. This is reassuring, both for infertility specialists and for parents who conceived through ART in case of threatened preterm birth.