Determinants of fetal growth variability in ART conceptions

The review by Li and collaborators provides a comprehensive synthesis of current evidence on the association between assisted reproductive technologies (ART) and altered growth in the offspring. The contribution tackles a clinically relevant issue in reproductive medicine, discussing the multifaceted contributors to birthweight in ART conceptions. The authors provide a broad and nuanced perspective on a multifactorial phenomenon by incorporating variables such as types of maternal infertility, ART protocols, embryo manipulation, genetic contributions, and pregnancy complications like hypertension and diabetes [1].

Fetal growth is determined by a complex interplay of genetic, maternal, placental, and environmental factors, and ART could theoretically influence any of these features. Studies have shown that both small for gestational age (SGA) and large for gestational age (LGA) neonates are more frequently encountered in the ART population when compared to naturally conceived pregnancies. However, defining which and how many of the mechanisms involved can be attributed specifically to factors inherent to ART remains a challenging task. While the impact exerted, for instance, by different types of maternal infertility appears inherently non-modifiable, other potentially modifiable factors, similarly associated with impaired fetal growth, may instead be addressed; thereby allowing the implementation of corrective strategies to mitigate their adverse effects.

The evidence currently available indicates that the type of ART treatment exerts an effect on fetal growth with remarkable interest in factors such as controlled ovarian stimulation, embryo transfer type, endometrial preparation strategies, and embryo culture conditions. As extensively discussed by Li and colleagues in their review, the supraphysiological E2 levels achieved during controlled ovarian stimulation may be associated with impaired post-transfer implantation success and compromised placental development through several proposed mechanisms, including inhibition of trophoblastic invasion, altered remodeling of the uterine spiral arteries, and endometrial morphological changes. The type of embryo transfer itself (namely fresh-ET versus frozen-ET, FET) is also associated with effects on birthweight, with seemingly opposite outcomes between fresh-ET and FET: FET is correlated with a higher rate of LGA and a lower rate of SGA compared with fresh-ET [2].

Multiple hypotheses have been advanced to explain this divergence in fetal growth according to the type of ET. On one side, pregnancies resulting from frozen embryo transfer showed a greater proportion of larger crown–rump lengths compared to fresh transfers, which may partly account for the higher rates of LGA and macrosomia in this group [3]. Moreover, it appears that the more favorable hormonal environment in FET cycles (i.e., the avoidance of ovarian hyperstimulation during fresh-ET cycles) and the selective preservation of higher-quality embryos through the freeze–thaw process are among the mechanisms involved. In any case, improved placental development seems to play a central role in the observed reduction of LBW and increase in LGA within the FET population, as further supported by the finding that mean uterine artery pulsatility index (UtA-PI) values are lower in these pregnancies compared with those achieved after fresh-ET [4, 5]. Nevertheless, the increased uterine and placental perfusion in pregnancies resulting from FET is of particular interest, especially given their unexpected greater risk of pre-eclampsia, suggesting the existence of a distinct etiology, pathophysiology or phenotype of pre-eclampsia in these pregnancies and underscoring the need for further research to elucidate the underlying mechanisms. Natural-cycle frozen embryo transfer maintains corpus luteum function and physiological hormone levels, supporting healthier placental development and more balanced birthweight outcomes [6]. In contrast, the absence of corpus luteum in hormone replacement therapy cycles or the supraphysiological hormone exposure from multiple corpora lutea in fresh transfers may disrupt placental function, increasing risks of abnormal birthweight including both SGA and LGA.

Embryo manipulation and trophectoderm biopsy may theoretically impair trophoblast progress and influence placental development and fetal growth. In particular, the increasingly widespread use of preimplantation genetic testing (PGT) in recent years has raised concerns regarding safety and long-term consequences. The evidence currently available on the association between PGT and impaired fetal growth remains conflicting [7], and currently, caution should be adopted until further studies clarify this relationship.

Maternal gestational complications add further complexity by disrupting the intrauterine environment and influencing fetal development. The increased risk of hypertensive disorders of pregnancy contributes to the fetal growth alterations observed in this population. Prophylaxis with low-dose Aspirin in cases at increased risk of pre-eclampsia, as determined by the combined screening test established by the Fetal Medicine Foundation, is now widely adopted in clinical practice. Gestational diabetes is also prevenient in ART conceptions related to advanced maternal age, as well as metabolic imbalances related to polycystic ovarian syndrome. Another preventive approach to reduce the risk of cardiovascular and metabolic complications is to limit exposure to modifiable factors such as high maternal BMI, smoking, and poor dietary habits, as these are strongly associated with gestational hypertension, gestational diabetes, and an increased likelihood of fetal growth abnormalities.

Besides the exact mechanisms involved in the alterations in birthweight observed in children conceived through ART, understanding this relationship is crucial in guiding clinicians on the optimal management of such pregnancies. The development of a mathematical model and a risk score for impaired fetal growth, taking into account the numerous variables involved, would be of great interest, with the ultimate aim of providing each patient with a personalized pregnancy management pathway. All ART pregnancies should routinely undergo first-trimester combined screening according to the Fetal Medicine Foundation protocol, as well as second-trimester uterine artery Doppler studies. In the third trimester, multiple assessments of fetal growth and maternal–fetal Doppler parameters should be performed, with the dual objective of early detection of placental dysfunction and SGA or LGA at later stages. Promising avenues also include the integration of angiogenic factors such as soluble fms-like tyrosine kinase-1/placental growth factor into the clinical monitoring of these pregnancies, which, when combined with Doppler studies, may allow for more effective and timely recognition of placental dysfunction, which are by far the greatest contributors of preterm birth for these pregnancies [8].

In summary, this article highlights both modifiable and non-modifiable factors that differentiate intrauterine growth in fetuses conceived through ART from those conceived naturally. Optimizing preconception conditions, ART procedures, addressing modifiable risk factors, and implementing obstetric interventions to minimize pregnancy and delivery complications of SGA and LGA may collectively improve outcomes for ART conceptions, particularly when aberrant fetal growth is present.

Author contribution

Paolo Ivo Cavoretto: methods and conceptual design, draft writing, revision, supervision; Serena Girardelli: revision, editing, supervision; Mirko Pozzoni: draft writing, revision, supervision. All authors reviewed and approved the final version of the manuscript.

Data availability

Data sharing is not applicable because no new data were produced or analyzed.

Declarations

Competing interests

The authors declare no competing interests.