Fetal programming in assisted reproductive technologies

Abstract

[eng] INTRODUCTION: Pregnancies conceived through assisted reproductive techniques (ART) represent up to 7.9% of births in European countries, with an increasing trend. The safety aspects of ART have gained relevance in recent decades, especially since different studies found an association between these techniques and worse perinatal outcomes, cardiac remodeling and dysfunction, and suboptimal neurodevelopment. HYPOTHESIS: Different ART procedures are associated with different patterns of fetal heart and brain development, as well as different risk profiles for preeclampsia. OBJECTIVES: To describe patterns of fetal cardiac and neurological development and the behavior of preeclampsia biomarkers associated with different ART strategies to evaluate the risk profile of each technique in terms of health for subjects born after ART. METHODOLOGY: A prospective cohort study of singleton pregnancies exposed and not exposed to different ART was carried out. A total of 683 pregnancies were recruited, including spontaneous pregnancies from fertile (n=199) and subfertile (n=100) couples, pregnancies after unstimulated in vitro fertilization (IVF) cycles (n=34), stimulated IVF cycles with fresh (n=185) and frozen (n=165) embryo transfer. Pregnancies with a diagnosis of fetal anomalies and/or suspected or confirmed intrauterine infection were excluded. A fetal ultrasound assessment was performed in the third trimester of gestation and maternal and umbilical cord blood samples were collected at birth. The main outcomes were the presence and pattern of fetal cardiovascular remodeling and dysfunction, fetal neurodevelopment assessed by ultrasound between 27 and 35 weeks of gestational age, and the biomarker profile of preeclampsia at delivery in maternal and cord blood. Three cohort studies and two nested case-control studies were conducted. The association between different types of ART and offspring outcomes has been modeled considering multiple covariates. RESULTS: Previously published findings on cardiac remodeling and dysfunction in fetuses conceived by ART have been confirmed in this research project. Cardiac findings in ART fetuses appear to be associated with the IVF procedure per se, not underlying infertility or ovarian stimulation. Fetuses conceived by ART also showed differences in cerebral cortical folding during the third trimester of intrauterine life, associated with worse neurological development at 12 months of corrected age. Both cardiac and neurological findings were more pronounced in stimulated cycles with fresh embryo transfer. Finally, we report more altered levels of heme scavengers related to the development of preeclampsia hemopexin and α1-microglobulin in the IVF population with embryo transfer in the absence of corpus luteum (artificial cycles), supporting the hypothesis that the activity of the corpus luteum could positively influence perinatal outcome through lower levels of oxidative stress. CONCLUSIONS: (1) Fetuses conceived by IVF with fresh and frozen embryo transfer show signs of cardiac remodeling and suboptimal function, with more pronounced changes after fresh embryo transfer. (2) Fetuses conceived spontaneously by subfertile couples do not show the signs of cardiac remodeling and dysfunction previously observed in IVF fetuses, and their cardiac structural and functional characteristics are similar to those of fetuses conceived spontaneously by fertile couples. (3) ART fetuses show signs of cardiac remodeling as compared to those conceived spontaneously by fertile couples, even after IVF cycles in natural cycle (without prior ovarian stimulation). (4) Fetuses conceived by ART show a distinctive cerebral cortical development pattern and suboptimal infant neurodevelopment, with more pronounced changes in fresh embryo transfer cases. (5) Pregnancies that lack a corpus luteum at the time of conception present more altered concentrations of heme binders in pregnancies with preeclampsia, suggesting that the activity of the corpus luteum could impact perinatal outcomes through lower levels of oxidative stress. (6) These results highlight the importance of future studies evaluating adverse perinatal outcomes and long-term cardiovascular and neurological health in individuals conceived through ART.

[cat] INTRODUCCIÓ: Els naixements per tècniques de reproducció assistida (TRA) representen fins al 7,9% a països europeus, amb tendència en augment. Diferents estudis qüestionen la seva seguretat, associant-les a pitjors resultats perinatals i a funció cardíaca i neurodesenvolupament subòptims. HIPÒTESI: Diferents procediments de TRA s'associen a diferents perfils de risc de preeclàmpsia (PE) i patrons de desenvolupament cardíac i cerebral fetal. OBJECTIUS: Descriure el comportament de biomarcadors de PE i els patrons de desenvolupament cardíac i neurològic fetal associats a diferents TRA per avaluar el perfil de risc en termes de salut per a aquesta població. METODOLOGIA: Cohort prospectiva de 683 embarassos únics incloent gestacions espontànies de parelles fèrtils (n=199) i subfèrtils (n=100), cicles de fertilització in vitro (FIV) no estimulats (n=34), estimulats amb transferència embrionària (TE) en fresc (n=185) i congelat (n=165). Es va realitzar una ecografia fetal en tercer trimestre i es van recollir mostres de sang maternofetal al part, estudiant l'estructura i funció cardíaques, neurodesenvolupament fetal i perfil de biomarcadors de PE al part. L'associació entre les diferents TRA i els resultats es va modelar considerant múltiples covariables. RESULTATS: Es van confirmar les troballes publicades sobre la remodelaciò i disfunció cardíaca en fetus concebuts per TRA, que semblen estar associades al procediment de FIV per se, no a la infertilitat subjacent ni a l'estimulació ovàrica. Aquests fetus també van mostrar diferències en el plegament cortical cerebral, associades a un pitjor desenvolupament neurològic als 12 mesos. Les troballes cardíaques i neurològiques van ser més pronunciades en cicles estimulats amb TE a fresc. Finalment, els embarassos iniciats sense cos luti van presentar concentracions més alterades de biomarcadors de PE, suggerint que l'activitat del cos luti impactaria els resultats perinatals a través de nivells més baixos d'estrès oxidatiu. CONCLUSIONS: En aquest estudi s´han constatat diferents patrons de risc perinatal, cardiovascular i de neurodesenvolupament associades a diferents estratègies de reproducció assistida. Aquests resultats destaquen la importància de futurs estudis que avaluïn els resultats perinatals adversos i la salut cardiovascular i neurològica a llarg termini en els individus concebuts mitjançant TRA.