Cardiac remodeling in fetuses conceived by ARTs: fresh versus frozen embryo transfer

Abstract

STUDY QUESTION Do fetuses from frozen embryo transfer (FET) present signs of cardiac remodeling and suboptimal function similar to those observed in fetuses from fresh embryo transfer (ET)? SUMMARY ANSWER Fetuses from both fresh ET and FET present signs of fetal cardiac remodeling and suboptimal function, with more pronounced changes after fresh ET as compared to FET. WHAT IS KNOWN ALREADY Our group and others have previously demonstrated that fetuses and children conceived by ARTs present cardiac remodeling and suboptimal function. These fetuses show dilated atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation. Cardiac changes were already present in utero and persisted after birth. Most of the ART fetuses included in previous publications were from fresh ET. However, singletons from FET have different perinatal outcomes compared to those from fresh ET. There are no previous studies comparing cardiac morphology and function between fetuses following fresh and FET. STUDY DESIGN, SIZE, DURATION This is a prospective cohort study of 300 singleton pregnancies recruited from 2017 to 2020, including 100 spontaneously conceived (SC) pregnancies, 100 fetuses conceived by IVF with FET, and 100 fetuses conceived by IVF with fresh ET. Fetal structural and functional echocardiography was performed in all pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS Pregnancies conceived by IVF were recruited from a single assisted reproduction center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation for FET, laboratory procedures, and embryo culture conditions. SC pregnancies from fertile couples were selected from the general population and matched to IVF pregnancies by maternal age. Epidemiological and perinatal outcomes were collected in all cases. Fetal echocardiography was performed at 28–33 weeks of pregnancy to assess cardiac structure and function in all pregnancies. All echocardiographic comparisons were adjusted by maternal age, nulliparity, birthweight centile, preeclampsia, and prematurity. MAIN RESULTS AND THE ROLE OF CHANCE Parental age, ethnicity, body mass index and smoking were similar among the study groups. Median gestational age at echocardiography and estimated fetal weight were similar in all study groups. Both fresh ET and FET groups showed similar fetal echocardiographic changes, with more pronounced features in the fresh ET as compared to FET pregnancies. Fetuses conceived by IVF showed larger atria (right atria-to-heart ratio: fresh ET mean 18.1% (SD 3.2) vs FET 18.0% (3.9) vs SC 17.3% (3.2); linear tendency P-value <0.001), more globular ventricles (right ventricular sphericity index: fresh ET 1.62 (0.29) vs FET 1.61 (0.25) vs SC 1.68 (0.26); <0.001) and thicker myocardial walls (relative wall thickness: fresh ET 0.79 (0.21) vs FET 0.74 (0.22) vs SC 0.65 (0.25); <0.001) as compared to SC pregnancies. Both fresh ET and FET groups also had signs of suboptimal systolic and diastolic function, with reduced tricuspid annular systolic peak velocity (fresh ET 7.17 cm/s (1.22) vs FET 7.41 cm/s (1.19) vs SC 7.58 cm/s (1.32); <0.001) and increased left myocardial performance index (fresh ET 0.53 (0.08) vs FET 0.53 (0.08) vs SC 0.50 (0.09); <0.001) as compared to SC pregnancies. LIMITATIONS, REASONS FOR CAUTION The cardiac changes reported here are subclinical, with most cardiovascular indexes lying within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with the long-term cardiovascular disease remains to be proven. The observed milder fetal cardiac features in FET fetuses cannot condition the choice of this technique and must be considered together with the global perinatal results related to these gestations. WIDER IMPLICATIONS OF THE FINDINGS The identification of cardiac remodeling in fetuses conceived by IVF with fresh ET and FET represents an opportunity for early detection. Future studies are warranted to study the potential long-term consequences of these findings. STUDY FUNDING/COMPETING INTEREST(S) This project has been partially funded with support from the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the author, and the Commission cannot be held responsible for any use, which may be made of the information contained therein. Additionally, the research leading to these results has received funding from ‘la Caixa’ Foundation under grant agreement LCF/PR/GN18/10310003, the Instituto de Salud Carlos III (PI15/00130, PI17/00675, PI18/00073) integrated into the Plan Nacional de I + D+I and cofinanced by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER) ‘Una manera de hacer Europa’, Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant n° 1531. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A

The association between assisted reproductive technology and cardiac remodeling in fetuses and early infants: a prospective cohort study

“…2). Consistent with previous studies showing cardiac morphological changes in ART fetuses [6,19], in the present study, we demonstrated a globular enlarged LV and a larger RV in ART fetuses. From a pathophysiological perspective, a spherical dilated shape will weaken the contractile properties of the ventricle [20,21].…”

“…With regard to diastolic performance, we observed increased mitral E' in ART fetuses. However, previous studies described unchanged or reduced mitral E' [6,19]. Thus, the changes in mitral E' that are reported here need to be further validated.…”

“…A previous study reported larger atria and globular ventricles in fetuses conceived by fresh ET compared to those by FET [22]. Most recently, Boutet et al [19] demonstrated larger atria, thicker myocardial walls, and more impaired systolic function in a fresh ET group when compared to an FET population. In the present study, we found that cardiac morphology and function were comparable between IVF and ICSI groups as well as between fresh ET and FET groups.…”

Fetal neurosonography and infant neurobehavior following conception by assisted reproductive technology with fresh or frozen embryo transfer

“…The observed differences between our three study groups could have been triggered by their different intrauterine vasoactive and hormonal milieu 56 , 57 , 58 , 59 , 60 , 61 , but also by changes in cardiac function: brain and heart development take place simultaneously in utero and often share morphogenetic programs 62 . Fetuses conceived by ART show differences in growth and cardiac shape and function compared with SC fetuses, fresh ET being associated with fetal smallness 6 , 63 and cardiac remodeling and dysfunction 64 , 65 , and frozen ET with macrosomia 63 , hypertensive disorders of pregnancy 5 , 66 and milder cardiac changes 65 , 67 .…”

Cardiac remodeling from the fetus to adulthood

“…A recent study by Boutet et al compared fetal echocardiography parameters at 28-33 weeks of gestation in pregnancies conceived by fresh and frozen embryo transfer to spontaneously conceived pregnancies. 48 Surprisingly, the results demonstrated that cardiac remodeling is more prominent in cases of in vitro fertilization with fresh embryo transfer.…”