Spontaneously Conceived Pregnancies Research Articles

Is There a Cumulative Effect for Congenital Heart Defects in Monochorionic Twins after Assisted Reproduction? - A Retrospective Analysis at a Tertiary Referral Center.

The aim of our study was to compare maternal, chorionicity and neonatal complications in monochorionic (MC) twins between spontaneously conceived (SC) and assisted reproductive technologies (ART) pregnancies. This was a retrospective cohort study between January 2010 to December 2019 at a tertiary referral University center. All consecutive pregnancies with MC twins that delivered at our University hospital were included. Maternal, chorionicity and neonatal complications were recorded and compared between SC and ART pregnancies. 393 MC pregnancies were included for final analysis, including 353 (89.8%) SC and 40 (10.2%) pregnancies conceived after ART. Hypothyroidism was the only maternal condition seen significantly more often in ART pregnancies (35.0% vs 12.5%, p=0.001). There were no significant differences in chorionicity complications, such as twin-twin transfusion syndrome, selective fetal growth restriction and twin anemia-polycythemia sequence (40.0% in ART pregnancies vs 31.6% in SC pregnancies, p=0.291). At least one congenital anomaly in one twin was seen significantly more often in ART pregnancies (18.8% vs 8.1%, p=0.004), especially congenital heart defects (16.3% vs 6.2%, p=0.005). There were no other significant differences in neonatal outcomes between both groups, however, there were non-significant trends in gestational age at delivery (34 weeks in ART pregnancies vs 35 weeks, p=0.078) and birthweight (1951g±747 in ART pregnancies vs 2143g±579, p=0.066). This is the largest cohort study to date comparing maternal, chorionicity and neonatal complications between MC twin pregnancies after ART and after SC. Hypothyroidism was the only maternal condition occurring more frequently in pregnancies conceived after ART. There were no significant differences in chorionicity complications, in contrast to previously reported studies. While MC twins and ART pregnancies per se are known to be at risk for congenital heart defects, there seems to be a cumulative effect in MC pregnancies conceived after ART.

Subfertility versus ART: unraveling the origins of fetal cardiac programming.

Do spontaneously conceived (SC) fetuses from subfertile couples show the same signs of cardiac remodeling as those observed after IVF treatments? As opposed to fetuses from IVF, SC fetuses from subfertile couples do not show cardiac remodeling and present a similar cardiac structure and function to those of SC fetuses from fertile couples. Subjects conceived by IVF present signs of cardiac remodeling and suboptimal function in utero and during childhood, including larger atria, more globular and thicker ventricles, reduced longitudinal motion, and impaired relaxation as compared to SC individuals from fertile couples. There are no previous publications investigating the independent cardiac programming effects of infertility in SC fetuses from subfertile couples (with time-to-pregnancy (TTP) over 12 months). A prospective cohort study of 289 singleton pregnancies exposed and not exposed to subfertility recruited from 2019 to 2021, including 96 SC pregnancies from fertile couples (TTP under 12 months), 97 SC from subfertile couples (TTP over 12 months), and 96 from IVF after fresh embryo transfer. Fetal echocardiography was performed in all pregnancies. Epidemiological data and perinatal outcomes were collected in all pregnancies. The overall attrition rate was 15.7%. SC from subfertile couples and IVF pregnancies were identified as eligible at pregnancy diagnosis, and eligible SC pregnancies from fertile couples who attended our maternal-fetal unit were invited to participate at third trimester, being matched to the other groups by maternal age. Fetal echocardiography was performed at 29-34 weeks of pregnancy to assess cardiac structure and function, and results were adjusted by parental age, maternal smoking status, child's birth order, birthweight centile, gestational age, and estimated fetal weight at scan. Parental age, ethnicity, BMI, and smoking exposure, median gestational age and estimated fetal weight were similar in all study groups. There were no significant differences in infertility duration or etiology between the subfertile and the IVF populations (TTP: subfertile median 35 months (interquartile range 20-48) versus IVF: 47 (25-61); P-value = 0.051). While both fertile and subfertile SC groups presented similar fetal cardiac results, IVF fetuses showed larger atria (right atria-to-heart ratio: IVF mean 18.9% (SD 3.4) versus subfertile 17.8% (3.5) versus fertile 17.6% (3.3); adjusted P-value < 0.001), more globular ventricles (right ventricular sphericity index: IVF 1.56 (0.25) versus subfertile 1.72 (0.26) versus fertile 1.72 (0.26); <0.001), and thicker myocardial walls (relative wall thickness: IVF 0.86 (0.22) versus subfertile 0.64 (0.13) versus fertile 0.64 (0.18); <0.001). Whereas SC fetuses from fertile and subfertile couples had preserved cardiac function, IVF fetuses showed signs of suboptimal systolic and diastolic function, with reduced tricuspid ring displacement (IVF 7.26 mm (1.07) versus subfertile 8.04 mm (1.18) versus fertile 7.89 mm (1.51); <0.001) and increased left myocardial performance index (IVF 0.49 (0.08) versus subfertile 0.45 (0.09) versus fertile 0.45 (0.10); <0.001). A sub-analysis including only unexplained infertility cases in subfertile SC and IVF groups showed similar results. The fetal cardiac changes reported here are subclinical, and most of the cardiovascular parameters were within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with long-term cardiovascular disease remains to be demonstrated. Subfertility per se does not seem to be associated to fetal cardiac remodeling, which has been previously described in IVF fetuses. Future studies are warranted to further investigate other factors related to the observed fetal cardiac changes associated with ART. 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, PI16/00861, PI17/00675, PI18/00073, INT21/00027)-co-funded by the European Union, Cerebra Foundation for the Brain Injured Child (Carmarthen, Wales, UK) and AGAUR 2017 SGR grant no 1531. The authors have no conflicts of interest to declare. N/A.

P-771 Subfertility versus in vitro fertilization procedures: unravelling the origins of fetal cardiac remodeling in assisted reproductive technologies

Abstract Study question Do spontaneously conceived (SC) fetuses from subfertile couples present signs of cardiac remodeling as those observed after in vitro fertilization (IVF) treatments? Summary answer SC fetuses from subfertile couples do not associate cardiac remodeling, and their cardiac structure and function are similar to those of SC from fertile couples. What is known already Fetuses and children from IVF associate cardiac remodeling and suboptimal function, including dilated atria, more globular and thicker ventricles, reduced longitudinal motion and impaired relaxationin uteroand after birth. Fetal cardiac changes have been demonstrated both after fresh and frozen embryo transfer. The SC fetuses used as ‘controls’ in our previous publications were conceived by fertile couples thus making it difficult to separate the contribution of infertilityper sefrom the IVF procedures on cardiac programming. There are no previous cardiovascular studies investigating the independent effects of infertility in SC fetuses from subfertile couples (time-to-pregnancy (TTP) over 12 months). Study design, size, duration Prospective cohort study of 289 singleton pregnancies recruited from 2017 to 2021, including 96 SC pregnancies from fertile couples (TTP less than 12 months), 97 SC from subfertile couples (TTP over 12 months) and 96 from IVF after fresh ET. Fetal echocardiography was performed in all pregnancies. Epidemiological data and perinatal outcomes were collected in all pregnancies. Participants/materials, setting, methods IVF pregnancies from our centre were identified as eligible at pregnancy diagnosis. Eligible SC pregnancies from fertile and subfertile couples who attended our Maternal-Fetal Unit were invited to participate at third trimester, being matched to the IVF pregnancies by maternal age. Fetal echocardiography was performed at 29-34 weeks of pregnancy to assess cardiac structure and function. Echocardiographic comparisons were adjusted by nulliparity, birthweight centile, gestational age and estimated fetal weight at scan. Main results and the role of chance Parental age, ethnicity, body mass index and smoking exposure, median gestational age and estimated fetal weight were similar in all study groups. There were no significant differences in infertility duration or aetiology between the subfertile and the IVF populations (TTP: subfertile median 30 months [IQR 20-54] versus IVF: 47 [25-61]; p-value=0.052). While both fertile and subfertile SC groups presented similar fetal cardiac results, IVF fetuses showed larger atria (right atria-to-heart ratio: IVF mean 18.9% [SD 3.4] versus subfertile 17.8% [3.5] versus fertile 17.6% [3.3]; adjusted P-value&amp;lt;0.001), more globular ventricles (right ventricular sphericity index: IVF 1.56 [0.25] versus subfertile 1.72 [0.26] versus fertile 1.72 [0.26]; &amp;lt;0.001), and thicker myocardial walls (relative wall thickness: IVF 0.86 [0.22] versus subfertile 0.64 [0.13] versus fertile 0.64 [0.18]; &amp;lt;0.001). Whereas SC fetuses from fertile and subfertile couples had preserved cardiac function, IVF fetuses showed signs of suboptimal systolic and diastolic function with reduced tricuspid ring displacement (IVF 7.26 mm [1.07] versus subfertile 8.04 mm [1.18] versus fertile 7.89 mm [1.51]; &amp;lt;0.001) and increased left myocardial performance index (IVF 0.49 [0.08] versus subfertile 0.45 [0.09] versus fertile 0.45 [0.10]; &amp;lt;0.001). A sub-analysis including only unexplained infertility cases in subfertile SC and IVF groups showed similar results. Limitations, reasons for caution The fetal cardiac changes reported here are subclinical, with most cardiovascular parameters lying within normal ranges. Although echocardiographic changes are recognized as potential cardiovascular risk factors, their association with long-term cardiovascular disease remains to be proven. Wider implications of the findings Subfertility per se does not seem to be associated to fetal cardiac remodeling, which have been previously described in IVF fetuses. Future studies are warranted to further investigate the factors related to fetal cardiac changes associated to ART. Trial registration number Not a trial

Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis.

Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain. This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI. PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET). This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies. This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.

P–766 Neurodevelopment in fetuses conceived by assisted reproductive technologies following fresh and frozen embryo transfer

Abstract Study question Do in vitro fertilization (IVF) offspring present different neurodevelopment assessed by fetal neurosonography and infant neurobehavioral tests as compared to those spontaneously conceived (SC)? Summary answer IVF offspring, especially those obtained after fresh embryo-transfer (ET), showed subtle structural differences in fetal neurosonography and poorer neurobehavioral scores at twelve months of age. What is known already The number of pregnancies following assisted reproductive technologies (ART) is currently increasing worldwide. Concerns about the neurodevelopment of subjects conceived by IVF have been rising and mostly studied in children and adolescents with inconsistent results. Many of the identified risk associations were only observed in subgroups or disappeared after adjustment for covariates, mainly multiple pregnancy and gestational age at birth. It is unknown whether fetal brain development and cortical folding differ prenatally in IVF fetuses as compared to SC. Study design, size, duration This is the first study examining fetal neurodevelopment by neurosonography in IVF fetuses. A prospective cohort study of 210 singleton pregnancies recruited from 2017 to 2020, including 70 SC gestations, 70 conceived by IVF following frozen ET (FET) and 70 IVF after fresh ET. Fetal neurosonography was performed in all pregnancies. Additionally, Ages &amp; Stages Questionnaires (ASQ) were obtained at 12 months of corrected age. Participants/materials, setting, methods IVF pregnancies were recruited from a single Assisted Reproduction Center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation, laboratory procedures and embryo culture conditions. SC pregnancies were randomly selected from low-risk fertile couples and paired to IVF by maternal age. Fetal neurosonography including transvaginal approach was performed at 32±2 weeks of gestation, measured off-line by a single investigator and normalized by biparietal or occipitofrontal diameter. ASQ were obtained postnatally, at 12 months of corrected age. Main results and the role of chance Study groups were similar and comparable regarding maternal age, body mass index, study level and employment rate together with exposure to smoke, alcohol, aspirin and corticoids during pregnancy, gestational age (32±2 weeks) and estimated fetal weight (1700±400g) at neurosonography. As compared to SC pregnancies, both IVF populations showed differences in cortical development with reduced parieto-occipital (fresh ET 12.5mm [SD 2.5] vs FET 13.4 [2.6] vs SC 13.4 [2.6]), cingulate (fresh ET 5.8 [IQR 4.2–7.4] vs FET 5.8 [4.1–7.5] vs SC 6.5 [4.8–7.8]) and calcarine (fresh ET 13.5 [IQR 10.1–16.1] vs FET 14.5 [12.1–15.8] vs SC 16.4 [14.3–17.9]) sulci depth together with lower Sylvian fissure grading. Cortical development changes were more pronounced in the fresh ET group as compared to FET. Corpus callosum length and insula depth were lower in FET and fresh ET groups, respectively. Neurosonographic changes remained statistically significant after adjustment by ethnicity, gender, gestational age and weight centile at scan. IVF infants showed worse ASQ scores, especially in fresh ET for communication, personal-social, fine-motor and problem-solving skills. Gross-motor scores were significantly lower in FET as compared to SC and fresh ET. Differences were statistically significant after adjustment by maternal ethnicity, study level, employment status, breastfeeding, gender and corrected age. Limitations, reasons for caution The reported neurodevelopmental differences are subtle, with most neurosonographic findings lying within normal ranges. Infertility factors contribution to the outcome cannot be unraveled from the ART procedure itself. The milder features found in FET individuals cannot condition the techniqués choice and must be considered together with their global perinatal results. Wider implications of the findings: Neurosonography is an appropriate tool to identify subtle brain differences between fetuses exposed and not exposed to ART. Prenatal features were consistent with postnatal neurobehavioral findings. These results support the relevance of a neurodevelopmental follow-up in IVF patients. Further studies are warranted to assess the long-term performance in these subjects. Trial registration number Not applicable

P-766 Neurodevelopment in fetuses conceived by assisted reproductive technologies following fresh and frozen embryo transfer

Abstract Study question Do in vitro fertilization (IVF) offspring present different neurodevelopment assessed by fetal neurosonography and infant neurobehavioral tests as compared to those spontaneously conceived (SC)? Summary answer IVF offspring, especially those obtained after fresh embryo-transfer (ET), showed subtle structural differences in fetal neurosonography and poorer neurobehavioral scores at twelve months of age. What is known already The number of pregnancies following assisted reproductive technologies (ART) is currently increasing worldwide. Concerns about the neurodevelopment of subjects conceived by IVF have been rising and mostly studied in children and adolescents with inconsistent results. Many of the identified risk associations were only observed in subgroups or disappeared after adjustment for covariates, mainly multiple pregnancy and gestational age at birth. It is unknown whether fetal brain development and cortical folding differ prenatally in IVF fetuses as compared to SC. Study design, size, duration This is the first study examining fetal neurodevelopment by neurosonography in IVF fetuses. A prospective cohort study of 210 singleton pregnancies recruited from 2017 to 2020, including 70 SC gestations, 70 conceived by IVF following frozen ET (FET) and 70 IVF after fresh ET. Fetal neurosonography was performed in all pregnancies. Additionally, Ages &amp; Stages Questionnaires (ASQ) were obtained at 12 months of corrected age. Participants/materials, setting, methods IVF pregnancies were recruited from a single Assisted Reproduction Center, ensuring homogeneity in IVF stimulation protocols, endometrial preparation, laboratory procedures and embryo culture conditions. SC pregnancies were randomly selected from low-risk fertile couples and paired to IVF by maternal age. Fetal neurosonography including transvaginal approach was performed at 32±2 weeks of gestation, measured off-line by a single investigator and normalized by biparietal or occipitofrontal diameter. ASQ were obtained postnatally, at 12 months of corrected age. Main results and the role of chance Study groups were similar and comparable regarding maternal age, body mass index, study level and employment rate together with exposure to smoke, alcohol, aspirin and corticoids during pregnancy, gestational age (32±2 weeks) and estimated fetal weight (1700±400g) at neurosonography. As compared to SC pregnancies, both IVF populations showed differences in cortical development with reduced parieto-occipital (fresh ET 12.5mm [SD 2.5] vs FET 13.4 [2.6] vs SC 13.4 [2.6]), cingulate (fresh ET 5.8 [IQR 4.2-7.4] vs FET 5.8 [4.1-7.5] vs SC 6.5 [4.8-7.8]) and calcarine (fresh ET 13.5 [IQR 10.1-16.1] vs FET 14.5 [12.1-15.8] vs SC 16.4 [14.3-17.9]) sulci depth together with lower Sylvian fissure grading. Cortical development changes were more pronounced in the fresh ET group as compared to FET. Corpus callosum length and insula depth were lower in FET and fresh ET groups, respectively. Neurosonographic changes remained statistically significant after adjustment by ethnicity, gender, gestational age and weight centile at scan. IVF infants showed worse ASQ scores, especially in fresh ET for communication, personal-social, fine-motor and problem-solving skills. Gross-motor scores were significantly lower in FET as compared to SC and fresh ET. Differences were statistically significant after adjustment by maternal ethnicity, study level, employment status, breastfeeding, gender and corrected age. Limitations, reasons for caution The reported neurodevelopmental differences are subtle, with most neurosonographic findings lying within normal ranges. Infertility factors contribution to the outcome cannot be unraveled from the ART procedure itself. The milder features found in FET individuals cannot condition the techniqués choice and must be considered together with their global perinatal results. Wider implications of the findings Neurosonography is an appropriate tool to identify subtle brain differences between fetuses exposed and not exposed to ART. Prenatal features were consistent with postnatal neurobehavioral findings. These results support the relevance of a neurodevelopmental follow-up in IVF patients. Further studies are warranted to assess the long-term performance in these subjects. Trial registration number not applicable

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

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)? 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. 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. 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. 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. 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. 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. 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. 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. N/A.

Evaluation of Uterine Artery Doppler and Estrogen Milieu in Oocyte Donation Pregnancies-A Pilot Study.

Oocyte donations (OD) represent 4.5% of all in vitro fertilization (IVF) cycles. While OD pregnancies face increased risks of obstetrical complications, especially pregnancy-induced hypertension and pre-eclampsia (PE), little is known about the physiology and the physiopathology of placentation. We performed a prospective case-control study to analyze uterine artery Doppler pulsatility index (UtA-PI) and serum maternal 17β-estradiol (17β-E) at 11 + 0 to 13 + 6 weeks’ gestation in singleton pregnancies with different modes of conception. Study groups were: 55 OD, 48 IVF with autologous oocytes from fresh cycles (Autologous-Fresh IVF), 10 IVF with autologous oocytes from frozen cycles (Autologous-Frozen IVF) and 122 spontaneously conceived pregnancies (SC). The mean UtA-PI and serum maternal 17β-E at 11 to 13 + 6 weeks were significantly lower in OD as compared to SC and autologous IVF, either from fresh or frozen cycles. Oocyte donation presents lower UtA-PI and lower serum 17β-E in the first trimester of pregnancy. The etiology of these particularr differences is likely multifactorial and deserves further investigation.

Maternal Mental Health in Assisted and Natural Conception: A Prospective Cohort Study.

This study sought to compare the pregnancy and postpartum self-reported mood and mental health status of women who conceived with assisted reproductive technology (ART) with those of women who conceived spontaneously. In this prospective cohort study, 1176 pregnant women from prenatal clinics in the Ontario Birth Study were enrolled. In the pregnancy and the postpartum period, women who conceived with ART, including in vitro fertilization and intrauterine insemination, were compared with women who conceived spontaneously regarding depression and anxiety at 12-16 weeks and 24-28 weeks gestation and 6-10 weeks postpartum. The following main outcome measures were used: Edinburgh Postnatal Depression Scale, two-item Patient Health Questionnaire, State Trait Anxiety Inventory six-item scale, and two-item Generalized Anxiety Disorder scale (Canadian Task Force Classification II-2). Women who conceived with ART demonstrated a decreased likelihood of depression compared with women who spontaneously conceived (SC) at 24-28 weeks gestation (Edinburgh Postnatal Depression Scale: ART 3.6% vs. SC 15%; P<0.01; two-item Patient Health Questionnaire: ART 0.0% vs. SC 4.0%; P = 0.027), as well as decreased perceived stress (mean score: ART 3.25 vs. SC 4.02; P<0.01). Women in the ART group also had a lower percentage of positive two-item Generalized Anxiety Disorder scores (ART 2.7% vs. SC 7.5%; P = 0.049). There was no difference in self-reported depression, anxiety, or perceived stress between groups at 12-16 weeks gestation or at 6-10 weeks postpartum. Women who conceived using ART reported decreased rates of depressive symptoms, perceived stress, and generalized anxiety during the second trimester of pregnancy compared with women who had SC pregnancies, and both groups experienced similar mental health status earlier in gestation and in the postpartum period.

The effect of body mass index (BMI) and gestational weight gain on adverse obstetrical outcomes in pregnancies following assisted reproductive technology as compared to spontaneously conceived pregnancies

ObjectiveTo compare the effect of pre-pregnancy body mass index (BMI) and inappropriate gestational weight gain (GWG) on adverse obstetrical outcomes among women undergoing assisted reproductive technology (ART) treatments as compared to spontaneously-conceived (SC) pregnancies. MethodsThis prospective cohort study included 1058 pregnant women from two medical centres; 504 women who conceived following ART treatments and 554 who conceived spontaneously. The women were recruited at 8 weeks of gestation and follow-up telephone interviews were conducted 6 weeks after delivery. Obstetrical outcomes included pregnancy hypertension, gestational diabetes (GD), low birth weight (LBW) (<2500g) and small for gestational age (SGA). Multivariate analyses were used to assess the effect of pre-pregnancy BMI and inappropriate GWG on these obstetrical outcomes adjusted for risk factors. ResultsThe effect of pre-pregnancy BMI and inappropriate GWG on adverse obstetrical outcomes did not differ between ART and SC pregnancies. Pre-pregnancy obesity was found to be associated with increased risk for pregnancy hypertension (OR=2.16; 95%CI 1.16–4.03), GD (OR=2.89; 95%CI 1.61–5.17), caesarian section (OR=1.77; 95%CI 1.10–2.85) and SGA (OR=1.91; 95%CI 1.05–3.46). GWG below recommendations was associated with increased risk for GD (OR=1.73; 95%CI 1.06–2.82) and SGA (OR=1.69; 95%CI 1.17–2.40) while GWG above recommendations was associated with increased risk for pregnancy hypertension (OR=1.77; 95%CI 1.02–3.06). ConclusionsPre-pregnancy obesity and inappropriate GWG were associated with adverse obstetrical outcomes in both ART and SC pregnancies. Emphasis should be given on the importance of an optimal pre-pregnancy BMI and appropriate GWG during pregnancy.

Are singleton pregnancies after assisted reproduction technology (ART) associated with a higher risk of placental anomalies compared with non-ART singleton pregnancies? A systematic review and meta-analysis.

Placental anomalies (placenta praevia, placental abruption, morbidly adherent placenta and cord insertion anomalies) are associated with maternal and fetal morbidity and mortality. It has been suggested these might be more prevalent in pregnancies after assisted reproduction technology (ART). To determine whether ART singleton pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. MEDLINE, EMBASE, CENTRAL, Web of Science and Scopus (January 2018). Cohort studies reporting placental anomalies in ART and non-ART singleton pregnancies. We report pooled odds ratios (OR) for the comparisons: (1) ART versus SC (spontaneously conceived), (2) ART versus non-ART (unspecified), (3) FET-ART (frozen-embryo transfer) versus SC, (4) ART versus non-ART (subfertile patients). Study quality was assessed using a modified Newcastle -Ottawa scale. 33 low/moderate quality studies evaluated 124 215 ART and 6 054 729 non-ART singleton pregnancies. Risk of placenta praevia, placental abruption and morbidly adherent placenta was higher in ART than SC pregnancies: odds ratio (OR) (OR 3.76, 95% CI 3.09-4.59); (OR 1.87, 95% CI 1.70-2.06) and (OR 2.27, 95% CI 1.79-2.87) respectively. Risk of placenta praevia and placental abruption was higher in ART than in non-ART (subfertile patients): (OR 2.51, 95% CI 2.12-2.98) and (OR 1.61, 95% CI 1.33-1.95) respectively. Results were similar when comparing ART with unspecified non-ART pregnancies. Risk of placenta praevia was higher, but not significantly so, in FET-ART than in SC pregnancies (OR 2.42, 95% CI 0.63-9.30). Singleton ART pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. A review of over 6 million singleton pregnancies finds increased risk of placental anomalies after ART.

Risk of spontaneous preterm birth in IVF-conceived twin pregnancies

Objective: To compare the mean transvaginal ultrasound (TVU) cervical length (CL) at midtrimester in screening for preterm birth in in vitro (IVF)-conceived twin pregnancies versus spontaneously-conceived twin pregnancies. Methods: This was a retrospective cohort study. Potential study subjects were identified at the time of a routine second trimester fetal ultrasound exam at 18 0/7 to 23 6/7-week gestation. All women with twin diamniotic pregnancies screened with a single TVU CL for this trial were included. Mean TVU CLs were compared between IVF-conceived twin pregnancies and spontaneously-conceived twin pregnancies. The relationship of TVU CL with gestational age at delivery was assessed. Incidence of short TVU CL, defined as TVU CL ≤30 mm, was also calculated in the two groups. The primary outcome was the mean of TVU CL. Distribution of CL was determined and normality was examined in both groups Results: A total of 668 women with diamniotic twin pregnancies who underwent TVU CL screening between 18 0/6 and 23 6/7 weeks were included. 158 (23.7%) were IVF-conceived pregnancies, and 510 (76.3%) were spontaneously-conceived pregnancies. No women received progesterone, pessary, or cerclage for preterm birth prevention during pregnancy. The mean TVU CL was significantly lower in the IVF-conceived group (32.2 ± 10.5 mm) compared to the spontaneously-conceived group (34.1 ± 9.1 mm) (mean difference (MD) − 1.90 mm, 95%CI −3.72 to −0.08). The incidence of TVU CL ≤30 mm was 30.4% in the IVF-conceived group and 21.6% in the spontaneously-conceived group (adjusted odds ratio (aOR) 1.59, 95%CI 1.06–2.37). IVF-conceived twins had a significantly higher risk of spontaneous preterm birth <34 weeks (32.9 versus 21.2%; aOR 1.83, 95% confidence interval (CI) 1.23–2.71) and higher rate of delivery due to spontaneous onset of labor (64.5 versus 54.9%; aOR 1.50, 95%CI 1.03–2.17). For any given TVU CL measured between 18 0–7 and 23 6/7 weeks, gestational age at delivery for IVF-conceived twins was earlier by about 1 week on average compared with spontaneously-conceived twins. Conclusions: The higher rate of spontaneous preterm birth in IVF-conceived twin pregnancies is predicted by lower midtrimester TVU CL, as well as by the lower gestational age at birth per any given CL in the IVF-conceived compared to the spontaneously-conceived twin pregnancies.

Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group.

Is the risk of hypertensive disorders in pregnancies conceived following specific assisted reproductive technology (ART) procedures different from the risk in spontaneously conceived (SC) pregnancies? ART pregnancies had a higher risk of hypertensive disorders, in particular following cryopreservation, with the highest risk seen in twin pregnancies following frozen-thawed cycles. The risk of hypertensive disorders is higher in ART pregnancies than in SC pregnancies. The increased risk may be partly explained by multiple pregnancies and underlying infertility, but a contribution from specific ART procedures has not been excluded. Population-based cohort study, including sibling design with nationwide data from health registers in Sweden, Denmark and Norway. All registered ART pregnancies and a sample of SC pregnancies with gestational age ≥22 weeks from 1988 to 2007 were included. ART singleton pregnancies (n = 47 088) were compared with SC singleton pregnancies (n = 268 599), matched on parity and birth year. ART twin pregnancies (n = 10 918) were compared with SC twin pregnancies (46 674). We used logistic regression to estimate adjusted odds ratios and risk differences for hypertensive disorders in pregnancies following IVF, ICSI and fresh or frozen-thawed cycles. We also compared fresh and frozen-thawed cycles within mothers who had conceived following both procedures using conditional logistic regression (sibling analysis). Hypertensive disorders were reported in 5.9% of ART singleton and 12.6% of ART twin pregnancies. Comparing singleton pregnancies, the risk of hypertensive disorders was higher after all ART procedures. The highest risk in singleton pregnancies was seen after frozen-thawed cycles [risk 7.0%, risk difference 1.8%, 95% confidence interval (CI) 1.2-2.8]. Comparing twin pregnancies, the risk was higher after frozen-thawed cycles (risk 19.6%, risk difference 5.1%, 95% CI 3.0-7.1), but not after fresh cycles. In siblings, the risk was higher after frozen-thawed cycles compared with fresh cycles within the same mother (odds ratio 2.63, 95% CI 1.73-3.99). There were no clear differences in risk for IVF and ICSI. The number of ART siblings in the study was limited. Residual confounding cannot be excluded. In addition, we did not have information on all SC pregnancies in each woman's history, and could therefore not compare risk in ART versus SC pregnancies in the same mother. Pregnancies following frozen-thawed cycles have a higher risk of hypertensive disorders, also when compared with fresh cycle pregnancies by the same mother. The safety aspects in frozen-thawed cycles merit further attention. Funding was received from the European Society for Human Reproduction and Embryology, the University of Copenhagen, the Danish Agency for Science, Technology and Innovation, the Nordic Federation of Societies of Obstetrics and Gynecology and the Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology. None of the authors has any competing interests to declare.

Cardiovascular dysfunction in offspring of ovarian-hyperstimulated women and effects of estradiol and progesterone: a retrospective cohort study and proteomics analysis.

The cardiovascular dysfunction in children born with assisted reproductive technologies has been of great concern. However, the association of ovarian hyperstimulation syndrome (OHSS), a complication of assisted reproductive technologies, with worse cardiovascular functions and underlying mechanism remains unknown. The objective of the study was to assess the cardiovascular functions of children born to mothers with OHSS and investigate the underlying regulator(s). This was a retrospective cohort recruited in a university hospital. We assessed the cardiovascular functions by Doppler echography in 42 children born to OHSS women, 34 children of mothers with non-OHSS in vitro fertilization, and 48 spontaneously conceived (SC) children (mean age ∼ 4.5 y). Groups were matched for gestational age at delivery and birth weight. An isobaric tag for relative and absolute quantitation-labeled proteomics analysis was performed with another set of umbilical arteries from OHSS and SC pregnancies (n = 3 for both groups). Children of OHSS mothers showed a significantly decreased mitral ratio of early to late mitral peak velocities, reduced systolic and diastolic diameters of common carotid arteries, and impaired flow-mediated dilation compared with non-OHSS in vitro fertilization and SC children. Intima-media thickness and arterial stiffness indices were similar in the three groups. In the proteomics study, 1640 proteins were identified from OHSS and SC umbilical arteries, and 40 differentially expressed proteins were selected for further analysis. Estradiol and progesterone were identified as activated upstream regulators. Children born to ovarian-hyperstimulated women displayed cardiovascular dysfunctions. The underlying mechanisms may involve the effects of supraphysiological estradiol and progesterone levels.

Nuchal translucency in twins according to mode of assisted conception and chorionicity

The impact of nuchal translucency (NT) screening in twins conceived after use of assisted reproduction technology (ART) has not been addressed properly in the literature. The aim of the current study was to assess, in a large cohort from a single center, NT in twins following various modes of ART as compared with NT in spontaneously-conceived twins and to differentiate results with regard to chorionicity. Retrospective data from 825 twin pregnancies were available for this study. All pregnant women underwent NT screening and chorionicity determination between 11 + 0 and 13 + 6 weeks' gestation in our center. Information about mode of conception and pregnancy outcome was obtained from hospital records and by telephone interviews. Twins were classified as having been conceived after in-vitro fertilization (IVF) with the woman's own or a donated embryo, after non-IVF ART or spontaneously. NT distribution in subgroups of fetuses was compared on the basis of the multiple of the normal median (MoM), SD of log10 MoM estimated by the 90(th) -10(th) centile range divided by 2.563 and the proportion of NT values exceeding the normal 95(th) centile which was 1.641 MoM in the singletons. NT values were statistically significantly higher in ART pregnancies as compared with spontaneously-conceived pregnancies (Wilcoxon rank-sum test, P < 0.05) with medians of 1.073 and 1.038 MoM, respectively, but the proportion with values above the normal 95(th) percentile did not differ (chi-square test, P = 0.89). Among the ART twins, NT values were significantly higher for those conceived using IVF methods (P < 0.005), with a median of 1.082 MoM, compared with a median of 1.022 MoM using other methods. However, although a greater proportion exceeded the 95(th) centile (7.3% compared with 4.8%) this difference did not reach statistical significance (P = 0.17). There were no differences in NT values according to chorionicity (Wilcoxon rank-sum test, P = 0.75). The standard deviation of log10 NT was similar for all subgroups of twins. The correlation coefficient between fetuses in ART pregnancies was statistically significantly lower than that in spontaneously-conceived pregnancies (P < 0.05) but no significant differences were found between types of ART or according to chorionicity. There was a small but significant increase in NT levels among ART pregnancies, which appeared to be confined to those conceived using IVF, and a small reduction in the correlation between fetuses. These effects probably have little impact on the estimated risk based on algorithms in use today.