Metabolic profiles of children aged 2-5 years born after frozen and fresh embryo transfer: A Chinese cohort study.

BACKGROUND: Frozen embryo transfer (FET) has become a widely employed assisted reproductive technology technique. There have historically been concerns regarding the long-term metabolic safety of FET technology in offspring due to pregnancy-induced hypertension and large for gestational age, both of which are well-recognized factors for metabolic dysfunction of children. Therefore, we aimed to compare the metabolic profiles of children born after frozen versus fresh embryo transfer at 2 to 5 years of age. METHODS AND FINDINGS: This was a prospective cohort study. Using data from the "Assisted Reproductive Technology borned KIDs (ARTKID)," a birth cohort of offspring born from assisted reproductive technology at the Institute of Women, Children and Reproductive Health, Shandong University, China. We included 4,246 singletons born after FET (n = 2,181) and fresh embryo transfer (n = 2,065) enrolled between 2008 and 2019 and assessed the glucose and lipid variables until the age of 2 to 5 years. During a mean follow-up of 3.6 years, no significant differences were observed in fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance Index, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels between offspring conceived by fresh and frozen embryo transfer in the crude model and adjusted model (adjusted for parental age, parental body mass index, parental education level, paternal smoking, parity, offspring age and sex). These results remained consistent across subgroup analyses considering offspring age, the stage of embryo transfer, and the mode of fertilization. Results from sensitivity analysis on children matched for age within the cohort remains the same. The main limitation of our study is the young age of the offspring. CONCLUSIONS: In this study, the impact of FET on glucose and lipid profiles during early childhood was comparable to fresh embryo transfer. Long-term studies are needed to evaluate the metabolic health of offspring born after FET.

Associations between Paternal Obesity and Cardiometabolic Alterations in Offspring via Assisted Reproductive Technology.

CONTEXT: Both assisted reproductive technology (ART) and obesity are associated with adverse cardiometabolic alterations in offspring. However, the combined effects of paternal obesity and ART on offspring cardiometabolic health are still unclear. OBJECTIVE: To clarify cardiometabolic changes in offspring of obese fathers conceived using ART. DESIGN: Retrospective cohort study conducted between June 2014 and October 2019. SETTING: Center for reproductive medicine. PATIENTS: A total of 2890 singleton visits aged 4-10 years were followed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age-and sex-specific z-score of body mass index(BMI), blood pressure, insulin resistance and lipid profile were examined. RESULTS: We observed a strong association between paternal BMI categories and offspring BMI, blood pressure, and insulin resistance. Compared to offspring of fathers with normal weight, multivariable-adjusted mean difference for BMI z-score were 0.53 (95%CI: 0.37-0.68) for obese fathers, 0.17 (95%CI: 0.05-0.30) for overweight fathers, and -0.55 (95%CI: -0.95--0.15) for underweight fathers; corresponding values for systolic blood pressure z-score were 0.21(95%CI: 0.07-0.35), 0.10 (95%CI: -0.01-0.21), and -0.24 (95%CI: -0.59-0.11), and corresponding values for HOMA-IR z-score were 0.31(95%CI: 0.16-0.46), 0.09(95%CI: -0.02-0.21), and -0.11 (95%CI: -0.48-0.28), respectively. The mediation analyses suggested that 57.48% to 94.75% of the associations among paternal obesity and offspring cardiometabolic alterations might be mediated by offspring BMI. CONCLUSIONS: Paternal obesity was associated with an unfavourable cardiometabolic profile in ART-conceived offspring. Mediation analyses indicated that offspring BMI was a possible mediator of the association between paternal obesity and the offspring impaired metabolic changes.

Relationship between anxiety and depressive trajectories of women who conceived through assisted reproductive technology and their children's emotional and behavioral problems: A prospective cohort study.

OBJECTIVE: This study aimed to examine the relationship between the anxiety and depressive trajectory of women conceived through assisted reproductive technology (ART) and their children's emotional and behavioral problems. METHODS: This prospective cohort study including 18,711 women, was conducted between July 2014 and December 2017. Self-rating scales for anxiety and depression were used before treatment, during the first trimester, and two to three years postpartum. A latent class growth analysis identified their maternal anxiety and depressive symptom trajectories. Multiple comparison and linear regression models were performed to assess the relationships between maternal trajectories and their offspring's emotional and behavioral problems. RESULTS: Three longitudinal heterogeneous trajectories of maternal anxiety and depressive symptoms were identified: resilient, recurrent, and emergent. After adjusting for covariates, children with mothers in the recurrent and emergent trajectory groups had higher Child Behavior Checklist/2-3 scores. Additionally, the participants with a recurrent trajectory had lower education and employment levels and younger maternal age at delivery. They also had a history of ovarian surgery, primipara, secondary infertility, polycystic ovary syndrome, and more embryo transferred cycles, including intracytoplasmic sperm injections. Those with resilient trajectories had higher antral follicle counts and GnRH antagonist protocol. Finally, the participants with emergent trajectories had a lower monthly income, primipara, ectopic pregnancy, and fresh embryo transfers. CONCLUSIONS: Infertile women's psychological stress was not alleviated by the ART-sociodemographic, infertility-related and treatment-related characteristics determined three mental health trajectories. Children with mothers in recurrent and emergent trajectories showed higher odds of experiencing emotional and behavioral problems.

Assisted Reproductive Technology Treatment, the Catalyst to Amplify the Effect of Maternal Infertility on Preterm Birth.

Objective: To identify the influence of different infertility causes and assisted reproductive technology (ART) treatment on perinatal outcomes and clarify the relationship between the maternal pathophysiological changes and artificial interventions. Methods: A total of 1,629 fertile women and 27,112 infertile women with sole infertility causes were prospectively recruited from July 2014 to December 2017, and 9,894 singletons were finally enrolled into the study. Pregnancies with more than one cause of infertility and/or multiple births were excluded. According to the causes of infertility and the exposure of ART treatment, the participants were divided into four groups, namely, fertile naturally conceived (NC) group, infertile NC group, female factor ART group, and male factor ART group. Perinatal outcomes, including gestational age of delivery (GA), birth weight (BW), preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), and large for gestational age (LGA), were compared among groups. Logistic regression was performed for the adjustment of several covariates. Results: The birth outcomes of the infertile NC group and fertile NC group, female factor ART group, and infertile NC group were comparable. Compared to the fertile NC group, the female factor ART group had a shorter GA (39.0 ± 1.6 vs. 39.3 ± 1.5 weeks, BW: P < 0.05). An interaction test showed that ART treatment had an interaction on the effect of female infertility on GA (P = 0.023). The female factor ART group also had a higher risk of PTB (OR 1.56, 95% CI 1.18-2.07) and LGA (OR 1.27, 95% CI 1.10-1.47) compared to the fertile NC group. The risk of PTB was increased for tubal factor ART (OR 1.49, 95% CI 1.12-2.00), ovulatory dysfunction ART (OR 1.87, 95% CI 1.29-2.72), and unexplained infertility ART (OR 1.88, 95% CI 1.11-3.17). The risk of LGA was increased for tubal factor ART (OR 1.28, 95% CI 1.11-1.48) and ovulatory dysfunction ART (OR 1.27, 95% CI 1.03-1.57). Conclusions: Our findings indicated that ART treatment could amplify the adverse effect of female infertility on neonates. Women with tubal factor infertility, ovulatory dysfunction, and unexplained infertility have a higher risk of PTB after ART treatment. Thus, clinicians should be vigilant in such patients and provide corresponding prevention strategies before and during pregnancy.

The Influence of the Vanishing Twin on the Perinatal Outcome of Surviving Singleton in IVF Pregnancy.

Objective: The purpose of this study was to clarify the influence of the vanishing twin (VT) on the perinatal outcomes in the surviving singleton and further identify the susceptible window. Study design: Retrospective cohort study. Methods: A total of 636 survivors of a vanished co-twin and 11,148 singleton controls were enrolled. The exposed group was further divided into early VT (EVT, VT ≤13 weeks, N = 593) and late VT subgroups (LVT, VT >13 weeks, N = 43) according to the gestational age of the twin vanishing. All participants were conceived through in vitro fertilization (IVF). Perinatal outcomes including gestational age, birthweight, and the incidence of preterm birth (PTB), low birthweight (LBW), small for gestational age (SGA), neonatal intensive care unit (NICU) admission, umbilical cord abnormality, jaundice of the newborn, and oligohydramnios were compared among the groups. Results: In our birth cohort, about 5.4% of all singleton deliveries originated from vanishing twin pregnancies. Compared with the singletons, both early and late VT pregnancy had a significantly lower birth weight (3337.57±532.24 g and 2916.05±526.07 g vs. 3446.15±526.07 g; p < 0.001 and p < 0.001), more frequent neonatal jaundice (47.0% and 60.5% vs. 40.6%; p = 0.002 and p = 0.008), and decreased incidence of umbilical cord abnormality (15.5% and 7.0% vs. 19.9%; p = 0.009 and p = 0.034). Newborns in the early VT group were more likely to manifest as SGA (5.4% vs. 3.6%, p = 0.002) and suffered oligohydramnios (5.4% vs. 3.4%; p = 0.008) than the primary singletons. In addition, the gestational age of late VT survivors was shorter than that of the controls (37.25 ± 3.25 vs. 39.04 ± 1.63, p = 0.001) and had a significantly higher risk of PTB (30.2% vs. 6.6%; p < 0.001) and NICU admission (27.9% vs. 9.4%, p < 0.001). All differences except for SGA maintain significance after adjusting for maternal age, BMI, and parity. Conclusions: Singletons with a vanished co-twin had worse perinatal outcomes compared with the original singletons, with LVT burden even much on the survival one. Therefore, close monitoring during the perinatal period was suggested in this type of neonates. Moreover, elective single embryo transfer should also be fully considered which could tackle the problem at its root.

Differential Lipidomic Characteristics of Children Born to Women with Polycystic Ovary Syndrome.

Objective: To describe the lipidomic characteristics of offspring born to polycystic ovary syndrome (PCOS) women (PCOS-off) and assess the associations between differential lipids and clinical phenotypes. Methods: Ultra performance liquid chromatography and mass spectrometry were performed on plasma samples from 70 PCOS-off and 71 healthy controls. The associations of differential metabolites with clinical phenotypes were examined by multiple linear regression. Results: Forty-four metabolites were significantly altered in PCOS-off, including 8 increased and 36 decreased. After stratification according to sex, 44 metabolites (13 increased and 31 decreased) were expressed differently in girls born to PCOS women (PCOS-g), most of which were glycerolipids. Furthermore, 46 metabolites (9 increased and 35 decreased) were expressed differently in boys born to PCOS women (PCOS-b), most of which were glycerophospholipids. Significant associations of metabolites with weight Z-score and high density lipoprotein cholesterol were found in PCOS-off. Triglycerides, low density lipoprotein cholesterol, and thyroid-stimulating hormone were separately correlated with some lipids in PCOS-g and PCOS-b. Conclusions: PCOS-off showed specific lipid profile alterations. The abnormal level of glycerophospholipids and sphingomyelin indicated the risk of glucose metabolism and cardiovascular diseases in PCOS-off. Some lipids, such as phosphatidylcholines, lysophosphatidylcholine and sphingomyelin, may be the potential markers. The results broadened our understanding of PCOS-offs' cardiometabolic status and emphasized more specific and detailed monitoring and management in this population.

Increased risk of metabolic dysfunction in children conceived by assisted reproductive technology.

AIMS/HYPOTHESIS: Assisted reproductive technology (ART) is the most widely used treatment for infertility and has resulted in millions of births worldwide. The safety of the offspring has been of the utmost concern. Previous studies suggested an increase in metabolic disorders in offspring later in life. The aim of the present study was to investigate metabolic changes at age 6-10 years in offspring conceived as a result of in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI). METHODS: A total of 380 children born from IVF/ICSI and a matched control group of 380 naturally conceived children, all aged 6-10 years, were recruited. Anthropometric measures, ultrasound and serum tests were performed for body mass, glucose metabolism and lipid profiles, and examination of vasculature structure. RESULTS: The children conceived by ART showed significantly higher fasting blood glucose and serum insulin levels and HOMA-IR (adjusted ß [95% CI]: fasting blood glucose 0.49 [0.42, 0.55]; loge-transformed insulin 0.28 [0.20, 0.35]; loge-transformed HOMA-IR 0.38 [0.30, 0.46]), as well as a lower HOMA-B and serum apolipoprotein A (ApoA) levels (adjusted ß [95% CI]: loge-transformed HOMA-B -0.19 [-0.27, -0.11]; ApoA -0.17 [-0.21, -0.13]), when compared with the control group. Furthermore, the ultrasound scan indicated elevated carotid intima-media thickness in children conceived by ART (ß 0.13 [95% CI 0.12, 0.13]). CONCLUSIONS/INTERPRETATION: Children conceived by IVF/ICSI have a less favourable glucose and cardiovascular metabolic profile in childhood when compared with naturally conceived children. The underlying mechanisms and potential long-term consequences need to be elucidated in future studies. Graphical abstract.