Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood.

Importance: People conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population. Objective: To investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study. Design, Setting, and Participants: This cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022. Exposures: Conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction). Main Outcomes and Measures: The main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups. Results: Up to 158 066 offspring (4329 conceived by ART) were included in each age-group meta-analysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were -0.27 (95% CI, -0.39 to -0.16) SD units at age younger than 3 months, -0.16 (95% CI, -0.22 to -0.09) SD units at age 17 to 23 months, -0.07 (95% CI, -0.10 to -0.04) SD units at age 6 to 9 years, and -0.02 (95% CI, -0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was -0.14 [95% CI, -0.20 to -0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, -0.15 to 0.15] SD units for frozen embryo transfer vs NC). More marked differences were seen for body fat measurements, and there was imprecise evidence that offspring conceived by ART developed greater adiposity by early adulthood (eg, ART vs NC difference in fat mass index at age older than 17 years: 0.23 [95% CI, -0.04 to 0.50] SD units). Conclusions and Relevance: These findings suggest that people conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.

First trimester fetal proportion volumetric measurements using a Virtual Reality approach.

OBJECTIVE: To establish feasibility and reproducibility of fetal proportion volumetric measurements, using three-dimensional (3D) ultrasound and a Virtual Reality (VR) system. METHODS: Within a population-based prospective birth cohort, 3D ultrasound datasets of 50 fetuses in the late first trimester were collected by three ultrasonographers in a single research center. V-scope software was used for volumetric measurements of total fetus, extremities, head-trunk, head, trunk, thorax, and abdomen. All measurements were performed independently by two researchers. Intraobserver and interobserver reproducibility were analyzed using Bland and Altman methods. RESULTS: Intraobserver and interobserver analyses of volumetric measurements of total fetus, head-trunk, head, trunk, thorax and abdomen showed intraclass correlation coefficients above 0.979, coefficients of variation below 7.51% and mean difference below 3.44%. The interobserver limits of agreement were within the ±10% range for volumetric measurements of total fetus, head-trunk, head and trunk. The interobserver limits of agreement for extremities, thorax and abdomen were -26.09% to 4.77%, -14.14% to 10.00% and -14.47% to 8.83%, respectively. CONCLUSION: First trimester fetal proportion volumetric measurements using 3D ultrasound and VR are feasible and reproducible, except volumetric measurements of the fetal extremities. These novel volumetric measurements may be used in future research to enable detailed studies on first trimester fetal development and growth.

Associations of maternal age at the start of pregnancy with placental function throughout pregnancy: The Generation R Study.

OBJECTIVE: To examine the associations of maternal age at the start of pregnancy across the full range with second and third trimester uterine and umbilical artery flow indices, and placental weight. STUDY DESIGN: In a population-based prospective cohort study among 8271 pregnant women, we measured second and third trimester uterine artery resistance and umbilical artery pulsatility indices and the presence of third trimester uterine artery notching using Doppler ultrasound. RESULTS: Compared to women aged 25-29.9 years, higher maternal age was associated with a higher third trimester uterine artery resistance index (difference for women 30-34.9 years was 0.10 SD (95% Confidence Interval (CI) 0.02 to 0.17), and for women aged ≥40 years 0.33 SD (95% CI 0.08 to 0.57), overall linear trend 0.02 SD (95% CI 0.01 to 0.03) per year). Compared to women aged 25-29.9 years, women younger than 20 years had an increased risk of third trimester uterine artery notching (Odds Ratio (OR) 1.97 (95% CI 1.30-3.00)). A linear trend was present with a decrease in risk of third trimester uterine artery notching per year increase in maternal age (OR 0.96 (95% CI 0.94 to 0.98)). Maternal age was not consistently associated with umbilical artery pulsatility indices or placental weight. CONCLUSIONS: Young maternal age is associated with higher risk of third trimester uterine artery notching, whereas advanced maternal age is associated with a higher third trimester uterine artery resistance index, which may predispose to an increased risk of pregnancy complications.

Associations of Maternal Early-Pregnancy Glucose Concentrations With Placental Hemodynamics, Blood Pressure, and Gestational Hypertensive Disorders.

BACKGROUND: Gestational diabetes mellitus is associated with increased risks of gestational hypertension and preeclampsia. We hypothesized that high maternal glucose concentrations in early pregnancy are associated with adverse placental adaptations and subsequently altered uteroplacental hemodynamics during pregnancy, predisposing to an increased risk of gestational hypertensive disorders. METHODS: In a population-based prospective cohort study from early pregnancy onwards, among 6,078 pregnant women, maternal early-pregnancy non-fasting glucose concentrations were measured. Mid and late pregnancy uterine and umbilical artery resistance indices were assessed by Doppler ultrasound. Maternal blood pressure was measured in early, mid, and late pregnancy and the occurrence of gestational hypertensive disorders was assessed using hospital registries. RESULTS: Maternal early-pregnancy glucose concentrations were not associated with mid or late pregnancy placental hemodynamic markers. A 1 mmol/l increase in maternal early-pregnancy glucose concentrations was associated with 0.71 mm Hg (95% confidence interval 0.22-1.22) and 0.48 mm Hg (95% confidence interval 0.10-0.86) higher systolic and diastolic blood pressure in early pregnancy, respectively, but not with blood pressure in later pregnancy. Also, maternal glucose concentrations were not associated with the risks of gestational hypertension or preeclampsia. CONCLUSIONS: Maternal early-pregnancy non-fasting glucose concentrations within the normal range are associated with blood pressure in early pregnancy, but do not seem to affect placental hemodynamics and the risks of gestational hypertensive disorders.

Second and third trimester fetal ultrasound population screening for risks of preterm birth and small-size and large-size for gestational age at birth: a population-based prospective cohort study

BACKGROUND: Preterm birth, small size for gestational age (SGA) and large size for gestational age (LGA) at birth are major risk factors for neonatal and long-term morbidity and mortality. It is unclear which periods of pregnancy are optimal for ultrasound screening to identify fetuses at risk of preterm birth, SGA or LGA at birth. We aimed to examine whether single or combined second and third trimester ultrasound in addition to maternal characteristics at the start of pregnancy are optimal to detect fetuses at risk for preterm birth, SGA and LGA. METHODS: In a prospective population-based cohort among 7677 pregnant women, we measured second and third trimester estimated fetal weight (EFW), and uterine artery pulsatility and umbilical artery resistance indices as placenta flow measures. Screen positive was considered as EFW or placenta flow measure < 10th or > 90th percentile. Information about maternal age, body mass index, ethnicity, parity, smoking, fetal sex and birth outcomes was available from questionnaires and medical records. Screening performance was assessed via receiver operating characteristic (ROC) curves and area under the curve (AUC) along with sensitivity at different false-positive rates. RESULTS: Maternal characteristics only and in combination with second trimester EFW had a moderate performance for screening for each adverse birth outcome. Screening performance improved by adding third trimester EFW to the maternal characteristics (AUCs for preterm birth 0.64 (95%CI 0.61 to 0.67); SGA 0.79 (95%CI 0.78 to 0.81); LGA 0.76 (95%CI 0.75; 0.78)). Adding third trimester placenta measures to this model improved only screening for risk of preterm birth (AUC 0.72 (95%CI 0.66 to 0.77) with sensitivity 37% at specificity 90%) and SGA (AUC 0.83 (95%CI 0.81 to 0.86) with sensitivity 55% at specificity 90%). Combining second and third trimester fetal and placental ultrasound did not lead to a better performance as compared to using only third trimester results. CONCLUSIONS: Combining single third trimester fetal and placental ultrasound results with maternal characteristics has the best screening performance for risks of preterm birth, SGA and LGA. As compared to second trimester screening, third trimester screening may double the detection of fetuses at risk of common adverse birth outcomes.

Population screening for gestational hypertensive disorders using maternal, fetal and placental characteristics: A population-based prospective cohort study.

OBJECTIVE: To determine screening performance of maternal, fetal and placental characteristics for selecting pregnancies at risk of gestational hypertension and preeclampsia in a low-risk multi-ethnic population. METHOD: In a prospective population-based cohort among 7124 pregnant women, we collected maternal characteristics including body mass index, ethnicity, parity, smoking and blood pressure in early-pregnancy. Fetal characteristics included second and third trimester estimated fetal weight and sex determined by ultrasound. Placental characteristics included first and second trimester placental growth factor concentrations and second and third trimester uterine artery resistance indices. RESULTS: Maternal characteristics provided the best screening result for gestational hypertension (area-under-the-curve [AUC] 0.79 [95% Confidence interval {CI} 0.76-0.81]) with 40% sensitivity at 90% specificity. For preeclampsia, the maternal characteristics model led to a screening performance of AUC 0.74 (95% CI 0.70-0.78) with 33% sensitivity at 90% specificity. Addition of second and third trimester placental ultrasound characteristics only improved screening performance for preeclampsia (AUC 0.78 [95% CI 0.75-0.82], with 48% sensitivity at 90% specificity). CONCLUSION: Routinely measured maternal characteristics, known at the start of pregnancy, can be used in screening for pregnancies at risk of gestational hypertension or preeclampsia within a low-risk multi-ethnic population. Addition of combined second and third trimester placental ultrasound characteristics only improved screening for preeclampsia.

Customized versus population birth weight charts for identification of newborns at risk of long-term adverse cardio-metabolic and respiratory outcomes: a population-based prospective cohort study.

BACKGROUND: Customized birth weight charts take into account physiological maternal characteristics that are known to influence fetal growth to differentiate between physiological and pathological abnormal size at birth. It is unknown whether customized birth weight charts better identify newborns at risk of long-term adverse outcomes than population birth weight charts. We aimed to examine whether birth weight classification according to customized charts is superior to population charts at identification of newborns at risk of adverse cardio-metabolic and respiratory health outcomes. METHODS: In a population-based prospective cohort study among 6052 pregnant women and their children, we measured infant catch-up growth, overweight, high blood pressure, hyperlipidemia, liver steatosis, clustering of cardio-metabolic risk factors, and asthma at age 10. Small size and large size for gestational age at birth was defined as birth weight in the lowest or highest decile, respectively, of population or customized charts. Association with birth weight classification was assessed using logistic regression models. RESULTS: Of the total of 605 newborns classified as small size for gestational age by population charts, 150 (24.8%) were reclassified as appropriate size for gestational age by customized charts, whereas of the total of 605 newborns classified as large size for gestational age by population charts, 129 (21.3%) cases were reclassified as appropriate size for gestational age by customized charts. Compared to newborns born appropriate size for gestational age, newborns born small size for gestational age according to customized charts had increased risks of infant catch-up growth (odds ratio (OR) 5.15 (95% confidence interval (CI) 4.22 to 6.29)), high blood pressure (OR 2.05 (95% CI 1.55 to 2.72)), and clustering of cardio-metabolic risk factors at 10 years (OR 1.66 (95% CI 1.18 to 2.34)). No associations were observed for overweight, hyperlipidemia, liver steatosis, or asthma. Newborns born large-size for gestational age according to customized charts had higher risk of catch-down-growth only (OR 3.84 (95% CI 3.22 to 4.59)). The direction and strength of the observed associations were largely similar when we used classification according to population charts. CONCLUSIONS: Small-size-for-gestational-age newborns seem to be at risk of long-term adverse cardio-metabolic health outcomes, irrespective of the use of customized or population birth weight charts.

Internal Podalic Version and Breech Extraction: Enhancing Realistic Sensations in a Simulation Model.

BACKGROUND: Experience with internal podalic version and breech extraction is diminishing, especially in the younger generation of obstetricians. Simulation training is essential to teach and maintain these skills. INSTRUMENT: We present a mannequin-based simulation method that enhances realistic sensations during training. EXPERIENCE: By positioning the fetal mannequin into a thin plastic bag filled with water, the impression of palpating, grabbing, and pulling the fetal feet through the plastic bag is similar to reaching feet through intact membranes. The unique approach of this realistic simulation model makes the experience fun and memorable, which contributes to the didactic value and success of the model. CONCLUSION: The simulation model we present mimics the situation and sensation obstetricians experience while performing internal podalic version and breech extraction.