Association between being large for gestational age and cardiovascular metabolic health in children conceived from assisted reproductive technology: a prospective cohort study.

BACKGROUND: To the best of our knowledge, no study has investigated the potential joint effect of large for gestational age (LGA) and assisted reproductive technology (ART) on the long-term health of children. METHODS: This was a prospective cohort study that recruited children whose parents had received ART treatment in the Center for Reproductive Medicine, Shandong Provincial Hospital, affiliated to Shandong University, between January 2006 and December 2017. Linear mixed model was used to compare the main outcomes. The mediation model was used to evaluate the intermediary effect of body mass index (BMI). RESULTS: 4138 (29.5%) children born LGA and 9910 (70.5%) children born appropriate for gestational age (AGA) were included in the present study. The offspring ranged from 0.4 to 9.9 years. LGAs conceived through ART were shown to have higher BMI, blood pressure, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance values, even after controlling for all covariates. The odds of overweight and insulin resistance are also higher in LGA subjects. After adjusting for all covariates, LGAs conceived through ART had BMI and BMI z-scores that were 0.48 kg/m2 and 0.34 units greater than those of AGAs, respectively. The effect of LGA on BMI was identified as early as infancy and remained consistently significant throughout pre-puberty. CONCLUSIONS: Compared to AGA, LGA children conceived from ART were associated with increased cardiovascular-metabolic events, which appeared as early as infancy and with no recovery by pre-puberty.

Is large for gestational age in singletons born after frozen embryo transfer associated with freezing technique or endometrial preparation protocol? A longitudinal national French study.

STUDY QUESTION: Is large for gestational age (LGA) observed in babies born after frozen embryo transfer (FET) associated with either the freezing technique or the endometrial preparation protocol? SUMMARY ANSWER: Artificial cycles are associated with a higher risk of LGA, with no difference in rate between the two freezing techniques (vitrification versus slow freezing) or embryo stage (cleaved embryo versus blastocyst). WHAT IS KNOWN ALREADY: Several studies have compared neonatal outcomes after fresh embryo transfer (ET) and FET and shown that FET is associated with improved neonatal outcomes, including reduced risks of preterm birth, low birthweight, and small for gestational age (SGA), when compared with fresh ET. However, these studies also revealed an increased risk of LGA after FET. The underlying pathophysiology of this increased risk remains unclear; parental infertility, laboratory procedures (including embryo culture conditions and freezing-thawing processes), and endometrial preparation treatments might be involved. STUDY DESIGN, SIZE, DURATION: A multicentre epidemiological data study was performed through a retrospective analysis of the standardized individual clinical records of the French national register of IVF from 2014 to 2018, including single deliveries resulting from fresh ET or FET that were prospectively collected in fertility centres. Complementary data were collected from the participating fertility centres and included the vitrification media and devices, and the endometrial preparation protocols. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from 35 French ART centres, leading to the inclusion of a total of 72 789 fresh ET, 10 602 slow-freezing FET, and 39 062 vitrification FET. Main clinical outcomes were presented according to origin of the transferred embryos (fresh, slow frozen, or vitrified embryos) and endometrial preparations for FET (ovulatory or artificial cycles), comparing five different groups (fresh, slow freezing-ovulatory cycle, slow freezing-artificial cycle, vitrification-ovulatory cycle, and vitrification-artificial cycle). Foetal growth disorders were defined in live-born singletons according to gestational age and sex-specific weight percentile distribution: SGA and LGA if <10th and ≥90th percentiles, respectively. Analyses were performed using linear mixed models with the ART centres as random effect. MAIN RESULTS AND THE ROLE OF CHANCE: Transfers led to, respectively, 19 006, 1798, and 9195 deliveries corresponding to delivery rates per transfer of 26.1%, 17.0%, and 23.5% after fresh ET, slow-freezing FET, and vitrification FET, respectively. FET cycles were performed in either ovulatory cycles (n = 21 704) or artificial cycles (n = 34 237), leading to 5910 and 10 322 pregnancies, respectively, and corresponding to pregnancy rates per transfer of 31.6% and 33.3%. A significantly higher rate of spontaneous miscarriage was observed in artificial cycles when compared with ovulatory cycles (33.3% versus 21.4%, P < 0.001, in slow freezing groups and 31.6% versus 21.8%, P < 0.001 in vitrification groups). Consequently, a lower delivery rate per transfer was observed in artificial cycles compared with ovulatory cycles both in slow freezing and vitrification groups (15.5% versus 18.9%, P < 0.001 and 22.8% versus 24.9%, P < 0.001, respectively). Among a total of 26 585 live-born singletons, 16 413 babies were born from fresh ET, 1644 from slow-freezing FET, and 8528 from vitrification FET. Birthweight was significantly higher in the FET groups than in the fresh ET group, with no difference between the two freezing techniques. Likewise, LGA rates were higher and SGA rates were lower in the FET groups compared with the fresh ET group whatever the method used for embryo freezing. In a multivariable analysis, the risk of LGA following FET was significantly increased in artificial compared with ovulatory cycles. In contrast, the risk of LGA was not associated with either the freezing procedure (vitrification versus slow freezing) or the embryo stage (cleaved embryo versus blastocyst) at freezing. Regarding the vitrification method, the risk of LGA was not associated with either the vitrification medium used or the embryo stage. LIMITATIONS, REASONS FOR CAUTION: No data were available on maternal context, such as parity, BMI, infertility cause, or maternal comorbidities, in the French national database. In particular, we cannot exclude that the increased risk of LGA observed following FET with artificial cycles may, at least partially, be associated with a confounding effect of some maternal factors. No information about embryo culture and incubation conditions was available. Most of the vitrification techniques were performed using the same device and with two main vitrification media, limiting the validity of a comparison of risk for LGA according to the device or vitrification media used. WIDER IMPLICATIONS OF THE FINDINGS: Our results seem reassuring, since no potential foetal growth disorders following embryo vitrification in comparison with slow freezing were observed. Even if other factors are involved, the endometrial preparation treatment seems to have the greatest impact on LGA risk following FET. FET during ovulatory cycles could minimize the risk for foetal growth disorders. STUDY FUNDING/COMPETING INTEREST(S): This work has received funding from the French Biomedicine Agency (Grant number: 19AMP002). None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Maternal Dietary Cholesterol and Egg Intake during Pregnancy and Large-for-Gestational-Age Infants: A Prospective Cohort Study.

BACKGROUND: Cholesterol plays a vital role in fetal growth and development during pregnancy. There remains controversy over whether pregnant females should limit their cholesterol intake. OBJECTIVES: The objective of this study was to investigate the association between maternal dietary cholesterol intake during pregnancy and infant birth weight in a Chinese prospective cohort study. METHODS: A total of 4146 mother-child pairs were included based on the Jiangsu Birth Cohort study. Maternal dietary information was assessed with a semiquantitative food-frequency questionnaire. Birth weight z-scores and large-for-gestational-age (LGA) infants were converted by the INTERGROWTH-21st neonatal weight-for-gestational-age standard. Poisson regression and generalized estimating equations were employed to examine the relationships between LGA and maternal dietary cholesterol across the entire pregnancy and trimester-specific cholesterol intake, respectively. RESULTS: The median intake of maternal total dietary cholesterol during the entire pregnancy was 671.06 mg/d, with eggs being the main source. Maternal total dietary cholesterol and egg-sourced cholesterol were associated with an increase in birth weight z-score, with per standard deviation increase in maternal total and egg-sourced dietary cholesterol being associated with an increase of 0.16 [95% confidence interval (CI): 0.07, 0.25] and 0.06 (95% CI: 0.03, 0.09) in birth weight z-score, respectively. Egg-derived cholesterol intake in the first and third trimesters was positively linked to LGA, with an adjusted relative risk of 1.11 (95% CI: 1.04, 1.18) and 1.09 (95% CI: 1.00, 1.18). Compared with mothers consuming ≤7 eggs/wk in the third trimester, the adjusted relative risk for having an LGA newborn was 1.37 (95% CI: 1.09, 1.72) for consuming 8-10 eggs/wk and 1.45 (95% CI: 1.12, 1.86) for consuming >10 eggs/wk (P-trend = 0.015). CONCLUSIONS: Maternal total dietary cholesterol intake, as well as consuming over 7 eggs/wk during pregnancy, displayed significant positive relationships with the incidence of LGA, suggesting that mothers should avoid excessive cholesterol intake during pregnancy to prevent adverse birth outcomes.

Impact of a modified screening approach during the COVID-19 pandemic on the diagnosis and outcomes of gestational diabetes mellitus: A population-level analysis of 90,518 pregnant women.

AIMS: To provide real-world evidence on the uptake of and outcomes associated with the modified gestational diabetes mellitus (GDM) screening approach offered during the COVID-19 pandemic compared with the standard screening approach. METHODS: All pregnancies between 01 January 2020 and 31 December 2021, in Alberta, Canada, were included in the study. We examined GDM screening and diagnosis rates, and large-for-gestational-age (LGA) outcomes. RESULTS: Annual GDM screening rates were > 95% during the study time period. Overall, 84.7%, and 11.6% of the 92,505 pregnancies underwent standard and modified screening for GDM, respectively. The use of modified screening was the highest among deliveries in August 2020 (49.8%) which corresponded to the early first wave of the pandemic. GDM diagnosis rate was lower in the modified screening (7.4%) than in the standard screening (12.3%, p < 0.001) group. The LGA rates in the modified screening with GDM and the standard screening with GDM groups were 24.8% and 12.6%, respectively (p < 0.001). Women in the modified screening with GDM group were at a higher risk of having an LGA infant (adjusted odds ratio: 3.46; 95% confidence interval: 2.93, 4.08) compared to the standard screening with no GDM group. CONCLUSIONS: The COVID-19 epidemic had no impact on screening for GDM. Women who underwent modified screening, based on HbA1c/random plasma glucose, had lower rates of GDM cases.

Accuracy of antenatal ultrasound in predicting large-for-gestational-age babies: population-based cohort study.

BACKGROUND: Pregnancies with large-for-gestational-age fetuses are at increased risk of adverse maternal and neonatal outcomes. There is uncertainty about how to manage birth in such pregnancies. Current guidelines recommend a discussion with women of the pros and cons of options, including expectant management, induction of labor, and cesarean delivery. For women to make an informed decision about birth, antenatal detection of large for gestational age is essential. OBJECTIVE: To investigate the ability of antenatal ultrasound scans to predict large for gestational age at birth. STUDY DESIGN: In this retrospective cohort study, we analyzed data from a routinely collected database from the West Midlands, United Kingdom. We included pregnancies that had an antenatal ultrasound-estimated fetal weight between 35+0 and 38+0 weeks gestation for any indication and a subgroup where the reason for the scan was that the fetus was suspected to be big. Large for gestational age was defined as >90th customized GROW percentile for estimated fetal weight as well as neonatal weight. In addition, we tested the performance of an uncustomized standard, with Hadlock fetal weight >90th percentile and neonatal weight >4 kg. We calculated diagnostic characteristics for the whole population and groups with different maternal body mass indexes. RESULTS: The study cohort consisted of 26,527 pregnancies, which, on average, had a scan at 36+4 weeks gestation and delivered 20 days later at a median of 39+3 weeks (interquartile range 15). In total, 2241 (8.4%) of neonates were large for gestational age by customized percentiles, of which 1459 (65.1%) had a scan estimated fetal weight >90th percentile, with a false positive rate of 8.6% and a positive predictive value of 41.0%. In the subgroup of 912 (3.4%) pregnancies scanned for a suspected large fetus, 293 (32.1%) babies were large for gestational age at birth, giving a positive predictive value of 50.3%, with a sensitivity of 77.1% and false positive rate of 36.0%. When comparing subgroups from low (<18.5 kg/m2) to high body mass index (>30 kg/m2), sensitivity increased from 55.6% to 67.8%, false positive rate from 5.2% to 11.5%, and positive predictive value from 32.1% to 42.3%. A total of 2585 (9.7%) babies were macrosomic (birthweight >4 kg), and of these, 1058 (40.9%) were large for gestational age (>90th percentile) antenatally by Hadlock's growth standard, with a false positive rate of 4.9% and a positive predictive value 41.0%. Analysis within subgroups showed better performance by customized than uncustomized standards for low body mass index (<18.5; diagnostic odds ratio, 23.0 vs 6.4) and high body mass index (>30; diagnostic odds ratio, 16.2 vs 8.8). CONCLUSION: Late third-trimester ultrasound estimation of fetal weight for any indication has a good ability to identify and predict large for gestational age at birth and improves with the use of a customized standard. The detection rate is better when an ultrasound is performed for a suspected large fetus but at the risk of a higher false positive diagnosis. Our results provide information for women and clinicians to aid antenatal decision-making about the birth of a fetus suspected of being large for gestational age.

The simultaneous occurrence of gestational diabetes and hypertensive disorders of pregnancy affects fetal growth and neonatal morbidity.

BACKGROUND: Gestational diabetes is associated with increased risk of hypertensive disorders of pregnancy, but there are limited data on fetal growth and neonatal outcomes when both conditions are present. OBJECTIVE: We evaluated the risk of abnormal fetal growth and neonatal morbidity in pregnancies with co-occurrence of gestational diabetes and hypertensive disorders of pregnancy. STUDY DESIGN: In a retrospective study of 47,093 singleton pregnancies, we compared the incidence of appropriate for gestational age birthweight in pregnancies affected by gestational diabetes alone, hypertensive disorders of pregnancy alone, or both gestational diabetes and hypertensive disorders of pregnancy with that in pregnancies affected by neither disorder using generalized estimating equations (covariates: maternal age, nulliparity, body mass index, insurance type, race, marital status, and prenatal care site). Secondary outcomes were large for gestational age birthweight, small for gestational age birthweight, and a neonatal morbidity composite outcome (stillbirth, hypoglycemia, hyperbilirubinemia, respiratory distress, encephalopathy, preterm delivery, neonatal death, and neonatal intensive care unit admission). RESULTS: The median (interquartile range) birthweight percentile in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy (50 [24.0-78.0]; N=179) was similar to that of unaffected pregnancies (50 [27.0-73.0]; N=35,833). However, the absolute rate of appropriate for gestational age birthweight was lower for gestational diabetes/hypertensive disorders of pregnancy co-occurrence (78.2% vs 84.9% for unaffected pregnancies). Adjusted analyses showed decreased odds of appropriate for gestational age birthweight in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy compared with unaffected pregnancies (adjusted odds ratio, 0.72 [95% confidence interval, 0.52-1.00]; P=.049), and in pregnancies complicated by gestational diabetes alone (adjusted odds ratio, 0.78 [0.68-0.89]; P<.001) or hypertensive disorders of pregnancy alone (adjusted odds ratio, 0.73 [0.66-0.81]; P<.001). The absolute risk of large for gestational age birthweight was greater in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy (14.5%) than in unaffected pregnancies (8.2%), without apparent difference in the risk of small for gestational age birthweight (7.3% vs 6.9%). However, in adjusted models comparing pregnancies with gestational diabetes/hypertensive disorders of pregnancy co-occurrence with unaffected pregnancies, neither an association with large for gestational age birthweight (adjusted odds ratio, 1.33 [0.88-2.00]; P=.171) nor small for gestational age birthweight (adjusted odds ratio, 1.32 [0.80-2.19]; P=.293) reached statistical significance. Gestational diabetes/hypertensive disorders of pregnancy co-occurrence carried an increased risk of neonatal morbidity that was greater than that observed with either condition alone (gestational diabetes/hypertensive disorders of pregnancy: adjusted odds ratio, 3.13 [2.35-4.17]; P<.001; gestational diabetes alone: adjusted odds ratio, 2.01 [1.78-2.27]; P<.001; hypertensive disorders of pregnancy alone: adjusted odds ratio, 1.38 [1.26-1.50]; P<.001). CONCLUSION: Although pregnancies with both gestational diabetes and hypertensive disorders of pregnancy have a similar median birthweight percentile to those affected by neither condition, pregnancies concurrently affected by both conditions have a higher risk of abnormal fetal growth and neonatal morbidity.

Comparing population-based fetal growth standards in a US cohort.

BACKGROUND: No fetal growth standard is currently endorsed for universal use in the United States. Newer standards improve upon the methodologic limitations of older studies; however, before adopting into practice, it is important to know how recent standards perform at identifying fetal undergrowth or overgrowth and at predicting subsequent neonatal morbidity or mortality in US populations. OBJECTIVE: To compare classification of estimated fetal weight that is <5th or 10th percentile or >90th percentile by 6 population-based fetal growth standards and the ability of these standards to predict a composite of neonatal morbidity and mortality. STUDY DESIGN: We used data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be cohort, which recruited nulliparous women in the first trimester at 8 US clinical centers (2010-2014). Estimated fetal weight was obtained from ultrasounds at 16 to 21 and 22 to 29 weeks of gestation (N=9534 women). We calculated rates of fetal growth restriction (estimated fetal weight <5th and 10th percentiles; fetal growth restriction<5 and fetal growth restriction<10) and estimated fetal weight >90th percentile (estimated fetal weight>90) from 3 large prospective fetal growth cohorts with similar rigorous methodologies: INTERGROWTH-21, World Health Organization-sex-specific and combined, Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific and unified, and the historic Hadlock reference. To determine whether differential classification of fetal growth restriction or estimated fetal weight >90 among standards was clinically meaningful, we then compared area under the curve and sensitivity of each standard to predict small for gestational age or large for gestational age at birth, composite perinatal morbidity and mortality alone, and small for gestational age or large for gestational age with composite perinatal morbidity and mortality. RESULTS: The standards classified different proportions of fetal growth restriction and estimated fetal weight>90 for ultrasounds at 16 to 21 (visit 2) and 22 to 29 (visit 3) weeks of gestation. At visit 2, the Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific, World Health Organization sex-specific and World Health Organization-combined identified similar rates of fetal growth restriction<10 (8.4%-8.5%) with the other 2 having lower rates, whereas Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific identified the highest rate of fetal growth restriction<5 (5.0%) compared with the other references. At visit 3, World Health Organization sex-specific classified 9.2% of fetuses as fetal growth restriction<10, whereas the other 5 classified a lower proportion as follows: World Health Organization-combined (8.4%), Eunice Kennedy Shriver National Institute of Child Health and Human Development race-ethnic-specific (7.7%), INTERGROWTH (6.2%), Hadlock (6.1%), and Eunice Kennedy Shriver National Institute of Child Health and Human Development unified (5.1%). INTERGROWTH classified the highest (21.3%) as estimated fetal weight>90 whereas Hadlock classified the lowest (8.3%). When predicting composite perinatal morbidity and mortality in the setting of early-onset fetal growth restriction, World Health Organization had the highest area under the curve of 0.53 (95% confidence interval, 0.51-0.53) for fetal growth restriction<10 at 22 to 29 weeks of gestation, but the areas under the curve were similar among standards (0.52). Sensitivity was generally low across standards (22.7%-29.1%). When predicting small for gestational age birthweight with composite neonatal morbidity or mortality, for fetal growth restriction<10 at 22 to 29 weeks of gestation, World Health Organization sex-specific had the highest area under the curve (0.64; 95% confidence interval, 0.60-0.67) and INTERGROWTH had the lowest (area under the curve=0.58; 95% confidence interval 0.55-0.62), though all standards had low sensitivity (7.0%-9.6%). CONCLUSION: Despite classifying different proportions of fetuses as fetal growth restriction or estimated fetal weight>90, all standards performed similarly in predicting perinatal morbidity and mortality. Classification of different percentages of fetuses as fetal growth restriction or estimated fetal weight>90 among references may have clinical implications in the management of pregnancies, such as increased antenatal monitoring for fetal growth restriction or cesarean delivery for suspected large for gestational age. Our findings highlight the importance of knowing how standards perform in local populations, but more research is needed to determine if any standard performs better at identifying the risk of morbidity or mortality.

Decreased complexity of glucose time series index associated with adverse pregnancy outcomes in gestational diabetes mellitus.

AIM: We investigated the relationship between the complexity of the glucose time series index (CGI) during pregnancy and adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: In this retrospective cohort study, 388 singleton pregnant women with GDM underwent continuous glucose monitoring (CGM) at a median of 26.86 gestational weeks. CGI was calculated using refined composite multiscale entropy based on CGM data. The participants were categorized into tertiles according to their baseline CGI (CGI <2.32, 2.32-3.10, ≥3.10). Logistic regression was used to assess the association between CGI and composite adverse outcomes or large for gestational age (LGA). The discrimination performance of CGI was estimated using receiver operating characteristic analysis. RESULTS: Of the 388 participants, 71 (18.3%) had LGA infants and 63 (16.2%) had composite adverse outcomes. After adjustments were made for confounders, compared with those with a high CGI (CGI ≥3.10), participants with a low CGI (CGI <2.32) had a higher risk of composite adverse outcomes (odds ratio: 12.10, 95% confidence interval: 4.41-33.18) and LGA (odds ratio: 12.68, 95% confidence interval: 4.04-39.75). According to the receiver operating characteristic analysis, CGI was significantly better than glycated haemoglobin and conventional CGM indicators for the prediction of adverse pregnancy outcomes (all p < .05). CONCLUSION: A lower CGI during pregnancy was associated with composite adverse outcomes and LGA. CGI, a novel glucose homeostasis predictor, seems to be superior to conventional glucose indicators for the prediction of adverse pregnancy outcomes in women with GDM.

The clinical performance and population health impact of birthweight-for-gestational age indices at term gestation.

BACKGROUND: The assessment of birthweight for gestational age and the identification of small- and large-for-gestational age (SGA and LGA) infants remain contentious, despite the recent creation of the Intergrowth 21st Project and World Health Organisation (WHO) birthweight-for-gestational age standards. OBJECTIVE: We carried out a study to identify birthweight-for-gestational age cut-offs, and corresponding population-based, Intergrowth 21st and WHO centiles associated with higher risks of adverse neonatal outcomes, and to evaluate their ability to predict serious neonatal morbidity and neonatal mortality (SNMM) at term gestation. METHODS: The study population was based on non-anomalous, singleton live births between 37 and 41 weeks' gestation in the United States from 2003 to 2017. SNMM included 5-min Apgar score <4, neonatal seizures, need for assisted ventilation, and neonatal death. Birthweight-specific SNMM was modelled by gestational week using penalised B-splines. The birthweights at which SNMM odds were minimised (and higher by 10%, 50% and 100%) were estimated, and the corresponding population, Intergrowth 21st, and WHO centiles were identified. The clinical performance and population impact of these cut-offs for predicting SNMM were evaluated. RESULTS: The study included 40,179,663 live births and 991,486 SNMM cases. Among female singletons at 39 weeks' gestation, SNMM odds was lowest at 3203 g birthweight, and 10% higher at 2835 g and 3685 g (population centiles 11th and 82nd, Intergrowth centiles 17th and 88th and WHO centiles 15th and 85th). Birthweight cut-offs were poor predictors of SNMM, for example, the cut-offs associated with 10% and 50% higher odds of SNMM among female singletons at 39 weeks' gestation resulted in a sensitivity, specificity, and population attributable fraction of 12.5%, 89.4%, and 2.1%, and 2.9%, 98.4% and 1.3%, respectively. CONCLUSIONS: Reference- and standard-based birthweight-for-gestational age indices and centiles perform poorly for predicting adverse neonatal outcomes in individual infants, and their associated population impact is also small.

Multivariable prediction models for fetal macrosomia and large for gestational age: A systematic review.

BACKGROUND: The identification of large for gestational age (LGA) and macrosomic fetuses is essential for counselling and managing these pregnancies. OBJECTIVES: To systematically review the literature for multivariable prediction models for LGA and macrosomia, assessing the performance, quality and applicability of the included model in clinical practice. SEARCH STRATEGY: MEDLINE, EMBASE and Cochrane Library were searched until June 2022. SELECTION CRITERIA: We included observational and experimental studies reporting the development and/or validation of any multivariable prediction model for fetal macrosomia and/or LGA. We excluded studies that used a single variable or did not evaluate model performance. DATA COLLECTION AND ANALYSIS: Data were extracted using the Checklist for critical appraisal and data extraction for systematic reviews of prediction modelling studies checklist. The model performance measures discrimination, calibration and validation were extracted. The quality and completion of reporting within each study was assessed by its adherence to the TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) checklist. The risk of bias and applicability were measured using PROBAST (Prediction model Risk Of Bias Assessment Tool). MAIN RESULTS: A total of 8442 citations were identified, with 58 included in the analysis: 32/58 (55.2%) developed, 21/58 (36.2%) developed and internally validated and 2/58 (3.4%) developed and externally validated a model. Only three studies externally validated pre-existing models. Macrosomia and LGA were differentially defined by many studies. In total, 111 multivariable prediction models were developed using 112 different variables. Model discrimination was wide ranging area under the receiver operating characteristics curve (AUROC 0.56-0.96) and few studies reported calibration (11/58, 19.0%). Only 5/58 (8.6%) studies had a low risk of bias. CONCLUSIONS: There are currently no multivariable prediction models for macrosomia/LGA that are ready for clinical implementation.

Perinatal outcome of fetuses predicted to be large-for-gestational age on universal third-trimester ultrasound in non-diabetic pregnancy.

OBJECTIVE: To describe the perinatal outcome of fetuses predicted to be large-for-gestational age (LGA) on universal third-trimester ultrasound in non-diabetic pregnancies of women attempting vaginal delivery. METHODS: This was a prospective population-based cohort study of patients from a single tertiary maternity unit in the UK offering universal third-trimester ultrasound and practicing expectant management of suspected LGA until 41-42 weeks. All women with a singleton pregnancy and an estimated due date between January 2014 and September 2019 were included. Women delivering before 37 weeks, those having a planned Cesarean delivery, those with pre-existing or gestational diabetes, those with fetal abnormalities and those who did not undergo a third-trimester scan were excluded from the assessment of perinatal outcome of cases with LGA predicted on ultrasound after implementation of the universal scan period. Association of LGA on universal third-trimester ultrasound screening and perinatal adverse outcome was assessed, with the exposures of interest being estimated fetal weight (EFW) at the 90th -95th , > 95th and > 99th percentile. The reference group was composed of fetuses with EFW at the 30th -70th percentile. Analysis was performed using multivariate logistic regression. The evaluated adverse perinatal outcomes included a composite outcome of admission to neonatal intensive care unit, Apgar score < 7 at 5 min and arterial cord pH < 7.1 (CAO1) and a composite outcome of stillbirth, neonatal death and hypoxic ischemic encephalopathy (CAO2). Secondary maternal outcomes were induction of labor, mode of delivery, postpartum hemorrhage, shoulder dystocia and obstetric anal sphincter injury. RESULTS: Cases with EFW > 95th percentile on universal third-trimester scan were at increased risk of CAO1 (adjusted odds ratio (aOR), 2.18 (95% CI, 1.69-2.80)) and CAO2 (aOR, 2.58 (95% CI, 1.05-6.34)). Cases with EFW at the 90th -95th percentile had a less pronounced increase in the risk of CAO1 (aOR, 1.35 (95% CI, 1.02-1.78)) and were not at increased risk of CAO2. All pregnancies with a fetus predicted to be LGA were at increased risk of all of the evaluated secondary maternal outcomes except for obstetric anal sphincter injury. The risk of adverse maternal outcome was typically higher with increasing EFW. Post-hoc exploration of data suggested that shoulder dystocia had a limited contribution to composite adverse perinatal outcomes in LGA cases (population attributable fraction of 10.8% for CAO1 and 29.1% for CAO2). CONCLUSIONS: Cases with EFW > 95th percentile are at increased risk of severe adverse perinatal outcome, such as death and hypoxic ischemic encephalopathy. These findings should aid antenatal counseling regarding the associated risk and delivery options. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of large-for-gestational age at 36 weeks' gestation: two-dimensional ultrasound vs three-dimensional ultrasound vs magnetic resonance imaging.

OBJECTIVE: To compare the performance of two-dimensional ultrasound (2D-US), three-dimensional ultrasound (3D-US) and magnetic resonance imaging (MRI) at 36 weeks' gestation in predicting the delivery of a large-for-gestational-age (LGA) neonate, defined as birth weight ≥ 95th percentile, in patients at high and low risk for macrosomia. METHODS: This was a secondary analysis of a prospective observational study conducted between January 2017 and February 2019. Women with a singleton pregnancy at 36 weeks' gestation underwent 2D-US, 3D-US and MRI within 15 min for estimation of fetal weight. Weight estimations and birth weight were plotted on a growth curve to obtain percentiles for comparison. Participants were considered high risk if they had at least one of the following risk factors: diabetes mellitus, estimated fetal weight ≥ 90th percentile at the routine third-trimester ultrasound examination, obesity (prepregnancy body mass index ≥ 30 kg/m2) or excessive weight gain during pregnancy. The outcome was the diagnostic performance of each modality in the prediction of birth weight ≥ 95th percentile, expressed as the area under the receiver-operating-characteristics curve (AUC), sensitivity, specificity and positive and negative predictive values. RESULTS: A total of 965 women were included, of whom 533 (55.23%) were high risk and 432 (44.77%) were low risk. In the low-risk group, the AUCs for birth weight ≥ 95th percentile were 0.982 for MRI, 0.964 for 2D-US and 0.962 for 3D-US; pairwise comparisons were non-significant. In the high-risk group, the AUCs were 0.959 for MRI, 0.909 for 2D-US and 0.894 for 3D-US. A statistically significant difference was noted between MRI and both 2D-US (P = 0.002) and 3D-US (P = 0.002), but not between 2D-US and 3D-US (P = 0.503). In the high-risk group, MRI had the highest sensitivity (65.79%) compared with 2D-US (36.84%, P = 0.002) and 3D-US (21.05%, P < 0.001), whereas 3D-US had the highest specificity (98.99%) compared with 2D-US (96.77%, P = 0.005) and MRI (96.97%, P = 0.004). CONCLUSIONS: At 36 weeks' gestation, MRI has better performance compared with 2D-US and 3D-US in predicting birth weight ≥ 95th percentile in patients at high risk for macrosomia, whereas the performance of 2D-US and 3D-US is comparable. For low-risk patients, the three modalities perform similarly. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Trimester-specific association between fetal growth and physical activity in pregnant women: total physical activity vs moderate-to-vigorous exercise.

OBJECTIVE: To investigate the trimester-specific associations between maternal total physical activity level vs moderate-to-vigorous exercise and fetal growth disorders. METHODS: We analyzed 2062 mother-neonate pairs participating in the longitudinal China Medical University Birth Cohort Study. The Pregnancy Physical Activity Questionnaire was used to assess the physical activity level of women during the three trimesters. A higher level of total physical activity was defined as meeting or exceeding the cohort-specific 75th percentile, and a higher level of exercise was defined according to the Physical Activity Guidelines for Americans. Fetal growth disorder was defined as small-for-gestational age (SGA) or large-for-gestational age (LGA) at birth. RESULTS: Of the neonates included in this study, 7.1% were SGA and 15.5% were LGA. A higher level of total physical activity during the first trimester (adjusted relative risk (aRR), 0.62 (95% CI, 0.42-0.91)) and second trimester (aRR, 0.62 (95% CI, 0.41-0.95)) was associated with a lower risk of SGA, and a higher level of total physical activity during the third trimester was associated with a lower risk of LGA (aRR, 0.73 (95% CI, 0.54-0.97)). When analyzing physical activity by subtype, a higher level of occupational physical activity during the first and second trimesters was associated negatively with SGA risk, and higher levels of occupational and low-intensity physical activity during the first trimester were associated negatively with LGA risk. No significant association was found between maternal adherence to the Physical Activity Guidelines for Americans and risk of fetal growth disorders. CONCLUSIONS: A higher total physical activity level during the first and second trimesters was associated with a decreased risk of SGA, whereas a higher total physical activity level in the third trimester was associated with a decreased risk of LGA. Pregnant women should be advised to increase their total physical activity levels instead of focusing on engaging in only moderate-to-vigorous exercise. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Timing of induction of labor in suspected macrosomia: retrospective cohort study, systematic review and meta-analysis.

OBJECTIVE: Large-for-gestational-age (LGA) is associated with several adverse maternal and neonatal outcomes. Although many studies have found that early induction of labor (eIOL) in LGA reduces the incidence of shoulder dystocia (SD), no current guidelines recommend this particular strategy, due to concerns about increased rates of cesarean delivery (CD) and neonatal complications. The purpose of this study was to assess whether the timing of IOL in LGA fetuses affects maternal and neonatal outcomes in a single center; and to combine these results with the evidence reported in the literature. METHODS: This study comprised two parts. The first was a retrospective cohort study that included: consecutive patients with singleton pregnancy, an estimated fetal weight (EFW) ≥90th percentile on ultrasound (US) between 35+0 and 39+0 weeks of gestation (WG), who were eligible for normal vaginal delivery. The second part was a systematic review of literature and meta-analysis that included the results of the first part as well as all previously reported studies that have compared IOL to expectant management in patients with LGA. The perinatal outcomes were CD, operative vaginal delivery (OVD), SD, brachial plexus palsy, anal sphincter injury, postpartum hemorrhage (PPH), APGAR score, umbilical arterial pH, neonatal intensive care unit (NICU) admission, use of continuous positive airway pressure (CPAP), intracranial hemorrhage (ICH), phototherapy, and bone fracture. RESULTS: Retrospective cohort: of the 547 patients, 329 (60.1%) were induced and 218 (39.9%) entered spontaneous labor. Following covariate balancing, CD was significantly higher in the IOL group in comparison to the spontaneous labor group. This difference only became apparent beyond 40WG (hazard ratio: 1.9, p=0.030). The difference between both groups for shoulder dystocia was not statistically significant. Systematic review and metanalysis: 17 studies were included in addition to our own results giving a total sample size of 111,300 participants. When IOL was performed <40+0WG, the risk for SD was significantly lower in the IOL group (OR: 0.64, 95%CI: 0.42-0.98, I2 =19%). There was no significant difference in CD rate between IOL and expectant management after pooling the results of these 17 studies. However, when removing the studies in which IOL was done exclusively before 40+0WG, the risk for CD in the remaining studies (IOL not exclusively <40+0WG) was significantly higher in the IOL group (odds ratio [OR]: 1.46, 95% confidence interval [95%CI]: 1.02-2.09, I2 =56%). There were no statistically significant differences between IOL and expectant management for the remaining perinatal outcomes. Nulliparity, history of CD, and low Bishop score but not methods of induction were independent risk factors for intrapartum CD in patients who were induced for LGA. CONCLUSION: Timing of IOL in patients with suspected macrosomia significantly impacts perinatal adverse outcomes. IOL has no impact on rates of SD but does increase CD when considered irrespective of gestational age, but it may decrease the risk of SD without increasing the risk of other adverse maternal outcomes, in particular cesarean section when performed before 40+0 WG. (GRADE: Low/Very low). This article is protected by copyright. All rights reserved.

Maternal age-specific risks for adverse birth weights according to gestational weight gain: a prospective cohort in Chinese women older than 30.

BACKGROUND: It is unclear whether the effects of abnormal gestational weight gain (GWG) on birth outcomes are differently in women with different maternal ages. This study aimed to investigate maternal age-specific association between GWG and adverse birth weights in Chinese women older than 30. METHODS: 19,854 mother-child dyads were selected from a prospective cohort study in Southwest China between 2019 and 2022. Logistic regression model was used to assess the association between GWG, which defined by the 2009 Institute of Medicine guidelines, and adverse birth weights including large- and small-for-gestational-age (LGA and SGA), stratified by maternal age (31-34 years and ≥ 35 years). RESULTS: In both maternal age groups, excessive and insufficient GWG were associated with increased odds of LGA and SGA, respectively. After women were categorized by pre-pregnancy body mass index, the associations remained significant in women aged 31-34 years, whereas for women aged ≥ 35 years, the association between excessive GWG and the risk of LGA was only significant in normal weight and overweight/obese women, and the significant effect of insufficient GWG on the risk of SGA was only observed in underweight and overweight/obese women. Moreover, among overweight/obese women, the magnitude of the association between insufficient GWG and the risk of SGA was greater in those aged ≥ 35 years (31-34 years: OR 2.08, 95% CI 1.19-3.55; ≥35 years: OR 2.65, 95% CI 1.47-4.74), while the impact of excessive GWG on the risk of LGA was more pronounced in those aged 31-34 years (31-34 years: OR 2.18, 95% CI 1.68-2.88; ≥35 years: OR 1.71, 95% CI 1.30-2.25). CONCLUSIONS: The stronger associations between abnormal GWG and adverse birth weights were mainly observed in women aged 31-34 years, and more attention should be paid to this age group.

Maternal overweight and obesity and its association with metabolic changes and fetal overgrowth in the absence of gestational diabetes mellitus: A prospective cohort study.

INTRODUCTION: Previous studies indicated an association between fetal overgrowth and maternal obesity independent of gestational diabetes mellitus (GDM). However, the underlying mechanisms beyond this possible association are not completely understood. This study investigates metabolic changes and their association with fetal and neonatal biometry in overweight and obese mothers who remained normal glucose-tolerant during gestation. MATERIAL AND METHODS: In this prospective cohort study 893 women who did not develop GDM were categorized according to their pregestational body mass index (BMI): 570 were normal weight, 220 overweight and 103 obese. Study participants received a broad metabolic evaluation before 16 weeks and were followed up until delivery to assess glucose levels during the oral glucose tolerance test (OGTT) at mid-gestation as well as fetal biometry in ultrasound and pregnancy outcome data. RESULTS: Increased maternal BMI was associated with an adverse metabolic profile at the beginning of pregnancy, including a lower degree of insulin sensitivity (as assessed by the quantitative insulin sensitivity check index) in overweight (mean difference: -2.4, 95% CI -2.9 to -1.9, p < 0.001) and obese (mean difference: -4.3, 95% CI -5.0 to -3.7, p < 0.001) vs normal weight women. Despite not fulfilling diagnosis criteria for GDM, overweight and obese mothers showed higher glucose levels at fasting and during the OGTT. Finally, we observed increased measures of fetal subcutaneous tissue thickness in ultrasound as well as higher proportions of large-for-gestational-age infants in overweight (18.9%, odds ratio [OR] 1.74, 95% CI 1.08-2.78, p = 0.021) and obese mothers (21.0%, OR 1.99, 95% CI 1.06-3.59, p = 0.027) vs normal weight controls (11.8%). The risk for large for gestational age was further determined by OGTT glucose (60 min: OR 1.11, 95% CI 1.02-1.21, p = 0.013; 120 min: OR 1.13, 95% CI 1.02-1.27, P = 0.025, for the increase of 10 mg/dL) and maternal triglyceride concentrations (OR 1.11, 95% CI 1.01-1.22, p = 0.036, for the increase of 20 mg/dL). CONCLUSIONS: Mothers affected by overweight or obesity but not GDM had a higher risk for fetal overgrowth. An impaired metabolic milieu related to increased maternal BMI as well as higher glucose levels at mid-gestation may impact fetal overgrowth in women still in the range of normal glucose tolerance.

Glycemic control assessed by continuous glucose monitoring during pregnancy in women with type 1 diabetes and its association with preeclampsia, an observational Swedish cohort study.

INTRODUCTION: Women with type 1 diabetes have an increased risk of preeclampsia (PE), but it is not fully understood if degree of glycemic control is associated with this risk. The aim of this study was to assess glycemic control during pregnancy analyzed by continuous glucose monitoring (CGM) in women with and without PE and to investigate if glycemic control is associated with increased risk of PE. MATERIAL AND METHODS: A total of 120 pregnant Swedish women with type 1 diabetes using CGM were included. Background factors and pregnancy outcomes were collected from medical records. CGM data were collected via the internet-based platform Diasend. Mean glucose, standard deviation of mean glucose, percentage of time in target, time below target, and time above target were presented for each trimester in women who did or did not develop PE. Associations between CGM-derived metrics and PE were analyzed with logistic regression and adjusted for confounders. RESULTS: Twenty-two women (18.3%) developed PE. There were no significant differences in maternal characteristics between women with and without PE. Glycemic control improved in each trimester but was suboptimal in both groups. Time in target increased from 59% in the non-PE group and 54% in the PE group in the first trimester to 65% in both groups in the third trimester. There were no significant associations between glycemic control and PE after adjustment for confounders. CONCLUSIONS: Degree of glycemic control during pregnancy assessed by CGM was not associated with development of PE in women with type 1 diabetes. However, more research is needed to understand the role of glycemic control in relation to development of PE.

First trimester maternal serum PAPP-A and free ß-hCG levels and risk of SGA or LGA in women with and without GDM.

BACKGROUND: Maternal gestational diabetes (GDM), small (SGA) and large (LGA) for gestational age neonates are associated with increased morbidity in both mother and child. We studied how different levels of first trimester pregnancy associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (fß-hCG) were associated with SGA and LGA in GDM pregnancies and controls. METHODS: Altogether 23 482 women with singleton pregnancies participated in first trimester combined screening and delivered between 2014 and 2018 in Northern Finland and were included in this retrospective case-control study. Women with GDM (n = 4697) and controls without GDM (n = 18 492) were divided into groups below 5th and 10th or above 90th and 95th percentile (pc) PAPP-A and fß-hCG MoM levels. SGA was defined as a birthweight more than two standard deviations (SD) below and LGA more than two SDs above the sex-specific and gestational age-specific reference mean. Odds ratios were adjusted (aOR) for maternal age, BMI, ethnicity, IVF/ICSI, parity and smoking. RESULTS: In pregnancies with GDM the proportion of SGA was 2.6% and LGA 4.5%, compared to 3.3% (p = 0.011) and 1.8% (p < 0.001) in the control group, respectively. In ≤ 5th and ≤ 10th pc PAPP-A groups, aORs for SGA were 2.7 (95% CI 1.5-4.7) and 2.2 (95% CI 1.4-3.5) in the GDM group and 3.8 (95% CI 3.0-4.9) and 2.8 (95% CI 2.3-3.5) in the reference group, respectively. When considering LGA, there was no difference in aORs in any high PAPP-A groups. In the low ≤ 5 percentile fß-hCG MoM group, aORs for SGA was 2.3 (95% CI 1.8-3.1) in the control group. In fß-hCG groups with GDM there was no association with SGA and the only significant difference was ≥ 90 percentile group, aOR 1.6 (95% CI 1.1-2.5) for LGA. CONCLUSION: Association with low PAPP-A and SGA seems to be present despite GDM status. High PAPP-A levels are not associated with increased LGA risk in women with or without GDM. Low fß-hCG levels are associated with SGA only in non-GDM pregnancies.

Maternal height, and ethnicity and birth weight: A retrospective cohort study of uncomplicated term vaginal deliveries in Malaysia.

BACKGROUND: Small for gestational age (SGA) and large for gestational age (LGA) are designations given to neonates based solely on birthweight, with no distinction made for maternal height. However, there is a possibility that maternal height is significantly correlated with neonatal birthweight, and if so, SGA and LGA cutoffs specific to maternal height may be a more precise and useful tool for clinicians. To explore this possibility, we analyzed the association between maternal height and ethnicity and neonate birthweight in women with low-risk, 37- to 40-week gestation, singleton pregnancies who gave birth vaginally between 2010 and 2017 (n = 354,488). For this retrospective cohort study, we used electronic obstetric records obtained from the National Obstetrics Registry in Malaysia. METHODS: National Obstetric Registry (NOR) data were used to calculate the 10th and 90th birthweight percentiles for each maternal height group by gestational age and neonatal sex. Multiple linear regression models, adjusted for maternal age, weight, parity, gestational age, and neonatal sex, were used to examine the association between neonate birthweight and maternal ethnicity and height. The following main outcome measures were assessed: small for gestational age (<10th percentile), large for gestational age (>90th percentile), and birthweight. RESULTS: The median height was 155 cm (IQR, 152-159), with mothers of Chinese descent being the tallest (median (IQR): 158 cm (154-162)) and mothers of Orang Asli (Indigenous) descent the shortest (median (IQR): 151 cm (147-155)). The median birthweight was 3000 g (IQR, 2740-3250), with mothers of Malay and Chinese ethnicity and Others having, on average, the heaviest babies, followed by other Bumiputeras (indigenous) mothers, mothers of Indian ethnicity, and lastly, mothers of Orang Asli ethnicity. For infants, maternal age, height, weight, parity, male sex, and gestational age were positively associated with birthweight. Maternal height had a positive association with neonate birthweight (B = 7.08, 95% CI: 6.85-7.31). For ethnicity, compared with neonates of Malay ethnicity, neonates of Chinese, Indian, Orang Asli, and other Bumiputera ethnicities had lower birthweights. CONCLUSION: Birthweight increases with maternal height among Malaysians of all ethnicities. SGA and LGA cutoffs specific to maternal height may be useful to guide pregnancy management.

Effects of ambient air pollution on the risk of small- and large-for-gestational-age births: an analysis using national birth data in Japan.

OBJECTIVES: Small-for-gestational-age (SGA) and large-for-gestational-age (LGA) births are major adverse birth outcomes related to newborn health. In contrast, the association between ambient air pollution levels and SGA or LGA births has not been investigated in Japan; hence, the purpose of our study is to investigate this association. METHODS: We used birth data from Vital Statistics in Japan from 2017 to 2021 and municipality-level data on air pollutants, including nitrogen dioxide (NO2), sulfur dioxide (SO2), photochemical oxidants, and particulate matter 2.5 (PM2.5). Ambient air pollution levels throughout the first, second, and third trimesters, as well as the whole pregnancy, were calculated for each birth. The association between SGA/LGA and ambient levels of the air pollutants was investigated using crude and adjusted log-binomial regression models. In addition, a regression model with spline functions was also used to detect the non-linear association. RESULTS: We analyzed data from 2,434,217 births. Adjusted regression analyses revealed statistically significant and positive associations between SGA birth and SO2 level, regardless of the exposure period. Specifically, the risk ratio for average SO2 values throughout the whole pregnancy was 1.014 (95% confidence interval [CI] 1.009, 1.019) per 1 ppb increase. In addition, regression analysis with spline functions indicated that an increase in risk ratio for SGA birth depending on SO2 level was linear. Furthermore, statistically significant and negative associations were observed between LGA birth and SO2 except for the third trimester. CONCLUSIONS: It was suggested that ambient level of SO2 during the pregnancy term is a risk factor for SGA birth in Japan.