Maternal and neonatal outcomes according to the timing of diagnosis of hyperglycaemia in pregnancy: a nationwide cross-sectional study of 695,912 deliveries in France in 2018.

AIMS/HYPOTHESIS: We aimed to assess maternal-fetal outcomes according to various subtypes of hyperglycaemia in pregnancy. METHODS: We used data from the French National Health Data System (Système National des Données de Santé), which links individual data from the hospital discharge database and the French National Health Insurance information system. We included all deliveries after 22 gestational weeks (GW) in women without pre-existing diabetes recorded in 2018. Women with hyperglycaemia were classified as having overt diabetes in pregnancy or gestational diabetes mellitus (GDM), then categorised into three subgroups according to their gestational age at the time of GDM diagnosis: before 22 GW (GDM<22); between 22 and 30 GW (GDM22-30); and after 30 GW (GDM>30). Adjusted prevalence ratios (95% CI) for the outcomes were estimated after adjusting for maternal age, gestational age and socioeconomic status. Due to the multiple tests, we considered an association to be statistically significant according to the Holm-Bonferroni procedure. To take into account the potential immortal time bias, we performed analyses on deliveries at ≥31 GW and deliveries at ≥37 GW. RESULTS: The study population of 695,912 women who gave birth in 2018 included 84,705 women (12.2%) with hyperglycaemia in pregnancy: overt diabetes in pregnancy, 0.4%; GDM<22, 36.8%; GDM22-30, 52.4%; and GDM>30, 10.4%. The following outcomes were statistically significant after Holm-Bonferroni adjustment for deliveries at ≥31 GW using GDM22-30 as the reference. Caesarean sections (1.54 [1.39, 1.72]), large-for-gestational-age (LGA) infants (2.00 [1.72, 2.32]), Erb's palsy or clavicle fracture (6.38 [2.42, 16.8]), preterm birth (1.84 [1.41, 2.40]) and neonatal hypoglycaemia (1.98 [1.39, 2.83]) were more frequent in women with overt diabetes. Similarly, LGA infants (1.10 [1.06, 1.14]) and Erb's palsy or clavicle fracture (1.55 [1.22, 1.99]) were more frequent in GDM<22. LGA infants (1.44 [1.37, 1.52]) were more frequent in GDM>30. Finally, women without hyperglycaemia in pregnancy were less likely to have preeclampsia or eclampsia (0.74 [0.69, 0.79]), Caesarean section (0.80 [0.79, 0.82]), pregnancy and postpartum haemorrhage (0.93 [0.89, 0.96]), LGA neonate (0.67 [0.65, 0.69]), premature neonate (0.80 [0.77, 0.83]) and neonate with neonatal hypoglycaemia (0.73 [0.66, 0.82]). Overall, the results were similar for deliveries at ≥37 GW. Although the estimation of the adjusted prevalence ratio of perinatal death was five times higher (5.06 [1.87, 13.7]) for women with overt diabetes, this result was non-significant after Holm-Bonferroni adjustment. CONCLUSIONS/INTERPRETATION: Compared with GDM22-30, overt diabetes, GDM<22 and, to a lesser extent, GDM>30 were associated with poorer maternal-fetal outcomes.

Elevated first-trimester neutrophil elastase and proteinase 3 increase the risk of gestational diabetes mellitus and adverse fetal outcomes.

BACKGROUND: Chronic inflammation plays a vital role in the development of gestational diabetes mellitus (GDM). Studies in mouse models show that neutrophil serine proteases (NSPs), neutrophil elastase (NE) and proteinase-3 (PR3) are important drivers of chronic inflammation with consequent metabolic disturbances. This study evaluated the association of NE and PR3 with GDM development and adverse fetal outcomes. METHOD(S): This was a prospective cohort study. Serum PR3 and NE concentration was measured in all enrolled pregnant women in the first and the second trimester to determine the connection between NSPs and GDM and adverse fetal outcomes. Logistic regression, spline regression and linear regression analyses were applied to investigate the association of NE or PR3 with GDM development and adverse fetal outcomes. The concentration of NE and PR3 in placental biopsies was evaluated by semi-quantitative analysis of immunohistochemistry staining. RESULT(S): NE or PR3 concentration in the first trimester, rather than the second, increased more significantly in women with GDM than in those without, regardless of pre-pregnancy body mass index and age. There was a stepwise increase in GDM occurrence as well as comprehensive adverse fetal outcomes across tertiles of NE and PR3. NE and PR3 were positively associated with neutrophil count, pre-pregnancy BMI, plasma glucose level and newborn weight. Logistic regression revealed NE or PR3 to be independent risk factors for the development of GDM and comprehensive adverse fetal outcomes. Spline regression showed a significant increased risk of GDM occurrence and comprehensive adverse fetal outcomes when serum NE concentration exceeded 417.60 ng/mL and a similar result for PR3 and GDM occurrence when the latter exceeded 88.52 ng/mL. Immunohistochemistry data confirmed that enriched NE and PR3 content in placental tissue may have contributed to the development of GDM. CONCLUSION(S): This work demonstrates that excessive first-trimester NE and PR3 increase the risk of GDM development and comprehensive adverse fetal outcomes.

Gestational diabetes in twin pregnancies-a pathology requiring treatment or a benign physiological adaptation?

There is level-1 evidence that screening for and treating gestational diabetes in singleton pregnancies reduce maternal and neonatal morbidity. However, similar data for gestational diabetes in twin pregnancies are currently lacking. Consequently, the current approach for the diagnosis and management of gestational diabetes in twin pregnancies is based on the same diagnostic criteria and glycemic targets used in singleton pregnancies. However, twin pregnancies have unique physiological characteristics, and many of the typical gestational diabetes-related complications are less relevant for twin pregnancies. These differences raise the question of whether the greater increase in insulin resistance observed in twin pregnancies (which is often diagnosed as diet-treated gestational diabetes) should be considered physiological and potentially beneficial in which case alternative criteria should be used for the diagnosis of gestational diabetes in twin pregnancies. In this review, we summarize the most up-to-date evidence on the epidemiology, pathophysiology, and clinical consequences of gestational diabetes in twin pregnancies and review the available data on twin-specific screening and diagnostic criteria for gestational diabetes. Although twin pregnancies are associated with a higher incidence of diet-treated gestational diabetes, diet-treated gestational diabetes in twin pregnancies is less likely to be associated with adverse outcomes and accelerated fetal growth than in singleton pregnancies and may reduce the risk for intrauterine growth restriction. In addition, there is currently no evidence that treatment of diet-treated gestational diabetes in twin pregnancies improves outcomes, whereas preliminary data suggest that strict glycemic control in such cases might increase the risk for intrauterine growth restriction. Overall, these findings provide support to the hypothesis that the greater transient increase in insulin resistance observed in twin pregnancies is merely a physiological exaggeration of the normal increase in insulin resistance observed in singleton pregnancies (that is meant to support 2 fetuses) rather than a pathology that requires treatment. These data illustrate the need to develop twin-specific screening and diagnostic criteria for gestational diabetes to avoid overdiagnosis of gestational diabetes and to reduce the risks associated with overtreatment of diet-treated gestational diabetes in twin pregnancies. Although data on twin-specific screening and diagnostic criteria are presently scarce, preliminary data suggest that the optimal screening and diagnostic criteria in twin pregnancies are higher than those currently used in singleton pregnancies.

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.

Paternal and maternal birthweight and offspring risk of macrosomia at term gestations: A nationwide population study.

BACKGROUND: There is a paucity of data on whether parents' macrosomia (birthweight ≥4500 g) status influences the risk of macrosomia in the offspring. The role of maternal overweight in the generational effect of macrosomia is not known. OBJECTIVE: To estimate the risk of macrosomia by parental birthweight at term and evaluate if this risk varied with maternal body mass index (BMI, kg/m2) early in pregnancy. METHODS: We used data from the Medical Birth Registry of Norway on all singleton term births (37-42 gestational weeks) during 1967-2017. The primary exposure was parental macrosomia, and the outcome was macrosomia in the second generation. The secondary exposure was maternal BMI. We used binomial regression to calculate relative risk (RR) with a 95% confidence interval. We assessed potential unmeasured confounding and selection bias using a probabilistic bias analysis and performed analyses with and without imputation for variables with missing values. RESULTS: The data included 647,957 singleton parent-offspring trios born at term. The prevalence of macrosomia was 3.2% (n = 41,396) in the parental generation and 4.0% (n = 25,673) in the offspring generation. Macrosomia in parents was associated with an increased risk of macrosomia in offspring, with the RR for both parents were born macrosomic being 6.53 (95% confidence interval [CI] 5.31, 8.05), only mother macrosomic 3.37 (95% CI 3.17, 3.57) and only father macrosomic RR 2.22 (95% CI 2.12, 2.33). These risks increased by maternal BMI in early pregnancy: if both parents were born macrosomic, 17% of infants were macrosomic among mothers with normal BMI. If both parents were macrosomic and the mothers were obese, 31% of offspring were macrosomic. Macrosomia-related adverse outcomes did not differ with parental macrosomia status. CONCLUSIONS: Parents' weight at birth and maternal BMI appear to be strongly associated with macrosomia in the offspring delivered at term gestations.

Fasting blood glucose as a screening measure for late-onset gestational diabetes in the third trimester.

OBJECTIVE: To investigate the positive rate of late-onset gestational diabetes mellitus (GDM) by additional fasting blood glucose (FBG) screening at 32-34 gestational weeks (GW) and analyse the perinatal outcomes of late-onset GDM after standard treatment. DESIGN: An Prospective cohort study. SETTING: Single centre in China. POPULATION: 1130 singleton pregnancies with negative GDM screening in their first and second trimester. METHODS: Additional FBG testing was performed at 32-34 GW. Pregnancies with FBG ≥5.1 mmol/L were diagnosed as GDM and received standardized treatment. Perinatal outcomes were collected and compared. MAIN OUTCOME MEASURES: Diagnosis of late-onset GDM, obstetric and neonatal outcomes. RESULTS: 6.3% (71/1130) of participants had FBG values ≥5.1 mmol/L and were diagnosed with late-onset GDM. Sixty-five (91.5%) were treated by dietary therapy and 6 (8.5%) by insulin therapy. The perinatal outcomes of full-term delivery were compared. The incidence of macrosomia (22.7% vs. 5.1%, adjusted odds ratio (aOR) 5.51, 95% confidence interval (CI) 1.83-16.61, p = 0.002) and NICU transferring (18.3% vs. 10.1%, aOR 1.94, 95% CI 1.01-3.74, p = 0.046) was significantly higher in late-onset GDM group than that in FBG <5.1 mmol/L group. Elevated FBG was associated with overweight or obesity during pregnancy (54.9% vs. 34.9%, OR 2.27, 95% CI 1.40-3.68, p = 0.001). CONCLUSIONS: 6.3% of singleton pregnancies with normal GDM screening results in the first and second trimester were found to have late-onset GDM by additional FBG screening at 32-34 GW, and their risk of macrosomia during a full-term pregnancy remains significantly higher after standard treatment.

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.

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.

Mediating effect of gestational weight gain on the preventive effect of exercise during pregnancy on macrosomia: a randomized clinical trial.

OBJECTIVE: We sought to investigate the impact of individualized exercise guidance during pregnancy on the incidence of macrosomia and the mediating effect of gestational weight gain (GWG). DESIGN: A prospective randomized clinical trial. SETTING: A Hospital in Xingtai District, Hebei Province. POPULATION: Older than 20 years of age, mid-pregnancy, and singleton pregnant women without contraindications to exercise during pregnancy. METHODS: A randomized clinical trial was conducted from December 2021 to September 2022 to compare the effects of standard prenatal care with individualized exercise guidance on the incidence of macrosomia. MAIN OUTCOME MEASURE: Incidence of macrosomia. RESULTS: In all, 312 singleton women were randomized into an intervention group (N = 162) or a control group (N = 150). Participants who received individualized exercise guidance had a significantly lower incidence of macrosomia (3.73% vs. 13.61%, P = 0.002) and infants large for gestational age (9.94% vs. 19.73%, P = 0.015). However, no differences were observed in the rate of preterm birth (1.86% vs. 3.40%, P = 0.397) or the average gestational age at birth (39.14 ± 1.51 vs. 38.69 ± 1.85, P = 0.258). Mediation analysis revealed that GWG mediated the effect of exercise on reducing the incidence of macrosomia. CONCLUSION: Individualized exercise guidance may be a preventive tool for macrosomia, and GWG mediates the effect of exercise on reducing the incidence of macrosomia. However, evidence does not show that exercise increases the rate of preterm birth or affects the average gestational age at birth. TRIAL REGISTRATION: The trial is registered at www.clinicaltrails.gov [registration number: NCT05760768; registration date: 08/03/2023 (retrospectively registered)].

A first trimester prediction model and nomogram for gestational diabetes mellitus based on maternal clinical risk factors in a resource-poor setting.

BACKGROUND: The implementation of universal screening for Gestational Diabetes Mellitus (GDM) is challenged by several factors key amongst which is limited resources, hence the continued reliance on risk factor-based screening. Effective identification of high-risk women early in pregnancy may enable preventive intervention. This study aimed at developing a GDM prediction model based on maternal clinical risk factors that are easily assessable in the first trimester of pregnancy in a population of Nigerian women. METHODS: This was a multi-hospital prospective observational cohort study of 253 consecutively selected pregnant women from which maternal clinical data was collected at 8-12 weeks gestational age. Diagnosis of GDM was made via a one-step 75-gram Oral Glucose Tolerance Test (OGTT) at 24-28 weeks of gestation. A GDM prediction model and nomogram based on selected maternal clinical risk factors was developed using multiple logistic regression analysis, and its performance was assessed by Receiver Operator Curve (ROC) analysis. Data analysis was carried out using Statistical Package for Social Sciences (SPSS) version 25 and Python programming language (version 3.0). RESULTS: Increasing maternal age, higher body mass index (BMI), a family history of diabetes mellitus in first-degree relative and previous history of foetal macrosomia were the major predictors of GDM. The model equation was: LogitP = 6.358 - 0.066 × Age - 0.075 × First trimester BMI - 1.879 × First-degree relative with diabetes mellitus - 0.522 × History of foetal macrosomia. It had an area under the receiver operator characteristic (ROC) curve (AUC) of 0.814 (95% CI: 0.751-0.877; p-value < 0.001), and at a predicted probability threshold of 0.745, it had a sensitivity of 79.2% and specificity of 74.5%. CONCLUSION: This first trimester prediction model reliably identifies women at high risk for GDM development in the first trimester, and the nomogram enhances its practical applicability, contributing to improved clinical outcomes in the study population.

Ultrasound prediction of fetal macrosomia in pregnancies complicated by diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVES: To report the diagnostic accuracy of ultrasound in identifying fetuses with macrosomia in pregnancies complicated by gestational or pregestational diabetes. METHODS: Medline, Embase and Cochrane databases were searched. Inclusion criteria were singleton pregnancies complicated by diabetes undergoing third-trimester ultrasound evaluation. The index test was represented by ultrasound estimation of fetal macrosomia (estimated fetal weight EFW or abdominal circumference AC >90th or 95th percentile). Subgroup analyses were also performed. Sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio were computed using the hierarchical summary receiver-operating characteristics model. RESULTS: Twenty studies were included in the systematic review including 8,530 pregnancies complicated by diabetes. Ultrasound showed an overall moderate accuracy in identifying fetuses with macrosomia with a sensitivity of 71.2 % (95 % CI 63.1-78.2), a specificity of 88.6 % (95 % CI 83.9-92.0). The interval between ultrasound and birth of two weeks showed the highest sensitivity and specificity (71.6 %, 95 % CI 47.9-87.3 and 91.7, 95 % CI 86.2-95.5). EFW sensitivity and specificity were 76.6 % (95 % CI 70.1-82.3) and 82.9 % (95 % CI 80.9-84.8), while AC 84.8 % (95 % CI 78.2-90.0) and 73.7 % (95 % CI 71.0-76.4). CONCLUSIONS: Ultrasound demonstrates an overall good diagnostic accuracy in detecting fetal macrosomia in pregnancies with diabetes.

Prenatal exposure to ambient air pollution and risk of fetal overgrowth: Systematic review of cohort studies.

OBJECTIVES: Fetal overgrowth has detrimental effects on both the mother and the fetus. The global issue of ambient air pollution has been found to contribute to fetal overgrowth through various pathways. This study aimed to identify the association between prenatal exposure to ambient air pollution and the risk of fetal overgrowth. METHODS: We identified articles between January 2013 and February 2024 by searching the Web of Sciences(WoS), PubMed, Proquest, Scopus, and Google Scholar databases. Quality assessment was performed using the Newcastle Ottawa scale. This review was provided based on the PRISMA guideline and registered with PROSPERO, "CRD42023488936". RESULTS: The search generated 1719 studies, of which 22 cohort studies were included involving 3,480,041 participants. Results on the effects of air pollutants on fetal overgrowth are inconsistent because they vary in population and geographic region. But in general, the results indicate that prenatal exposure to air pollutants, specifically PM2.5, NO2, and SO2, is linked to a higher likelihood of fetal overgrowth(macrosomia and large for gestational age). Nevertheless, the relationship between CO and O3 pollution and fetal overgrowth remains uncertain. Furthermore, PM10 has a limited effect on fetal overgrowth. It is essential to consider the time that reproductive-age women are exposed to air pollution. Exposure to air pollutants before conception and throughout pregnancy has a substantial impact on the fetus's vulnerability to overgrowth. CONCLUSIONS: Fetal overgrowth has implications for the health of both mother and fetus. fetal overgrowth can cause cardiovascular diseases, obesity, type 2 diabetes, and other diseases in adulthood, so it is considered an important issue for the health of the future generation. Contrary to popular belief that air pollution leads to intrauterine growth restriction and low birth weight, this study highlights that one of the adverse consequences of air pollution is macrosomia or LGA during pregnancy. Therefore governments must focus on implementing initiatives that aim to reduce pregnant women's exposure to ambient air pollution to ensure the health of future generations.

Is It Diabetes or Just Macrosomia? Fetal Myocardial Performance Index in Large-for-Gestational Age Fetuses.

Our aim in this study was to investigate whether there is an association between large-for-gestational age (LGA) fetuses and myocardial performance index (MPI). This is a cross-sectional study conducted from July 2022 to July 2023. Prospectively gathered data from 65 LGA cases and 65 age and gestational-age (GA)-matched controls were analyzed. Presence of polyhydramnios and diabetes were recorded in the study group. Fetal left ventricular mod-MPI, peak systolic velocity (PSV) of E and A waves, umbilical and middle cerebral artery (MCA) pulsatility indexes (PI) were sonographically measured. Association between these sonographic measures and LGA fetuses were sought. The LGA group had 33 diabetic cases (22 GDM and 11 PGDM). The LGA group had greater mod-MPI (0.51 vs. 0.45, p = 0.0048). The LGA group also had prolonged isovolumetric contraction time (ICT), compared to controls (37 ms vs. 33 ms, p = 0.008). ICT was longer in LGA fetuses with non-diabetic mothers (38 ms vs. 33 ms, p = 0.009). LGA fetuses with polyhydramnios but without diabetic mothers had also longer ICT (39 ms vs. 33 ms, p = 0.002). Mod-MPI was similar in controls and LGA without diabetes/LGA with polyhydramnios but without diabetes subgroups. Our results indicate that fetal mod-MPI values are higher in LGA fetuses and ICT is prolonged among LGA fetuses irrespective of presence of maternal diabetes.

Pathologic maternal and neonatal outcomes associated with programmed embryo transfer.

PURPOSE: In this first of two companion papers, we critically review the evidence recently published in the primary literature, which addresses adverse maternal and neonatal pregnancy outcomes associated with programmed embryo transfer cycles. We next consider whether these pathological pregnancy outcomes might be attributable to traditional risk factors, unknown parental factors, embryo culture, culture duration, or cryopreservation. Finally, in the second companion article, we explore potential etiologies and suggest strategies for prevention. METHODS: Comprehensive review of primary literature. RESULTS: The preponderance of retrospective and prospective observational studies suggests that increased risk for hypertensive disorders of pregnancy (HDP) and preeclampsia in assisted reproduction involving autologous embryo transfer is associated with programmed cycles. For autologous frozen embryo transfer (FET) and singleton live births, the risk of developing HDP and preeclampsia, respectively, was less for true or modified natural and stimulated cycles relative to programmed cycles: OR 0.63 [95% CI (0.57-0.070)] and 0.44 [95% CI (0.40-0.50)]. Though data are limited, the classification of preeclampsia associated with programmed autologous FET was predominantly late-onset or term disease. Other adverse pregnancy outcomes associated with autologous FET, especially programmed cycles, included increased prevalence of large for gestational age infants and macrosomia, as well as higher birth weights. In one large registry study, FET was associated with fetal overgrowth of a symmetrical nature. Postterm birth and placenta accreta not associated with prior cesarean section, uterine surgery, or concurrent placenta previa were also associated with autologous FET, particularly programmed cycles. The heightened risk of these pathologic pregnancy outcomes in programmed autologous FET does not appear to be attributable to traditional risk factors, unknown parental factors, embryo culture, culture duration, or cryopreservation, although the latter may contribute a modest degree of increased risk for fetal overgrowth and perhaps HDP and preeclampsia in FET irrespective of the endometrial preparation. CONCLUSIONS: Programmed autologous FET is associated with an increased risk of several, seemingly diverse, pathologic pregnancy outcomes including HDP, preeclampsia, fetal overgrowth, postterm birth, and placenta accreta. Though the greater risk for preeclampsia specifically associated with programmed autologous FET appears to be well established, further research is needed to substantiate the limited data currently available suggesting that the classification of preeclampsia involved is predominately late-onset or term. If substantiated, then this knowledge could provide insight into placental pathogenesis, which has been proposed to differ between early- and late-onset or term preeclampsia (see companion paper for a discussion of potential mechanisms). If a higher prevalence of preeclampsia with severe features as suggested by some studies is corroborated in future investigations, then the danger to maternal and fetal/neonatal health is considerably greater with severe disease, thus increasing the urgency to find preventative measures. Presupposing significant overlap of these diverse pathologic pregnancy outcomes within subjects who conceive by programmed embryo transfer, there may be common etiologies.

Pathologic maternal and neonatal outcomes associated with programmed embryo transfer: potential etiologies and strategies for prevention.

PURPOSE: In the first of two companion papers, we comprehensively reviewed the recent evidence in the primary literature, which addressed the increased prevalence of hypertensive disorders of pregnancy, late-onset or term preeclampsia, fetal overgrowth, postterm birth, and placenta accreta in women conceiving by in vitro fertilization. The preponderance of evidence implicated frozen embryo transfer cycles and, specifically, those employing programmed endometrial preparations, in the higher risk for these adverse maternal and neonatal pregnancy outcomes. Based upon this critical appraisal of the primary literature, we formulate potential etiologies and suggest strategies for prevention in the second article. METHODS: Comprehensive review of primary literature. RESULTS: Presupposing significant overlap of these apparently diverse pathological pregnancy outcomes within subjects who conceive by programmed autologous FET cycles, shared etiologies may be at play. One plausible but clearly provocative explanation is that aberrant decidualization arising from suboptimal endometrial preparation causes greater than normal trophoblast invasion and myometrial spiral artery remodeling. Thus, overly robust placentation produces larger placentas and fetuses that, in turn, lead to overcrowding of villi within the confines of the uterine cavity which encroach upon intervillous spaces precipitating placental ischemia, oxidative and syncytiotrophoblast stress, and, ultimately, late-onset or term preeclampsia. The absence of circulating corpus luteal factors like relaxin in most programmed cycles might further compromise decidualization and exacerbate the maternal endothelial response to deleterious circulating placental products like soluble fms-like tyrosine kinase-1 that mediate disease manifestations. An alternative, but not mutually exclusive, determinant might be a thinner endometrium frequently associated with programmed endometrial preparations, which could conspire with dysregulated decidualization to elicit greater than normal trophoblast invasion and myometrial spiral artery remodeling. In extreme cases, placenta accreta could conceivably arise. Though lower uterine artery resistance and pulsatility indices observed during early pregnancy in programmed embryo transfer cycles are consistent with this initiating event, quantitative analyses of trophoblast invasion and myometrial spiral artery remodeling required to validate the hypothesis have not yet been conducted. CONCLUSIONS: Endometrial preparation that is not optimal, absent circulating corpus luteal factors, or a combination thereof are attractive etiologies; however, the requisite investigations to prove them have yet to be undertaken. Presuming that in ongoing RCTs, some or all adverse pregnancy outcomes associated with programmed autologous FET are circumvented or mitigated by employing natural or stimulated cycles instead, then for women who can conceive using these regimens, they would be preferable. For the 15% or so of women who require programmed FET, additional research as suggested in this review is needed to elucidate the responsible mechanisms and develop preventative strategies.

Same disease - different effect: maternal diabetes impact on birth weight stratified by fetal sex.

BACKGROUND: Male-sex is an independent risk factor for adverse perinatal outcomes. One example is gestational diabetes mellitus (GDM), which is associated with large gestational age neonates. It was previously described that fetal glucose metabolism is affected by fetal sex. PURPOSE: To examine whether the birth weight of neonates is affected differently by GDM according to fetal sex. METHODS: A retrospective normalized cohort analysis, using the open database of 2017 Natality Data from the National Vital Statistics System in the US. We compared the delta in neonatal birth weight, according to fetal sex, between pregnancies with or without GDM. Linear regression was used to take into consideration the effect of multiple confounders. For evaluation whether fetal sex is an independent risk factor for macrosomia (> 4000 and > 4500 g) following pregnancies complicated by GDM we used multivariate logistic regression. RESULTS: A significant relationship was found between the sex of the neonate and the delta in birth weight associated with GDM (P-value < 0.0001). The average weight gain in neonates to GDM pregnancies was 71 g in females, and 56 g in males. The prevalence of macrosomia above 4000 g and 4500 g that was attributed to GDM was higher in female-sex neonates compared to male-sex neonates (P < 0.05). CONCLUSION: According to our study results, female sex is associated with higher fetal weight gain in pregnancies complicated by GDM. Moreover, macrosomia's rate (> 4000 g and > 4500 g) attributed to GDM raised in a more significant manner in female-sex neonates.

Association between foetal sex and adverse neonatal outcomes in women with gestational diabetes.

AIMS: Foetal male sex is associated with adverse perinatal outcomes. However, studies evaluating the impact of foetal sex on perinatal outcomes in women with gestational diabetes (GDM) are scarce. We studied whether male new-born sex is associated with neonatal outcomes, in women with GDM. METHODS: This is a retrospective study based on the national Portuguese register of GDM. All women with live-born singleton pregnancies between 2012 and 2017 were eligible for study inclusion. Primary endpoints under analysis were neonatal hypoglycaemia, neonatal macrosomia, respiratory distress syndrome (RDS) and neonatal intensive care unit (NICU) admission. We excluded women with missing data on the primary endpoint. Pregnancy data and neonatal outcomes between female and male new-borns were compared. Multivariate logistic regression models were built. RESULTS: We studied 10,768 new-borns in mothers with GDM, 5635 (52.3%) male, 438 (4.1%) had neonatal hypoglycaemia, 406 (3.8%) were macrosomic, 671 (6.2%) had RDS, and 671 (6.2%) needed NICU admission. Male new-borns were more frequently small or large for gestational age. No differences were observed on maternal age, body mass index, glycated haemoglobin, anti-hyperglycaemic treatment, pregnancy complications or gestational age at delivery. In the multivariate regression analysis, male sex was independently associated with neonatal hypoglycaemia [OR 1.26 (IC 95%: 1.04-1.54), p = 0.02], neonatal macrosomia [1.94 (1.56-2.41), p < 0.001], NICU admission [1.29 (1.07-1.56), p = 0.009], and RDS [1.35 (1.05-1.73, p = 0.02]. CONCLUSIONS: Male new-borns have an independent 26% higher risk of neonatal hypoglycaemia, 29% higher risk of NICU admission, 35% higher risk of RDS, and almost twofold higher risk of macrosomia, compared to female new-borns.

TCF7L2 Polymorphism rs7903146 (C/T) and Gestational Diabetes Influence on Obstetric Outcome: A Romanian Case-Control Study.

Gestational diabetes mellitus (GDM) is one of the most frequent predictors of obstetric outcome among Romanian pregnant women. Thus, we aimed to investigate the role of rs7903146 (C/T) TCF7L2 gene polymorphism in the presence of GDM and to evaluate the influence on maternal-fetal outcomes in a cohort of pregnant women from Northern Transylvania. Our prospective case-control study was performed in a tertiary maternity center on 61 patients diagnosed with GDM and 55 normal pregnant patients. The patients were genotyped for rs7903146 (C/T) polymorphism of the TCF7L2 gene using the PCR-RFLP method between 24 and 28 weeks of gestation. The minor T allele was associated with a high risk of developing GDM (OR 1.71 [95% CI 0.82-3.59]) if both heterozygote and homozygote types were considered. Also, a higher risk of developing GDM was observed in homozygous carriers (OR 3.26 [95% CI 1.10-9.68]). Women with the TT genotype were more likely to require insulin therapy during pregnancy than other genotypes with a 5.67-fold increased risk ([1.61-19.97], p = 0.015). TT homozygote type was significantly associated with fetal macrosomia for birth weights greater than the 95th percentile (p = 0.034). The homozygous TT genotype is associated with an increased risk of developing GDM. Also, rs7903146 (C/T) TCF7L2 variant is accompanied by a high probability of developing insulin-dependent gestational diabetes mellitus (ID-GDM). The presence of at least one minor T allele was associated with a higher risk of fetal macrosomia.