Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy.

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.

Estimation of Fetal Weight: An Ultrasonography Study in Indian Population.

To create a reference chart for estimated fetal weight (EFW) in normal pregnancy for use in Indian population and compare it with reference chart from other population. This retrospective cross-sectional study included 300 normal singleton pregnancies coming for routine antenatal ultrasonography examination and was carried out at All India Institute of Medical Sciences, Jodhpur from September 2017 to April 2019. Ultrasonographic measurements included fetal biparietal diameter (cm), head circumference (cm), abdominal circumference (cm) and femur length (cm). Estimated fetal weight was calculated by using Hadlock algorithm which is already fed into ultrasonography machine. Reference chart with mean EFW for corresponding Gestational age (GA) in weeks was developed. Also Reference centiles (10th, 50th, 90th and 95th) were derived from this model. There was no statistically significant difference in age distribution of pregnant women (p=0.87). Statistically significant linear relationship found between EFW and advancing gestational age (p=0.0004). Maximum gain in EFW (34.05%) was observed after second trimester (28 week). Maximum and minimum fetal weight at 38 weeks of GA in our study found to be 3389 grams and 2567 grams respectively, which has significant difference. This could be due to huge difference in socio-economic and nutritional status among Indian population which might have impacted on maternal and fetal health. Estimated fetal weight was found to be at lower range in Indian population compared to reference chart developed into western population. Fetal weight to their corresponding GA is an important factor in determining growth and development in fetus. In normally developing fetus the EFW has linear correlation with advancing GA. A separate reference chart is required for every different population because ethnicity, nutrition and environmental factor can have impact on normal EFW values. This would help to avoid misdiagnosis of intrauterine growth retardation or macrosomia in fetuses and hence unnecessary medical interventions can be prevented during prenatal and perinatal period.

Prediction of adverse perinatal outcome by fetal biometry: comparison of customized and population-based standards.

OBJECTIVE: To compare the predictive performance of estimated fetal weight (EFW) percentiles, according to eight growth standards, to detect fetuses at risk for adverse perinatal outcome. METHODS: This was a retrospective cohort study of 3437 African-American women. Population-based (Hadlock, INTERGROWTH-21st , World Health Organization (WHO), Fetal Medicine Foundation (FMF)), ethnicity-specific (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)), customized (Gestation-Related Optimal Weight (GROW)) and African-American customized (Perinatology Research Branch (PRB)/NICHD) growth standards were used to calculate EFW percentiles from the last available scan prior to delivery. Prediction performance indices and relative risk (RR) were calculated for EFW < 10th and > 90th percentiles, according to each standard, for individual and composite adverse perinatal outcomes. Sensitivity at a fixed (10%) false-positive rate (FPR) and partial (FPR < 10%) and full areas under the receiver-operating-characteristics curves (AUC) were compared between the standards. RESULTS: Ten percent (341/3437) of neonates were classified as small-for-gestational age (SGA) at birth, and of these 16.4% (56/341) had at least one adverse perinatal outcome. SGA neonates had a 1.5-fold increased risk of any adverse perinatal outcome (P < 0.05). The screen-positive rate of EFW < 10th percentile varied from 6.8% (NICHD) to 24.4% (FMF). EFW < 10th percentile, according to all standards, was associated with an increased risk for each of the adverse perinatal outcomes considered (P < 0.05 for all). The highest RRs associated with EFW < 10th percentile for each adverse outcome were 5.1 (95% CI, 2.1-12.3) for perinatal mortality (WHO); 5.0 (95% CI, 3.2-7.8) for perinatal hypoglycemia (NICHD); 3.4 (95% CI, 2.4-4.7) for mechanical ventilation (NICHD); 2.9 (95% CI, 1.8-4.6) for 5-min Apgar score < 7 (GROW); 2.7 (95% CI, 2.0-3.6) for neonatal intensive care unit (NICU) admission (NICHD); and 2.5 (95% CI, 1.9-3.1) for composite adverse perinatal outcome (NICHD). Although the RR CIs overlapped among all standards for each individual outcome, the RR of composite adverse perinatal outcome in pregnancies with EFW < 10th percentile was higher according to the NICHD (2.46; 95% CI, 1.9-3.1) than the FMF (1.47; 95% CI, 1.2-1.8) standard. The sensitivity for composite adverse perinatal outcome varied substantially between standards, ranging from 15% for NICHD to 32% for FMF, due mostly to differences in FPR; this variation subsided when the FPR was set to the same value (10%). Analysis of AUC revealed significantly better performance for the prediction of perinatal mortality by the PRB/NICHD standard (AUC = 0.70) compared with the Hadlock (AUC = 0.66) and FMF (AUC = 0.64) standards. Evaluation of partial AUC (FPR < 10%) demonstrated that the INTERGROWTH-21st standard performed better than the Hadlock standard for the prediction of NICU admission and mechanical ventilation (P < 0.05 for both). Although fetuses with EFW > 90th percentile were also at risk for any adverse perinatal outcome according to the INTERGROWTH-21st (RR = 1.4; 95% CI, 1.0-1.9) and Hadlock (RR = 1.7; 95% CI, 1.1-2.6) standards, many times fewer cases (2-5-fold lower sensitivity) were detected by using EFW > 90th percentile, rather than EFW < 10th percentile, in screening by these standards. CONCLUSIONS: Fetuses with EFW < 10th percentile or EFW > 90th percentile were at increased risk of adverse perinatal outcomes according to all or some of the eight growth standards, respectively. The RR of a composite adverse perinatal outcome in pregnancies with EFW < 10th percentile was higher for the most-stringent (NICHD) compared with the least-stringent (FMF) standard. The results of the complementary analysis of AUC suggest slightly improved detection of adverse perinatal outcome by more recent population-based (INTERGROWTH-21st ) and customized (PRB/NICHD) standards compared with the Hadlock and FMF standards. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Gestational weight gain across continents and ethnicity: systematic review and meta-analysis of maternal and infant outcomes in more than one million women.

BACKGROUND: The association between Institute of Medicine (IOM) guidelines and pregnancy outcomes across ethnicities is uncertain. We evaluated the associations of gestational weight gain (GWG) outside 2009 IOM guidelines, with maternal and infant outcomes across the USA, western Europe and east Asia, with subgroup analyses in Asia. The aim was to explore ethnic differences in maternal prepregnancy body mass index (BMI), GWG and health outcomes across these regions. METHODS: Systematic review, meta-analysis and meta-regression of observational studies were used for the study. MEDLINE, MEDLINE In-Process, Embase and all Evidence-Based Medicine (EBM) Reviews were searched from 1999 to 2017. Studies were stratified by prepregnancy BMI category and total pregnancy GWG. Odds ratio (ORs) 95% confidence intervals (CI) applied recommended GWG within each BMI category as the reference. Primary outcomes were small for gestational age (SGA), preterm birth and large for gestational age (LGA). Secondary outcomes were macrosomia, caesarean section and gestational diabetes. RESULTS: Overall, 5874 studies were identified and 23 were included (n = 1,309,136). Prepregnancy overweight/obesity in the USA, Europe and Asia was measured at 42%, 30% and 10% respectively, with underweight 5%, 3% and 17%. GWG below guidelines in the USA, Europe and Asia was 21%, 18% and 31%, and above was 51%, 51% and 37% respectively. Applying regional BMI categories in Asia showed GWG above guidelines (51%) was similar to that in the USA and Europe. GWG below guidelines was associated with a higher risk of SGA (USA/Europe [OR 1.51; CI 1.39, 1.63]; Asia [1.63; 1.45, 1.82]) and preterm birth (USA/Europe [1.35; 1.17, 1.56]; Asia [1.06; 0.78, 1.44]) than GWG within guidelines. GWG above guidelines was associated with a higher risk of LGA (USA/Europe [1.93; 1.81, 2.06]; Asia [1.68; 1.51 , 1.87]), macrosomia (USA/Europe [1.87; 1.70, 2.06]; Asia [2.18; 1.91, 2.49]) and caesarean (USA/Europe [1.26; 1.21, 1.33]; Asia [1.37; 1.30, 1.45]). Risks remained elevated when regional BMI categories were applied for GWG recommendations. More women in Asia were categorised as having GWG below guidelines using World Health Organization (WHO) (60%) compared to regional BMI categories (16%), yet WHO BMI was not accompanied by increased risks of adverse outcomes. CONCLUSIONS: Women in the USA and western Europe have higher prepregnancy BMI and higher rates of GWG above guidelines than women in east Asia. However, when using regional BMI categories in east Asia, rates of GWG above guidelines are similar across the three continents. GWG outside guidelines is associated with adverse outcomes across all regions. If regional BMI categories are used in east Asia, IOM guidelines are applicable in the USA, western Europe and east Asia.

Unconditional and conditional standards for fetal abdominal circumference and estimated fetal weight in an ethnic Chinese population: a birth cohort study.

BACKGROUND: Diagnosis of intrauterine fetal growth restriction and prediction of small-for-gestation age are often based on fetal abdominal circumference or estimated fetal weight (EFW). The present study aims to create unconditional (cross-sectional) and conditional (longitudinal) standards of fetal abdominal circumference and EFW for use in an ethnic Chinese population. METHODS: In the Growing Up in Singapore Towards healthy Outcome (GUSTO) birth cohort study in Singapore, fetal biometric measurements were obtained at enrolment to antenatal care (11-12 weeks) and up to three more time points during pregnancy. Singleton pregnancies with a healthy profile defined by maternal, pregnancy and fetal characteristics and birth outcomes were selected for this analysis. The Hadlock algorithm was used to calculate EFW. Mixed effects model was used to establish unconditional and conditional standards in z-scores and percentiles for both genders pooled and for each gender separately. RESULTS: A total of 313 women were included, of whom 294 had 3 and 19 had 2 ultrasound scans other than the gestational age dating scan. Fetal abdominal circumference showed a roughly linear trajectory from 18 to 36 weeks of gestation, while EFW showed an accelerating trajectory. Gender differences were more pronounced in the 10(th) percentile than the 50(th) or 90(th) percentiles. As compared to other published charts, this population showed growth trajectories that started low but caught up at later gestations. CONCLUSIONS: Unconditional and conditional standards for monitoring fetal size and fetal growth in terms of abdominal circumference and EFW are available for this ethnic-Chinese population. Electronic spreadsheets are provided for their implementation.

Should we use customized fetal growth percentiles in urban Canada?

An increasingly common challenge in antenatal care of the small for gestational age (SGA) fetus is the distinction between the constitutionally (physiologically) small fetus and the fetus affected by pathological intrauterine growth restriction (IUGR). We discuss here the rationale and the evidence for the use of customized growth percentiles for the purpose of distinguishing between the fetus with true IUGR and the fetus with constitutional SGA. We also provide estimates of the potential effects of adopting ethnicity-specific birth weight curves on the rates of SGA and large for gestational age status in multi-ethnic metropolitan cities in North America and Europe, such as the City of Toronto. Using customized growth percentiles would result in a considerable decline in the rate of a false-positive diagnosis of SGA among visible minorities, and improve the detection rate of true large for gestational age fetuses among these groups.

La distinction entre les fœtus constitutionnellement (physiologiquement) petits et les fœtus affectés par un retard de croissance intra-utérin pathologique (RCIU) constitue un défi de plus en plus commun dans le cadre des soins prénataux prodigués aux fœtus présentant une hypotrophie fœtale (HF). Nous discutons ici de la logique et des données soutenant l'utilisation de percentiles de croissance adaptés aux fins de la distinction entre les fœtus présentant un réel RCIU et les fœtus présentant une HF constitutionnelle. Nous offrons également des estimations des effets potentiels de l'adoption de courbes de poids de naissance propres à une origine ethnique particulière sur les taux de fœtus présentant une HF et les taux de fœtus présentant une hypertrophie fœtale au sein de villes métropolitaines multiethniques d'Amérique du Nord et d'Europe (comme la ville de Toronto). L'utilisation de percentiles de croissance adaptés se traduirait en une baisse considérable du taux de diagnostic faux positif d'HF chez les minorités visibles, ainsi qu'en une amélioration du taux de détection des fœtus présentant une réelle hypertrophie fœtale chez ces groupes.

Customized weight curves for Spanish fetuses and newborns.

OBJECTIVES: To construct a model of customized birthweight curves for use in a Spanish population. MATERIALS AND METHODS: Data of 20 331 newborns were used to construct a customized birthweight model. Multiple regression analysis was performed with newborn weight as the dependent variable and gestational age (GA), sex and maternal (M) weight, height, parity and ethnic origin as the independent variables. Using the new model, 27,507 newborns were classified as adequate for GA (AGA), large for GA (LGA) or small for GA (SGA). The results were compared with those of other customized and non-customized models. RESULTS: The resulting formula for the calculation of optimal neonatal weight was: Optimum weight (g) = 3289.681 + 135.413*GA40-14.063*GA40(2)-0.838*GA40(3) + 113.889 (if multiparous) + 165.560 (if origin = Asia) + 161.550 (South America) + 67.927 (rest of Europe) +109.265 (North Africa) + 9.392*Maternal-Height + 4.856*Maternal-Weight-0.098*Maternal-Weight(2) + 0.001*Maternal-Weight(3) + 67.188*Sex + GA40*(6.890*Sex + 9.032 (If multiparous) +0.006*Maternal-Height(3) + 0.260*Maternal-Weight) + GA40(2) (-0.378*Maternal-Height - 0.008*Maternal-Height(2)) + GA40(3) (-0.032*Maternal-Height). Weight percentiles were obtained from standard data using optimum weight variation coefficient. Agreement between our customized model and other Spanish models was "good" (κ = 0.717 and κ = 0.736; p < 0.001). CONCLUSIONS: Our model is comparable to other Spanish models, but offers the advantage of being customized, updated and freely available on the web. The 30.6% of infants classified as SGA using our model would be considered as AGA following a non-customized model.

Fetal biometry: does patient ethnicity matter?

OBJECTIVE: To determine if fetal biometry varies according to race. METHODS: We performed a retrospective chart review of prenatal ultrasounds completed in our Perinatal Center from January 2009 to December 2010. Singleton pregnancies 17 to 22.9 weeks were included. Pregnancies complicated by IUGR, fetal anomalies, chronic maternal diseases, or dated by an ultrasound after the first trimester were excluded. Biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and humerus length (HL) were compared between African Americans (AA), Caucasians, and Hispanics using ANOVA and Student t-test. RESULTS: Included were 1327 AA, 147 Caucasian, and 86 Hispanic subjects. The AC was significantly smaller in AA than Caucasians (p = 0.008). There was no difference between AA and Caucasians in BPD, HC, FL, or HL. There were no differences between Hispanics and either Caucasians or AA in any of the biometries evaluated. CONCLUSIONS: A single fetal growth curve is not applicable across all ethnicities. AA fetuses have smaller AC then Caucasian fetuses from 17 to 22.9 weeks, which is typically the period when anatomic surveys are performed. Because AC contributes heavily to estimated fetal weight calculations, physicians may be over estimating growth restriction in AA patients. Ethnicity-specific fetal growth curves are indicated to limit unnecessary follow up.

Fetal growth curves for an ethnically diverse military population: the American Institute of Ultrasound in Medicine-accredited platform experience.

OBJECTIVE: To determine which fetal growth curve provided the best estimates of fetal weight for a cohort of ethnically diverse patients at sea level. METHODS: The study consisted of a population of 1,729 fetuses examined at sea level between January 1, 1997, and June 30, 2000, at 18 weeks, 28 weeks, and term. Gestational age (GA) based on menstrual dates was confirmed or adjusted by crown-rump length or early second-trimester biometry. Fetal weight was estimated by using biparietal diameter, head circumference, abdominal circumference, and femur length. Our fetal growth curves were analyzed with fourth-order polynomial regression analysis, applying four previously defined formulae for fetal growth. RESULTS: Fetal growth curves for estimated fetal weight demonstrated the expected parabolic shape, which varied according to the formulae used. Our curve best fit the following equation: estimated fetal weight = 4.522 - 0.22 x GA age + 0.25 x GA(2) - 0.001 x GA(3) + 5.248 x 10(-6) x GA(4) (R2 = 0.976). SD increased in concordance with GA. CONCLUSION: Madigan Army Medical Center serves a racially mixed, culturally diverse, military community with unrestricted access to prenatal care. Determination of the optimal population-appropriate growth curve at the correct GA assists clinicians in identifying fetuses at risk for growth restriction or macrosomia and therefore at risk for increased perinatal morbidity and death.

Ethnic differences in prenatal growth and the association with maternal and fetal characteristics.

OBJECTIVES: The objectives of this study were to determine ethnic differences in prenatal growth and to examine their association with differences in maternal and fetal characteristics such as maternal height, weight, age, parity and fetal gender. METHODS: A total of 1494 women from Rotterdam, The Netherlands, with a low-risk pregnancy who participated in a population-based cohort study, the Generation R Study, were offered three ultrasound examinations during pregnancy. Multilevel modeling was applied to determine ethnic differences in (estimated) fetal weight (including birth weight) and in the separate biometric variables that were used to calculate the estimated fetal weight (abdominal circumference, head circumference and femur length). Additionally the association of ethnic differences with maternal and fetal characteristics (i.e. maternal weight, height, age, parity and fetal gender) was studied. RESULTS: Turkish, Cape Verdian, Surinamese-Creole and Surinamese-Hindustani women had on average smaller fetuses than the native Dutch women. The differences became more pronounced towards term. In the Turkish group the differences were no longer statistically significant when adjusted for maternal weight, height, age, parity and fetal gender. In the Cape Verdian, Surinamese-Creole and Surinamese-Hindustani groups the differences decreased after adjustment (31%, 16% and 39%, respectively). CONCLUSIONS: This study shows that there are ethnic differences in fetal growth, which to a large extent may be attributed to differences in maternal weight, height, age and parity. For some ethnic groups, however, additional factors are involved, as differences remain significant after correction for fetal and maternal characteristics.

Ultrasonic prediction of term birth weight in Hispanic women. Accuracy in an outpatient clinic.

OBJECTIVE: To investigate the accuracy of ultrasonic fetal biometric algorithms for estimating term fetal weight. STUDY DESIGN: Ultrasonographic fetal biometric assessments were made in 74 Hispanic women who delivered at 37-42 weeks of gestation. Measurements were taken of the fetal biparietal diameter, head circumference, abdominal circumference and femur length. Twenty-seven standard fetal biometric algorithms were assessed for their accuracy in predicting fetal weight. Results were compared to those obtained by merely guessing the mean term birth weight in each case. RESULTS: The correlation between ultrasonically predicted and actual birth weights ranged from 0.52 to 0.79. The different ultrasonic algorithms estimated fetal weight to within +/- 8.6-15.0% (+/- 295-520 g) of actual birth weight as compared with +/- 13.6% (+/- 449 g) for guessing the mean birth weight in each case (mean +/- SD). The mean absolute prediction errors for 17 of the ultrasonic equations (63%) were superior to those obtained by guessing the mean birth weight by 3.2-5.0% (96-154 g) (P < .05). Fourteen algorithms (52%) were more accurate for predicting fetal weight to within +/- 15%, and 20 algorithms (74%) were more accurate for predicting fetal weight to within +/- 10% of actual birth weight than simply guessing the mean birth weight (P < .05). Ten ultrasonic equations (37%) showed significant utility for predicting fetal weight > 4,000 g (likelihood ratio > 5.0). CONCLUSION: Term fetal weight predictions using the majority of sonographic fetal biometric equations are more accurate, by up to 154 g and 5%, than simply guessing the population-specific mean birth weight.

Sonographic fetal weight estimation in a south-east Asian population.

OBJECTIVES: To determine the optimal sonographic fetal weight estimation formula for a mixed south-east Asian population near term. METHODS: Seventy-eight uncomplicated pregnancies were monitored between January 1996 and January 1997. Biparietal diameter, head circumference, abdominal circumference and femur length were measured and the following formulae were tested: Campbell, Shepherds and Hadlock. The estimated fetal weight was calculated by 12 different methods. The weight estimate was then projected forward to the time of delivery using the gestation-adjusted forward projection method. The weight estimation error was derived from the difference between the projected fetal weight and birth weight, and expressed as a percentage of birth weight. RESULTS: The mean time interval from the time of ultrasound fetal weight estimation to delivery was 4.4 days. The birth weight ranged between 2,330 to 4,215 g. The best performing formula was Hadlock's formula using the head circumference, abdominal circumference and femur, with the perimeters calculated using the ellipse function. The standard deviation of error for this formula was 8.66%. CONCLUSION: Even though the Hadlock formula was originally derived from an American population, it was equally useful in south-east Asian population.

A simple estimated fetal weight equation for fetuses between 24 and 34 weeks of gestation.

OBJECTIVE: To develop a mathematical equation that is simple, accurate and easy to use when applied to low-birth weight or preterm fetuses (< 35 weeks) and to assess previous normal ultrasonic fetal weight curves and make a comparison with normal fetal delivery weight curves. METHOD: In a large teaching hospital, 269 pregnant mothers were identified by the criteria of normalities, such as: well known LMP, regular menstrual cycles, no use of OCP for the last 3 months, no smoking and no history of diabetes. Birth-weight measurements (adjusted for maternal age, baby's sex, parity and week of gestation) were taken immediately after birth. RESULTS: Mean gestational age and mean birth' weight + S.D. were 29.5 + 3.02 weeks and 1530.238 237.856 g, respectively. With the aid of a scientific calculator the data were analyzed and a simple regression equation has been derived: EFW (kg) = 0.17 (G.A. - 20), S.D. - 235 g (Honarvar's Formula 1). CONCLUSION: For estimating weights of preterm or low-birth weight fetuses of less than 2500 g, this simple equation appears to be clinically reliable and easy to use and suggests that previous normal ultrasonic fetal weight curves may underestimate or overestimate normal fetal delivery weight between the 24th and 34th week of gestation. Our formula approximates actual birth weight better and recommends Ott's ultrasonic weight curve for Iranian population.