Predictive index for adverse perinatal outcome in pregnancies complicated by fetal growth restriction.

OBJECTIVES: To develop and validate an index predictive of adverse perinatal outcome (APO) in pregnancies meeting the consensus-based criteria for fetal growth restriction (FGR) endorsed by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). METHODS: This was a retrospective analysis of consecutive singleton non-anomalous gestations meeting the ISUOG-endorsed criteria for FGR at a single tertiary care center from November 2010 to August 2020. The dataset was divided randomly into a development set (two-thirds) and a validation set (one-third). The primary composite APO comprised one or more of: perinatal demise, Grade III-IV intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), seizures, hypoxic ischemic encephalopathy (HIE), necrotizing enterocolitis (NEC), sepsis, bronchopulmonary dysplasia (BPD) and length of stay in the neonatal intensive care unit (NICU) > 7 days. Regression analysis incorporated clinical factors readily available at the time of FGR diagnosis. The sum of ß coefficient-based weights yielded an index score, the performance of which was assessed in the validation set. Score cut-offs were selected to identify 'high-risk' and 'low-risk' ranges for which positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios were calculated. RESULTS: Of the 875 consecutive pregnancies that met the criteria for FGR and were included in the study cohort, 405 (46%) were complicated by one or more components of the composite APO, including 54 (6%) perinatal deaths, 22 (3%) neonates with Grade III-IV IVH and/or PVL, nine (1%) with seizures and/or HIE, 91 (10%) with BPD, 57 (7%) with sepsis, 21 (2%) with NEC, and 361 (41%) who remained in the NICU > 7 days. In addition, 270 (31%) pregnancies were delivered by Cesarean section for non-reassuring fetal status, 43 (5%) were admitted to the NICU for < 7 days, 79 (9%) had 5-min Apgar score < 7, 125/631 (20%) had a cord gas pH ≤ 7.1 and 35/631 (6%) had a base excess ≥ 12 mmol/L. The predictive index we developed included seven factors available at the time of FGR diagnosis: hypertensive disorder of pregnancy (HDP) (+8 points), chronic hypertension without HDP (+4 points), gestational age ≤ 32 weeks (+5 points), absent or reversed end-diastolic flow in the umbilical artery (+8 points), prepregnancy body mass index ≥ 35 kg/m2 (+3 points), isolated abdominal circumference < 3rd percentile (-4 points) and non-Hispanic black race (-2 points). The bias-corrected bootstrapped (1000 replicates) area under the receiver-operating-characteristics curve (AUC) of the predictive index for composite APO in the validation group was 0.88 (95% CI, 0.84-0.92), which was similar to that in the development group (AUC, 0.86 (95% CI, 0.82-0.89); P = 0.34). In the total cohort, 40% of pregnancies had a low-risk index score (≤ 2), associated with a NPV of 85% (95% CI, 81-88%) and a LR- of 0.21 (95% CI, 0.16-0.27), and 23% had a high-risk index score (≥ 10), associated with a PPV of 96% (95% CI, 93-98%) and a LR+ of 27.36 (95% CI, 14.33-52.23). Of the remaining pregnancies that had an intermediate-risk score, 50% were complicated by composite APO. CONCLUSION: An easy-to-use index incorporating seven clinical factors readily available at the time of FGR diagnosis is predictive of APO and may prove useful in counseling and management of pregnancies meeting the ISUOG-endorsed criteria for FGR. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Clinical phenotypes for risk stratification in small-for-gestational-age fetuses.

OBJECTIVE: To evaluate whether clinical phenotypes of small-for-gestational-age (SGA) fetuses can be identified and used for adverse perinatal outcome risk stratification to facilitate clinical decision-making. METHODS: This was a multicenter observational cohort study conducted in two tertiary care university hospitals. SGA fetuses were classified according to maternal, fetal and placental conditions using a two-step cluster algorithm, in which fetuses with more than one condition were assigned to the cluster associated with the highest mortality risk. Delivery and perinatal outcomes were compared using chi-square test among SGA clusters, and the associations between outcomes and each cluster were evaluated by calculating odds ratios (OR), adjusted for gestational age. RESULTS: The study included 17 631 consecutive singleton pregnancies, of which 1274 (7.2%) were defined as SGA at birth according to INTERGROWTH-21st standards. Nine SGA clinical phenotypes were identified using a predefined conceptual framework. All delivery and perinatal outcomes analyzed were significantly different among the nine phenotypes. The whole SGA cohort had a three-times higher risk of perinatal mortality compared with non-SGA fetuses (1.4% vs 0.4%; P < 0.001). SGA clinical phenotypes exhibited three patterns of perinatal mortality risk: the highest risk was associated with congenital anomaly (8.3%; OR, 17.17 (95% CI, 2.17-136.12)) and second- or third-trimester hemorrhage (8.3%; OR, 9.94 (95% CI, 1.23-80.02)) clusters; medium risk was associated with gestational diabetes (3.8%; OR, 9.59 (95% CI, 1.27-72.57)), preterm birth (3.2%; OR, 4.65 (95% CI, 0.62-35.01)) and intrauterine growth restriction (3.1%; OR, 5.93 (95% CI, 3.21-10.95)) clusters; and the lowest risk was associated with the remaining clusters. Perinatal mortality rate did not differ between SGA fetuses without other clinical conditions (54.1% of SGA fetuses) and appropriate-for-gestational-age fetuses (0.1% vs 0.4%; OR, 0.41 (95% CI, 0.06-2.94); P = 0.27). SGA combined with other obstetric pathologies increased significantly the risk of perinatal mortality, as demonstrated by the increased odds of perinatal death in SGA cases with gestational diabetes compared to non-SGA cases with the same condition (OR, 24.40 (95% CI, 1.31-453.91)). CONCLUSIONS: We identified nine SGA clinical phenotypes associated with different patterns of risk for adverse perinatal outcome. Our findings suggest that considering clinical characteristics in addition to ultrasound findings could improve risk stratification and decision-making for management of SGA fetuses. Future clinical trials investigating management of fetuses with SGA should take into account clinical information in addition to Doppler parameters and estimated fetal weight. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Placental disorders of pregnancy in subsequent IVF pregnancies - a sibling cohort.

RESEARCH QUESTION: To assess whether the incidence of placental disorders of pregnancy decreases with increasing parity in repeat IVF pregnancies, in the same way as natural pregnancies. DESIGN: This was a retrospective cohort of deliveries between November 2008 and January 2020, in a single university-affiliated medical centre. The study included women with only IVF-attained singleton pregnancies (no natural conception) with at least two deliveries, and compared the obstetric and perinatal outcomes between first, second and third deliveries. Each woman served as her own control. The primary outcome was the incidence of placental-related disorders of pregnancy, defined as small for gestational age (SGA) neonates and/or pre-eclampsia. RESULTS: A total of 307 first deliveries, 307 second deliveries and 49 third deliveries by the same women were compared. A trend for a decreased rate of pre-eclampsia was noted with increased parity (P = 0.06) and a significant decrease in the rate of SGA: 11.7% for first delivery, 7.8% for second delivery and 2.0% for third (P = 0.04). This difference in SGA incidence was maintained in a matched sub-analysis of the 49 women with three deliveries (P = 0.04), and after adjustment for fresh/frozen embryo transfer (P = 0.03). Although SGA and pre-eclampsia were generally more common in IVF than natural pregnancies, their decrease with increasing parity mimicked that in natural pregnancies. CONCLUSION: IVF pregnancies are associated with an increased risk of placental disorders of pregnancy. However, they exhibit a decrease in incidence with increasing parity.

Maternal betaine status, but not that of choline or methionine, is inversely associated with infant birth weight.

Maternal one-carbon metabolism during pregnancy is crucial for fetal development and programming by DNA methylation. However, evidence on one-carbon biomarkers other than folate is lacking. We, therefore, investigated whether maternal plasma methyl donors, that is, choline, betaine and methionine, are associated with birth outcomes. Blood samples were obtained from 115 women during gestation (median 26·3 weeks, 90 % range 22·7-33·0 weeks). Plasma choline, betaine, methionine and dimethylglycine were measured using HPLC-tandem MS. Multivariate linear and logistic regression models were used to estimate the association between plasma biomarkers and birth weight, birth length, the risk of small-for-gestational-age and large-for-gestational-age (LGA). Higher level of maternal betaine was associated with lower birth weight (-130·3 (95 % CI -244·8, -15·9) per 1 sd increment for log-transformed betaine). Higher maternal methionine was associated with lower risk of LGA, and adjusted OR, with 95 % CI for 1 sd increase in methionine concentration was 0·44 (95 % CI 0·21, 0·89). Stratified analyses according to infant sex or maternal plasma homocysteine status showed that reduction in birth weight in relation to maternal betaine was only limited to male infants or to who had higher maternal homocysteine status (≥5·1 µmol/l). Higher maternal betaine status was associated with reduced birth weight. Maternal methionine was inversely associated with LGA risk. These findings are needed to be replicated in future larger studies.

Prenatal vitamin D status and offspring's growth, adiposity and metabolic health: a systematic review and meta-analysis.

In this systematic review and meta-analysis of observational studies, we aimed to estimate the associations between prenatal vitamin D status and offspring growth, adiposity and metabolic health. We searched the literature in human studies on prenatal vitamin D status and offspring growth in PubMed, up to July 2017. Studies were selected according to their methodological quality and outcomes of interest (anthropometry, fat mass and diabetes in offspring). The inverse variance method was used to calculate the pooled mean difference (MD) with 95 % CI for continuous outcomes, and the Mantel-Haenszel method was used to calculate the pooled OR with 95 % CI for dichotomous outcomes. In all, thirty observational studies involving 35 032 mother-offspring pairs were included. Vitamin D status was evaluated by circulating 25-hydroxyvitamin D (25(OH)D) level. Low vitamin D status was based on each study's cut-off for low 25(OH)D levels. Low prenatal vitamin D levels were associated with lower birth weight (g) (MD -100·69; 95 % CI -162·25, -39·13), increased risk of small-for-gestational-age (OR 1·55; 95 % CI 1·16, 2·07) and an elevated weight (g) in infant at the age of 9 months (g) (MD 119·75; 95 % CI 32·97, 206·52). No associations were observed between prenatal vitamin D status and other growth parameters at birth, age 1 year, 4-6 years or 9 years, nor with diabetes type 1. Prenatal vitamin D may play a role in infant adiposity and accelerated postnatal growth. The effects of prenatal vitamin D on long-term metabolic health outcomes in children warrant future studies.

Is dietary macronutrient composition during pregnancy associated with offspring birth weight? An observational study.

There is lack of evidence on the differential impact of maternal macronutrient consumption: carbohydrates (CHO), fats and protein on birth weight. We investigated the association between maternal dietary macronutrient intakes and their sub-components such as saccharides and fatty acids and birth weight. This analyses included 1,196 women with singleton pregnancies who were part of the CAffeine and REproductive health study in Leeds, UK between 2003 and 2006. Women were interviewed in each trimester. Dietary information was collected twice using a 24-h dietary recall about 8-12 weeks and 13-27 weeks of gestation. Multiple linear regression models adjusted for alcohol and smoking in trimester 1, showed that each additional 10 g/d CHO consumption was associated with an increase of 4 g (95 % CI 1, 7; P=0·003) in birth weight. Conversely, an additional 10 g/d fat intake was associated with a lower birth weight of 8 g (95 % CI 0, 16; P=0·04) when we accounted for energy contributing macronutrients in each model, and maternal height, weight, parity, ethnicity, gestational age at delivery and sex of the baby. There was no evidence of an association between protein intake and birth weight. Maternal diet in trimester 2 suggested that higher intakes of glucose (10 g/d) and lactose (1 g/d) were both associated with higher birth weight of 52 g (95 % CI 4, 100; P=0·03) and 5 g (95 % CI 2, 7; P<0·001) respectively. These results show that dietary macronutrient composition during pregnancy is associated with birth weight outcomes. An appropriately balanced intake of dietary CHO and fat during pregnancy could support optimum birth weight.

Optimal protein intake during pregnancy for reducing the risk of fetal growth restriction: the Japan Environment and Children's Study.

Clinical trials show that protein supplement increases infant size in malnourished populations; however, epidemiological studies in high-income countries have reported mixed results. Although these findings suggest a non-linear relationship between maternal macronutrient intake and fetal growth, this relationship has not been closely examined. We assessed the association between maternal protein intake and fetal growth among 91 637 Japanese women with singletons in a nation-wide cohort study using validated FFQ. The respondents answered the FFQ twice, once during early pregnancy (FFQ1; 16·3 (sd 6·0) weeks), and second during mid-pregnancy (FFQ2, 28·1 (sd 4·1) weeks). Daily energy intake and percentage energy from protein, fats and carbohydrates were 7477 (sd 2577) kJ and 13·5 (sd 2·0), 29·5 (sd 6·5) and 55·3 (sd 7·8) %, respectively, for FFQ1, and 7184 (sd 2506) kJ and 13·6 (sd 2·1), 29·8 (sd 6·6) and 55·3 (sd 7·9) %, respectively, for FFQ2. The average birth weight was 3028 (sd 406) g, and 6350 infants (6·9 %) were small for gestational age (SGA). In both phases of the survey, birth weight was highest and the risk of SGA was lowest when the percentage energy from protein was 12 %, regardless of whether isoenergetic replacement was with fat or carbohydrates. Furthermore, when protein density in the maternal diet was held constant, birth weight was highest when 25 % of energy intake came from fat and 61 % came from carbohydrates during early pregnancy. We found maternal protein intake to have an inverse U-curve relationship with fetal growth. Our results strongly suggest that the effect of protein on birth weight is non-linear, and that a balanced diet fulfilling the minimum requirement for all macronutrients was ideal for avoiding fetal growth restriction.

Concentration of 25-hydroxyvitamin D from neonatal dried blood spots and the relation to gestational age, birth weight and Ponderal Index: the D-tect study.

Studies have suggested that vitamin D status at birth may be associated with a range of neonatal outcomes. The aim of this study was to assess the association between neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentration and gestational age, birth weight, Ponderal Index and size for gestational age. Neonatal capillary blood stored as dried blood spots was used to assess 25(OH)D3 concentrations among 2686 subjects selected from a random population sub-sample of individuals, born in Denmark from 1 May 1981 to 31 December 2002. There was an inverse association between 25(OH)D3 concentration and gestational age at birth of -0·006 (95 % CI -0·009, -0·003, P<0·001) weeks of gestation per 1 nmol/l increase in 25(OH)D3 concentration. An inverted U-shaped association between 25(OH)D3 and birth weight and Ponderal Index (P=0·04) was found, but no association with size for gestational age was shown. This study suggests that neonatal 25(OH)D3 concentration is associated with anthropometric measures at birth known to be correlated with many subsequent health outcomes such as obesity and type 2 diabetes.

Vitamin D levels during pregnancy and associations with birth weight and body composition of the newborn: a longitudinal multiethnic population-based study.

We investigated associations between serum 25-hydroxyvitamin D (25(OH)D) in pregnancy and birth weight and other neonatal anthropometric measures. The present study was a population-based, multiethnic cohort study of 719 pregnant women (59 % ethnic minorities) in Oslo, Norway, delivering a singleton neonate at term and with birth weight measurements. In a representative sample, anthropometric measurements were taken. Maternal 25(OH)D was measured at gestational weeks 15 and 28. Women with 25(OH)D <37 nmol/l were recommended vitamin D3 supplementation. Separate linear regression analyses were performed to model the associations between 25(OH)D and each of the outcomes: birth weight, crown-heel length, head circumference, abdominal circumference, sum of skinfolds, mid-upper arm circumference and ponderal index. In early pregnancy, 51 % of the women were vitamin D deficient (25(OH)D<50 nmol/l). In univariate analyses and in models adjusting for maternal age, parity, education, prepregnancy BMI, season, gestational age and neonate sex, maternal 25(OH)D was significantly associated with birth weight, head circumference, abdominal circumference and ponderal index (P<0·05 for all), when used as a continuous variable and categorised (consistently low, consistently high, increasing and decreasing level). However, after adjusting for ethnicity, 25(OH)D was no longer associated with any of the outcomes. Sex-specific associations for abdominal circumference and sum of skinfolds were found (P for interaction<0·05). In conclusion, in a multiethnic cohort of pregnant women with high prevalence of vitamin D deficiency, we found no independent relation between maternal vitamin D levels and any of the neonatal anthropometric measures, and the strong association between ethnicity and neonatal outcomes was not affected by maternal vitamin D status.

Maternal iron intake during pregnancy and birth outcomes: a cross-sectional study in Northwest China.

Previous studies have yielded conflicting results on the associations of maternal Fe intake with birth outcomes. This study aimed to investigate the associations between maternal Fe intake (total Fe from diet and supplements, dietary total Fe, haeme Fe, non-haeme Fe and Fe supplements use) and adverse birth outcomes in Shaanxi Province of Northwest China. In all, 7375 women were recruited using a stratified multistage random sampling method at 0-12 months (median 3; 10th-90th percentile 0-7) after delivery. Diets were collected by a validated FFQ and maternal characteristics were obtained via a standard questionnaire. The highest tertile of haeme Fe intake compared with the lowest tertile was negatively associated with low birth weight (LBW) (OR 0·68; 95 % CI 0·49, 0·94), small for gestational age (SGA) (OR 0·76; 95 % CI 0·62, 0·94) and birth defects (OR 0·55; 95 % CI 0·32, 0·89). Maternal haeme Fe intake was associated with a lower risk of intra-uterine growth retardation (IUGR) (medium tertile v. lowest tertile: OR 0·78; 95 % CI 0·61, 0·95; highest tertile v. lowest tertile: OR 0·76; 95 % CI 0·59, 0·93; P trend=0·045). The OR of LBW associated with Fe supplements use were as follows: during pregnancy: 0·72 (95 % CI 0·50, 0·95); in the second trimester: 0·67 (95 % CI 0·42, 0·98); in the third trimester: 0·47 (95 % CI 0·24, 0·93). We observed no associations of total Fe, dietary total Fe or non-haeme Fe intake with birth outcomes. The results suggest that maternal haeme Fe intake is associated with a reduced risk of LBW, SGA, IUGR and birth defects, and Fe supplements use during pregnancy reduces LBW risk.