Preeclampsia prediction with blood pressure measurements: A global external validation of the ALSPAC models.

OBJECTIVE: The prediction of preeclampsia in pregnancy has resulted in a plethora of prognostic models. Yet, very few make it past the development stage and most fail to influence clinical practice. The timely identification of high-risk pregnant women could deliver a tailored antenatal care regimen, particularly in low-resource settings. This study externally validated and calibrated previously published models that predicted the risk of preeclampsia, based on blood pressure (BP) at multiple time points in pregnancy, in a geographically diverse population. METHODS: The prospective INTERBIO-21st Fetal Study included 3,391 singleton pregnancies from Brazil, Kenya, Pakistan, South Africa, Thailand and the UK, 2012-2018. Preeclampsia prediction was based on baseline characteristics, BP and deviation from the expected BP trajectory at multiple time points in pregnancy. The prediction rules from the Avon Longitudinal Study of Parents and Children (ALSPAC) were implemented in the INTERBIO-21st cohort. RESULTS: Model discrimination was similar to the development cohort. Performance was best with baseline characteristics and a BP measurement at 34 weeks' gestation (AUC 0.85, 95 % CI 0.80-0.90). The ALSPAC models largely overestimated the true risk of preeclampsia incidence in the INTERBIO-21st cohort. CONCLUSIONS: After recalibration, these prediction models could potentially serve as a risk stratifying tool to help identify women who might benefit from increased surveillance during pregnancy.

Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study.

BACKGROUND: Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment. METHODS: In the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (≥18 years, with a BMI of less than 35 kg/m2, natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. Ultrasound scans were performed every 5±1 weeks until delivery to measure fetal growth and feto-placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants' health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis. FINDINGS: From Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20-25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto-placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1·5 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group. INTERPRETATION: Early pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity. FUNDING: Bill & Melinda Gates Foundation.

Association Between Preterm-Birth Phenotypes and Differential Morbidity, Growth, and Neurodevelopment at Age 2 Years: Results From the INTERBIO-21st Newborn Study.

Importance: The etiologic complexities of preterm birth remain inadequately understood, which may impede the development of better preventative and treatment measures. Objective: To examine the association between specific preterm-birth phenotypes and clinical, growth, and neurodevelopmental differences among preterm newborns compared with term newborns up to age 2 years. Design, Setting, and Participants: The INTERBIO-21st study included a cohort of preterm and term newborn singletons enrolled between March 2012 and June 2018 from maternity hospitals in 6 countries worldwide who were followed up from birth to age 2 years. All pregnancies were dated by ultrasonography. Data were analyzed from November 2019 to October 2020. Exposures/Interventions: Preterm-birth phenotypes. Main Outcomes and Measures: Infant size, health, nutrition, and World Health Organization motor development milestones assessed at ages 1 and 2 years; neurodevelopment evaluated at age 2 years using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) tool. Results: A total of 6529 infants (3312 boys [50.7%]) were included in the analysis. Of those, 1381 were preterm births (mean [SD] gestational age at birth, 34.4 [0.1] weeks; 5148 were term births (mean [SD] gestational age at birth, 39.4 [0] weeks). Among 1381 preterm newborns, 8 phenotypes were identified: no main maternal, fetal, or placental condition detected (485 infants [35.1%]); infections (289 infants [20.9%]); preeclampsia (162 infants [11.7%]); fetal distress (131 infants [9.5%]); intrauterine growth restriction (110 infants [8.0%]); severe maternal disease (85 infants [6.2%]); bleeding (71 infants [5.1%]); and congenital anomaly (48 infants [3.5%]). For all phenotypes, a previous preterm birth was a risk factor for recurrence. Each phenotype displayed differences in neonatal morbidity and infant outcomes. For example, infants with the no main condition detected phenotype had low neonatal morbidity but increased morbidity and hospitalization incidence at age 1 year (odds ratio [OR], 2.2; 95% CI, 1.8-2.7). Compared with term newborns, the highest risk of scoring lower than the 10th centile of INTER-NDA normative values was observed in the fine motor development domain among newborns with the fetal distress (OR, 10.6; 95% CI, 5.1-22.2) phenotype. Conclusions and Relevance: Results of this study suggest that phenotypic classification may provide a better understanding of the etiologic factors and mechanisms associated with preterm birth than continuing to consider it an exclusively time-based entity.

Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study.

Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks' gestation.

Adverse perinatal outcomes associated with antiretroviral therapy regimens: systematic review and network meta-analysis.

OBJECTIVE: Assess adverse perinatal outcomes associated with antenatal antiretroviral therapy (ART) regimens. DESIGN: Systematic review and network meta-analysis of randomized controlled trials (RCTS). METHODS: We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, EMBASE, and the Cochrane Central Register of Controlled Trials and four clinical trial databases from 1 January 1980 to 28 April 2018. We included RCTs of antenatal ART regimens in HIV-positive pregnant women, which assessed preterm birth (PTB), spontaneous preterm birth (sPTB), very preterm birth (VPTB), low birthweight (LBW), very low birthweight (VLBW), small-for-gestational-age (SGA), neonatal death (NND), and mother-to-child-transmission. We used random-effects network meta-analysis models to calculate relative risks for treatment comparisons and the hierarchy of treatments. RESULTS: Of 83 260 citations identified, 10 manuscripts were included, assessing 6285 women. Compared with zidovudine (ZDV) monotherapy, we found a higher risk of LBW after exposure to zidovudine/lamivudine/efavirenz (ZDV/3TC/EFV; relative risk 1.61; 95% CI 1.03-2.51), tenofovir disoproxil fumarate/emtricitabine/ritonavir-boosted lopinavir (TDF/FTC/LPV/r; 1.64; 1.18-2.29), or zidovudine/lamivudine/ritonavir-boosted lopinavir (ZDV/3TC/LPV/r; 1.87; 1.58-2.20). TDF/FTC/LPV/r carried an increased risk of VLBW, compared with ZDV monotherapy (5.40; 1.08-27.08). ZDV/3TC/LPV/r posed a higher risk of PTB than ZDV monotherapy (1.43; 1.08-1.91) and a higher risk of sPTB than zidovudine/lamivudine/abacavir (ZDV/3TC/ABC) (1.81; 1.21-2.71). LPV/r-containing regimens also carried the highest risks of VPTB, SGA and NND, although the limited data showed no significant differences. CONCLUSION: Of the ART regimens assessed in RCTs in pregnancy, LPV/r-containing regimens were associated with the highest risks of adverse perinatal outcomes.

Innate lymphoid cells are reduced in pregnant HIV positive women and are associated with preterm birth.

Preterm birth is the leading cause of neonatal and child mortality worldwide. Globally, 1.4 million pregnant women are estimated to be living with HIV/AIDS, the majority of whom live in sub-Saharan Africa. Maternal HIV infection and antiretroviral treatment (ART) have been associated with increased rates of preterm birth, but the underlying mechanisms remain unknown. Acute HIV infection is associated with a rapid depletion of all three subsets of innate lymphoid cells (ILCs), ILC1s, ILC2s and ILC3s, which is not reversed by ART. ILCs have been found at the maternal-fetal interface and we therefore investigated the potential association between maternal HIV infection, peripheral ILC frequencies and preterm birth. In our study of pregnant South African women with accurately dated pregnancies, we show that maternal HIV infection is associated with reduced levels of all three ILC subsets. Preterm birth was also associated with lower levels of all three ILC subsets in early pregnancy. ILC frequencies were lowest in HIV positive women who experienced preterm birth. Moreover, ILC levels were reduced in pregnancies resulting in spontaneous onset of preterm labour and in extreme preterm birth (< 28 weeks gestation). Our findings suggest that reduced ILC frequencies may be a link between maternal HIV infection and preterm birth. In addition, ILC frequencies in early pregnancy may serve as predictive biomarkers for women who are at risk of delivering preterm.

Perinatal outcomes associated with maternal HIV and antiretroviral therapy in pregnancies with accurate gestational age in South Africa.

OBJECTIVE: To assess the association of maternal HIV infection and antiretroviral therapy (ART) with perinatal outcomes among women with accurate pregnancy dating and birth weights. DESIGN: Prospective pregnancy cohort study in Soweto, South Africa. METHODS: Gestational age was estimated by first-trimester ultrasound and birth weight was measured in a standardized manner within 24 h of birth. The primary composite outcome 'adverse perinatal outcome' included preterm birth, low birth weight, small for gestational age, stillbirth and neonatal death (NND). Specific adverse perinatal outcomes were secondary outcomes. Logistic regression models adjusted for multiple confounders. RESULTS: Of 633 women included in the analysis, 229 (36.2%) were HIV positive and 404 (63.8%) HIV negative. Among 125 HIV-positive women who provided detailed information on HIV and ART, 96.7% had clinical stage 1 of HIV disease and 98.4% were on ART during pregnancy, mostly WHO-recommended efavirenz-based ART. Among 109 HIV-positive women with information on timing of ART initiation, 38 (34.9%) initiated ART preconception and 71 (65.1%) antenatally. No newborns were HIV positive. In univariable analysis, maternal HIV infection was associated with increased risk of the composite 'adverse perinatal outcome' [odds ratio (OR) 1.44; 95% confidence interval (CI) 1.03, 2.03], NND (OR 6.15; 95% CI 1.27, 29.88) and small for gestational age (OR 1.55; 95% CI 1.01, 2.37). After adjusting for confounders, maternal HIV infection remained associated with 'adverse perinatal outcome' (adjusted OR 1.47; 95% CI 1.01, 2.14) and NND (adjusted OR 7.82; 95% CI 1.32, 46.42). No associations with timing of ART initiation were observed. CONCLUSION: Despite high ART coverage, good maternal health and very low vertical HIV transmission rate, maternal HIV infection remained associated with increased risk of adverse perinatal outcomes. Larger studies using first trimester ultrasound for pregnancy dating are needed to further assess associations with specific adverse perinatal outcomes.

Deep clinical and biological phenotyping of the preterm birth and small for gestational age syndromes: The INTERBIO-21 st Newborn Case-Control Study protocol.

Background: INTERBIO-21 st is Phase II of the INTERGROWTH-21 st Project, the population-based, research initiative involving nearly 70,000 mothers and babies worldwide coordinated by Oxford University and performed by a multidisciplinary network of more than 400 healthcare professionals and scientists from 35 institutions in 21 countries worldwide. Phase I, conducted 2008-2015, consisted of nine complementary studies designed to describe optimal human growth and neurodevelopment, based conceptually on the WHO prescriptive approach. The studies generated a set of international standards for monitoring growth and neurodevelopment, which complement the existing WHO Child Growth Standards. Phase II aims to improve the functional classification of the highly heterogenous preterm birth and fetal growth restriction syndromes through a better understanding of how environmental exposures, clinical conditions and nutrition influence patterns of human growth from conception to childhood, as well as specific neurodevelopmental domains and associated behaviors at 2 years of age. Methods: In the INTERBIO-21 st Newborn Case-Control Study, a major component of Phase II, our objective is to investigate the mechanisms potentially responsible for preterm birth and small for gestational age and their interactions, using deep phenotyping of clinical, growth and epidemiological data and associated nutritional, biochemical, omic and histological profiles. Here we describe the study sites, population characteristics, study design, methodology and standardization procedures for the collection of longitudinal clinical data and biological samples (maternal blood, umbilical cord blood, placental tissue, maternal feces and infant buccal swabs) for the study that was conducted between 2012 and 2018 in Brazil, Kenya, Pakistan, South Africa, Thailand and the UK. Discussion: Our study provides a unique resource for the planned analyses given the range of potentially disadvantageous exposures (including poor nutrition, pregnancy complications and infections) in geographically diverse populations worldwide. The study should enhance current medical knowledge and provide new insights into environmental influences on human growth and neurodevelopment.