Selecting a birth weight standard for an indigenous population in a LMIC: A prospective comparative study.

OBJECTIVES: The aim of the present study was to compare birth weight (BW) distribution and proportion of BWs below or above specified percentiles in low-risk singleton pregnancies in healthy South African (SA) women of mixed ancestry with expected values according to four BW references and to determine the physiological factors affecting BW. METHODS: This was an ancillary study of a prospective multinational cohort study, involving 7060 women recruited between August 2007 and January 2015 in two townships of Cape Town, characterized by low socioeconomic status, and high levels of drinking and smoking. Detailed information about maternal and pregnancy characteristics, including harmful exposures, was gathered prospectively, allowing us to select healthy women with uncomplicated pregnancies without any known harmful exposures. In this cohort we compared the median BW and the proportion of BWs P90, 95 and 97 according to four reference standards (INTERGROWTH-21st, customized according to the method described by Mickolajczyk, Fetal Medicine Foundation and revised Fenton reference) with expected values. Appropriate parametric and nonparametric tests were used, and sensitivity analysis was performed for infant sex, first trimester bookings and women of normal body mass index (BMI). Multiple regression was used to explore effects of confounders. Written consent and ethics approval was obtained. RESULTS: The cohort included 739 infants. The INTERGROWTH-21st standard was closest for the actual BW-distribution and categories. Below-expected BW was associated with boys, younger, shorter, leaner women, lower parity and gravidity. Actual BW was significantly influenced by maternal weight, BMI, parity and gestational age. CONCLUSION: Of the four references assessed in this study, the INTERGROWTH-21st standard was closest for the actual BW distribution. Maternal variables significantly influence BW.

Associations between prenatal alcohol and tobacco exposure on Doppler flow velocity waveforms in pregnancy: a South African study.

BACKGROUND: The negative impact of prenatal alcohol and tobacco exposure (PAE and PTE) on fetal development and birth outcomes are well described, yet pathophysiologic mechanisms are less clear. Our aim was to investigate (1) the associations between quantity, frequency and timing (QFT) of PAE and PTE with blood flow velocities in arteries of the fetal-placental-maternal circulation and (2) the extent to which combined effect of QFT of PAE and/or PTE and Doppler flow velocity waveforms (FWV) predict infant birth weight. METHODS: The Safe Passage Study is a cohort based in urban Cape Town, South Africa. Recruitment occurred between 2007 and 2015. Information on QFT of PAE and PTE was collected prospectively at up to 4 occasions during pregnancy using a modified Timeline Follow-Back approach. Ultrasound examinations consisted of Doppler flow velocity waveforms of the uterine, umbilical (UA) and fetal middle cerebral arteries for the pulsatility index (PI) at 20-24 and 34-38 weeks. Exclusion criteria included: twin pregnancies, stillbirths, participants exposed to other drugs. The sample was divided into three groups (controls, PAE and PTE) and included 1396 maternal-fetal-dyads assessed during the second trimester; 1398 assessed during the third trimester. RESULTS: PTE was associated with higher UA PI values in second and third trimesters (p < 0.001), compared to the PAE and control group. The total amount of cigarettes smoked during pregnancy was positively correlated with UA PI values (r = 0.087, p < 0.001). There was a positive correlation between cigarettes smoked per day in trimester one (r = 0.091, p < 0.01), and trimester two (r = 0.075, p < 0.01) and UA PI (in trimester two), as well as cigarettes smoked per day in trimester two (r = 0.058, p < 0.05) and trimester three (r = 0.069, p < 0.05) and the UA PI in trimester three. Generalized additive models indicated that PAE in trimester two, PTE in trimester one and Doppler FWV in trimester three were significant predictors of birth weight in this sample. CONCLUSION: In our study, PTE in trimesters two and three resulted in increased vascular resistance of the placenta. These findings highlight nuance in associations between PAE, PTE and blood flow velocities in arteries of the fetal-placental-maternal circulation and birth weight, suggesting that quantity and timing are important factors in these relationships.

The impact of prenatal alcohol and/or tobacco exposure on brain structure in a large sample of children from a South African birth cohort.

BACKGROUND: Neuroimaging studies have emphasized the impact of prenatal alcohol exposure (PAE) on brain development, traditionally in heavily exposed participants. However, less is known about how naturally occurring community patterns of PAE (including light to moderate exposure) affect brain development, particularly in consideration of commonly occurring concurrent impacts of prenatal tobacco exposure (PTE). METHODS: Three hundred thirty-two children (ages 8 to 12) living in South Africa's Cape Flats townships underwent structural magnetic resonance imaging. During pregnancy, their mothers reported alcohol and tobacco use, which was used to evaluate PAE and PTE effects on their children's brain structure. Analyses involved the main effects of PAE and PTE (and their interaction) and the effects of PAE and PTE quantity on cortical thickness, surface area, and volume. RESULTS: After false-discovery rate (FDR) correction, PAE was associated with thinner left parahippocampal cortices, while PTE was associated with smaller cortical surface area in the bilateral pericalcarine, left lateral orbitofrontal, right posterior cingulate, right rostral anterior cingulate, left caudal middle frontal, and right caudal anterior cingulate gyri. There were no PAE × PTE interactions nor any associations of PAE and PTE exposure on volumetrics that survived FDR correction. CONCLUSION: PAE was associated with reduction in the structure of the medial temporal lobe, a brain region critical for learning and memory. PTE had stronger and broader associations, including with regions associated with executive function, reward processing, and emotional regulation, potentially reflecting continued postnatal exposure to tobacco (i.e., second-hand smoke exposure). These differential effects are discussed with respect to reduced PAE quantity in our exposed group versus prior studies within this geographical location, the deep poverty in which participants live, and the consequences of apartheid and racially and economically driven payment practices that contributed to heavy drinking in the region. Longer-term follow-up is needed to determine potential environmental and other moderators of the brain findings here and assess the extent to which they endure over time.

Effect of individual or comorbid antenatal depression and anxiety on birth outcomes and moderation by maternal traumatic experiences and resilience.

Background: Although antenatal depression and anxiety (e.g., negative antenatal mental health; NAMH) are individually associated with preterm birth (PTB) and infant neurological impairment, few studies account for comorbidity. Understanding how NAMH impacts PTB and infant neurological functioning by either singular (depression or anxiety) or comorbid status, as well as the way in which these effects can be moderated by additional risk or protective factors (traumatic experiences and trait resiliency) can contribute further understanding of NAMH effects on birth outcomes. Methods: The sample included 3042 mother-infant dyads from U.S. and South Africa cohorts of the Safe Passage Study (N = 3042). A four-category NAMH variable was created to categorize depression-only, anxiety-only, comorbid, or no NAMH statuses. Results: There were no NAMH main effects on PTB, however, anxiety-only and comorbid NAMH increased odds of PTB for mothers with higher rates of traumatic life experiences. Anxiety-only and comorbid NAMH were associated with increased odds of newborn neurological impairment, and the effect of comorbid NAMH was stronger for mothers with higher rates of traumatic experiences. Resiliency decreased odds of neurological impairment for mothers who reported depression-only or anxiety-only NAMH. Limitations: Limitations included potential artefacts of two cohorts that differed in rates of almost all variables, a single time point for measuring NAMH, and lack of pregnancy-specific NAMH measures. Conclusions: Especially when compared to mothers with no NAMH, comorbidity or singular-condition NAMH statuses associate with negative birth outcomes in nuanced ways, especially when considering additional contexts that may foster or protect against NAMH.

Placental pathology in spontaneous and iatrogenic preterm birth: Different entities with unique pathologic features.

INTRODUCTION: Placental pathology is an important contributor to the understanding of preterm birth and reveals major differences between spontaneous preterm birth (SPTB) and iatrogenic preterm birth (IPTB). The aim of this study was to investigate these relationships. METHODS: Research midwives collected placentas from 1101 women with singleton pregnancies who were enrolled in the Safe Passage Study. Trained pathology technologists prepared and processed placenta specimens for macroscopic and microscopic examination by designated pathologists. Statistical analyses were done with STATISTICA version 13. RESULTS: In SPTB we found more cases of accelerated villous maturation; however, the other features of maternal vascular malperfusion (MVM) were not present. The prevalence rate of funisitis was also increased. In IPTB, multiple features of MVM - accelerated villous maturation, distal villous hypoplasia, decidual arteriopathy, increased syncytial knots, increased perivillous fibrin, and prominent extravillous trophoblast were increased, as were features of fetal vascular malperfusion (FVM) - umbilical cord vessel thrombosis, avascular villi, and fetal vascular thrombosis. Increased syncytial knots were found in 26% of preterm stillbirths and in 29% of preterm infant demises as compared to 81% of IPTB infants alive at one year. DISCUSSION: SPTB and IPTB differ. The detected "abnormal" accelerated villous maturation pattern in SPTB and preterm demises, suggests an inability of the placenta to adapt and may be a trigger for SPTB. Funisitis was the only inflammatory response significant for SPTB. MVM and FVM are implicated in IPTB, but not an inflammatory process.

Trophoblast inclusions and adverse birth outcomes.

OBJECTIVE: Trophoblast inclusions-cross sections of abnormal trophoblast bilayer infoldings-have previously been associated with aneuploidy, placenta accreta, and prematurity. This study was conducted to establish the relationship between trophoblast inclusions and a range of placental, pregnancy, and birth outcomes in a patient population with high smoking and alcohol exposure. Specifically, we sought to evaluate the association between the presence of trophoblast inclusions and 1) three primary birth outcomes: full-term birth, preterm birth, and stillbirth; 2) gestational age at delivery; and 3) specific placental pathologies. METHODS: Two slides containing chorionic villi were evaluated from 589 placentas that were collected from Stellenbosch University in Cape Town, South Africa as part of the prospective, multicenter cohort Safe Passage Study of the Prenatal Alcohol and SIDS and Stillbirth Network. The subsample included 307 full-term live births, 212 preterm live births, and 70 stillbirths. RESULTS: We found that the odds of identifying at least one trophoblast inclusion across two slides of chorionic villi was significantly higher for placentas from preterm compared to term liveborn deliveries (OR = 1.74; 95% CI: 1.22, 2.49, p = 0.002), with an even greater odds ratio for placentas from stillborn compared to term liveborn deliveries (OR = 4.95; 95% CI: 2.78, 8.80, p < 0.001). Gestational age at delivery was inversely associated with trophoblast inclusion frequency. Trophoblast inclusions were significantly associated with small for gestational age birthweight, induction of labor, villous edema, placental infarction, and inflammation of the chorionic plate. CONCLUSIONS: The novel associations that we report warrant further investigation in order to understand the complex network of biological mechanisms through which the factors that lead to trophoblast inclusions may influence or reflect the trajectory and health of a pregnancy. Ultimately, this line of research may provide critical insights that could inform both clinical and research applications.

The Intricate Interactions between Maternal Smoking and Drinking During Pregnancy and Birthweight Z-Scores of Preterm Births.

BACKGROUND: The extent to which smoking and drinking in a local community is associated with nutrition and Z-scores of infants from spontaneous preterm deliveries, is uncertain. AIM: To investigate associations of different levels of maternal smoking and drinking in spontaneous preterm birth with infant birthweight Z-scores. METHODS: Information, including gestational age (determined by earliest ultrasound), maternal arm circumference (measured at enrolment), smoking-drinking data (obtained up to 4 occasions), birthweight data (obtained from medical records) and birthweight Z-scores (calculated from INTERGROWTH- 21st study), collected over a period of nine years was used to compare 407 spontaneous preterm births with 3 493 spontaneous term births Analyses of variance, correlations and multiple regression were performed in STATISTICA. RESULTS: Women with spontaneous preterm birth, had significantly lower gravidity and smaller arm circumference when compared to women with spontaneous birth at term. Women with spontaneous preterm birth drank more and heavier during pregnancy, and more smoked. Gestational age at birth was significantly longer in heavy-smokers-heavy-drinkers compared to heavy-smokers-no-drinkers (7.1 days) and in no-smokers-heavy-drinkers when compared to no-smokers-no-drinkers (11.2 days). Birthweight was significantly lower in low-smokers-heavy-drinkers when compared to low-smokers-no-drinkers (240g) and in heavy-smokers-low-drinkers when compared to no-smokers-low-drinkers (273g). Birthweight Z-scores were significantly lower in low-smokers-heavy-drinkers when compared to low-smokers-low-drinkers and low-smokers-no-drinkers; and, also significantly lower in heavy-smokers-low-drinkers when compared to low-smokers-low-drinkers and no-smokers-low-drinkers. CONCLUSION: Alcohol aggravates the detrimental effect of smoking on birthweight and birthweight Z-scores but seems to counteract the negative association of smoking with gestational age.

Trophoblast inclusions in the human placenta: Identification, characterization, quantification, and interrelations of subtypes.

We sought to examine placentas enriched for trophoblast inclusions (TIs) in order to characterize, quantify, and examine the interrelations between subtypes of TIs to better understand their underlying biology. We examined a cohort of 600 placentas from deliveries between 200 and 430 weeks of gestation. Forty-five percent of the placentas had at least one TI in the two slides examined. Four percent of the placentas had 10 or more TIs and two placentas had more than 70 TIs. Four distinct TI subtypes were observed: inclusionoids (early forming inclusions), inclusions, calcified inclusions, and calcified bodies. We suggest this reflects a developmental trajectory of TI maturation, the timing of which might be useful when comparing TI expression to clinical outcomes.

Association of socioeconomic status and clinical and demographic conditions with the prevalence of preterm birth.

OBJECTIVE: To examine the effects of socioeconomic and demographic conditions on the prevalence of preterm birth in a local community. METHODS: Pregnant women (aged ≥16 years) willing to provide informed consent in one of the two languages of the community were recruited in South Africa between August 2007 and January 2015. Specifically designed case report forms collected information and measurements prospectively. RESULTS: After reviewing the medical records of 5806 women, it was possible to identify those who had spontaneous preterm birth (SPTB), induced preterm birth (IPTB), or spontaneous term birth (STB). Women with IPTB (vs SPTB) were more obese and had higher education levels and household incomes; more had telephones and running water at home. They enrolled earlier and more developed hypertension and pre-eclampsia. Women with SPTB (vs STB) were less obese, shorter, had smaller arm circumferences and higher gravidities and Edinburgh Depression Scores, lower education, fewer telephones, and less running water at home. More women with SPTB used methamphetamine, cigarettes, and were heavier smokers. CONCLUSION: SPTB and IPTB should not be conflated. Programs to reduce the high prevalence of SPTB should include improving education, lifestyle, and socioeconomic conditions. Addressing hypertension should help reduce preterm inductions.