Mapping the Cord Blood Transcriptome of Pregnancies Affected by Early Maternal Anemia to Identify Signatures of Fetal Programming

Context Anemia during early pregnancy (EP) is common in developing countries and is associated with adverse health consequences for both mothers and children. Offspring of women with EP anemia often have low birth weight, which increases risk for cardiometabolic diseases, including type 2 diabetes (T2D), later in life. Objective We aimed to elucidate mechanisms underlying developmental programming of adult cardiometabolic disease, including epigenetic and transcriptional alterations potentially detectable in umbilical cord blood (UCB) at time of birth. Methods We leveraged global transcriptome- and accompanying epigenome-wide changes in 48 UCB from newborns of EP anemic Tanzanian mothers and 50 controls to identify differentially expressed genes (DEGs) in UCB exposed to maternal EP anemia. DEGs were assessed for association with neonatal anthropometry and cord insulin levels. These genes were further studied in expression data from human fetal pancreas and adult islets to understand their role in beta-cell development and/or function. Results The expression of 137 genes was altered in UCB of newborns exposed to maternal EP anemia. These putative signatures of fetal programming, which included the birth weight locus LCORL, were potentially mediated by epigenetic changes in 27 genes and associated with neonatal anthropometry. Among the DEGs were P2RX7, PIK3C2B, and NUMBL, which potentially influence beta-cell development. Insulin levels were lower in EP anemia-exposed UCB, supporting the notion of developmental programming of pancreatic beta-cell dysfunction and subsequently increased risk of T2D in offspring of mothers with EP anemia. Conclusions Our data provide proof-of-concept on distinct transcriptional and epigenetic changes detectable in UCB from newborns exposed to maternal EP anemia.Peer reviewe

Fetal growth and birth weight are independently reduced by malaria infection and curable sexually transmitted and reproductive tract infections in Kenya, Tanzania, and Malawi: A pregnancy cohort study

Objective Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We investigated the individual and combined effects of malaria and curable STIs/RTIs on fetal growth in Kenya, Tanzania, and Malawi. Methods This study was nested within a randomized trial comparing monthly intermittent preventive treatment for malaria in pregnancy with sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine, alone or combined with azithromycin. Fetal weight gain was assessed by serial prenatal ultrasound. Malaria was assessed monthly, and Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis and bacterial vaginosis at enrolment and in the third trimester. The effect of malaria and STIs/RTIs on fetal weight/birthweight Z-scores was evaluated using mixed-effects linear regression. Results 1,435 pregnant women had fetal/birth weight assessed 3,950 times. Compared to women without malaria or STIs/RTIs (n=399), malaria-only (n=267), STIs/RTIs-only (n=410) or both (n=353) were associated with reduced fetal growth (adjusted mean difference in fetal/birth weight Z-score [95% CI]: malaria=-0.18 [-0.31,-0.04], p=0.01]; STIs/RTIs=-0.14 [-0.26,-0.03], p=0.01]; both=-0.20 [-0.33,-0.07], p=0.003). Paucigravidae experienced the greatest impact. Conclusion Malaria and STIs/RTIs are associated with poor fetal growth especially among paucigravidae women with dual infections. Integrated antenatal interventions are needed to reduce the burden of both malaria and STIs/RTIs

Neonatal mortality risk of vulnerable newborns : A descriptive analysis of subnational, population-based birth cohorts for 238 143 live births in low- and middle-income settings from 2000 to 2017

Objective: We aimed to understand the mortality risks of vulnerable newborns (defined as preterm and/or born weighing smaller or larger compared to a standard population), in low- and middle-income countries (LMICs). Design: Descriptive multi-country, secondary analysis of individual-level study data of babies born since 2000. Setting: Sixteen subnational, population-based studies from nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. Population: Live birth neonates. Methods: We categorically defined five vulnerable newborn types based on size (large- or appropriate- or small-for-gestational age [LGA, AGA, SGA]), and term (T) and preterm (PT): T + LGA, T + SGA, PT + LGA, PT + AGA, and PT + SGA, with T + AGA (reference). A 10-type definition included low birthweight (LBW) and non-LBW, and a four-type definition collapsed AGA/LGA into one category. We performed imputation for missing birthweights in 13 of the studies. Main Outcome Measures: Median and interquartile ranges by study for the prevalence, mortality rates and relative mortality risks for the four, six and ten type classification. Results: There were 238 143 live births with known neonatal status. Four of the six types had higher mortality risk: T + SGA (median relative risk [RR] 2.8, interquartile range [IQR] 2.0–3.2), PT + LGA (median RR 7.3, IQR 2.3–10.4), PT + AGA (median RR 6.0, IQR 4.4–13.2) and PT + SGA (median RR 10.4, IQR 8.6–13.9). T + SGA, PT + LGA and PT + AGA babies who were LBW, had higher risk compared with non-LBW babies. Conclusions: Small and/or preterm babies in LIMCs have a considerably increased mortality risk compared with babies born at term and larger. This classification system may advance the understanding of the social determinants and biomedical risk factors along with improved treatment that is critical for newborn health.Peer reviewe

Prevalence and risk factors of preconception anemia: A community based cross sectional study of rural women of reproductive age in northeastern Tanzania.

BACKGROUND:Anemia is a major public health problem that adversely affects pregnancy outcomes. The prevalence of anemia among pregnant women before conception is not well known in Tanzania. The aim of this study was to determine the prevalence, types, and risk factors of preconception anemia in women of reproductive age from a rural Tanzanian setting. METHODS:Trained field workers visited households to identify all female residents aged 18-40 years and invited them to the nearby health facility for screening and enrolment into this study. Baseline samples were collected to measure hemoglobin levels, serum ferritin, vitamin B12, folate, C-reactive protein, alanine amino-transferase, the presence of malaria, HIV, and soil transmitted helminth infections. Anthropometric and socio-economic data were recorded alongside with clinical information of participants. Logistic regression analysis was used to determine the adjusted odds ratios (AOR) for the factors associated with preconception anemia. FINDINGS:Of 1248 women enrolled before conception, 36.7% (95% confidence interval (CI) 34.1-39.4) had anemia (hemoglobin <12 g/dL) and 37.6% (95% CI 34.9-40.4) had iron deficiency. For more than half of the anemic cases, iron deficiency was also diagnosed (58.8%, 95% CI 54.2-63.3). Anemia was independently associated with increased age (AOR 1.05, 95% CI 1.03-1.07), malaria infection at enrolment (AOR 2.21, 95% CI 1.37-3.58), inflammation (AOR 1.77, 95% CI 1.21-2.60) and iron deficiency (AOR 4.68, 95% CI 3.55-6.17). The odds of anemia were reduced among women with increased mid-upper arm circumference (AOR 0.90, 95% CI 0.84-0.96). CONCLUSION:Anemia among women of reproductive age before conception was prevalent in this rural setting. Increased age, iron deficiency, malaria infection and inflammation were significant risk factors associated with preconception anemia, whereas increased mid-upper arm circumference was protective against anemia. Interventions to ensure adequate iron levels as well as malaria control before conception are needed to prevent anemia before and during pregnancy and improve birth outcomes in this setting. TRIAL REGISTRATION:NCT02191683

Biosensor for Detecting Fetal Growth Restriction in a Low-Resource Setting

One strategy for improving detection of fetal growth restriction (FGR) is developing biosensors identifying placental dysfunction as a leading pathogenesis for FGR. The aim of this pilot study was to investigate the performance of a biosensor specified to detect placental dysfunction by means of maternal arterial turbulence acoustics in a low-resource setting. A cohort of 147 singleton pregnant women were prospectively followed with double-blinded biosensor tests, sonographic estimation of fetal weight (EFW) and Doppler flow at 26–28, 32–34 and 37–39 weeks of pregnancy. Full term live births with recorded birth weights (BWs) and without major congenital malformations were included. Outcomes were defined as (A) a solitary biometric measure (BW &lt; 3rd centile) and as (B) a biometric measure and contributory functional measure (BW &lt; 10th centile and antenatally detected umbilical artery pulsatility index &gt; 95th centile). Data from 118 women and 262 antenatal examinations were included. Mean length of pregnancy was 40 weeks (SD ± 8 days), mean BW was 3008 g (SD ± 410 g). Outcome (A) was identified in seven (6%) pregnancies, whereas outcome (B) was identified in one (0.8%) pregnancy. The biosensor tested positive in five (4%) pregnancies. The predictive performance for outcome (A) was sensitivity = 0.29, specificity = 0.97, p = 0.02, positive predictive value (PPV) was 0.40 and negative predictive value (NPV) was 0.96. The predictive performance was higher for outcome (B) with sensitivity = 1.00, specificity = 0.97, p = 0.04, PPV = 0.20 and NPV = 1.00. Conclusively, these pilot-study results show future potential for biosensors as screening modality for FGR in a low-resource setting

Fetal growth and birth weight are independently reduced by malaria infection and curable sexually transmitted and reproductive tract infections in Kenya, Tanzania, and Malawi: A pregnancy cohort study

Objective: Malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) are highly prevalent in sub-Saharan Africa and associated with poor pregnancy outcomes. We investigated the individual and combined effects of malaria and curable STIs/RTIs on fetal growth in Kenya, Tanzania, and Malawi. Methods: This study was nested within a randomized trial comparing monthly intermittent preventive treatment for malaria in pregnancy with sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine, alone or combined with azithromycin. Fetal weight gain was assessed by serial prenatal ultrasound. Malaria was assessed monthly, and Treponema pallidum, Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis and bacterial vaginosis at enrolment and in the third trimester. The effect of malaria and STIs/RTIs on fetal weight/birthweight Z-scores was evaluated using mixed-effects linear regression. Results: 1,435 pregnant women had fetal/birth weight assessed 3,950 times. Compared to women without malaria or STIs/RTIs (n=399), malaria-only (n=267), STIs/RTIs-only (n=410) or both (n=353) were associated with reduced fetal growth (adjusted mean difference in fetal/birth weight Z-score [95% CI]: malaria=-0.18 [-0.31,-0.04], p=0.01]; STIs/RTIs=-0.14 [-0.26,-0.03], p=0.01]; both=-0.20 [-0.33,-0.07], p=0.003). Paucigravidae experienced the greatest impact. Conclusion Malaria and STIs/RTIs are associated with poor fetal growth especially among paucigravidae women with dual infections. Integrated antenatal interventions are needed to reduce the burden of both malaria and STIs/RTIs

Effect of monthly intermittent preventive treatment with dihydroartemisinin–piperaquine with and without azithromycin versus monthly sulfadoxine–pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial

Background Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin–piperaquine is more effective than IPTp with sulfadoxine–pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine–pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin–piperaquine, alone or combined with azithromycin, can reduce adverse pregnancy outcomes compared with IPTp with sulfadoxine–pyrimethamine. Methods We did an individually randomised, double-blind, three-arm, partly placebo-controlled trial in areas of high sulfadoxine–pyrimethamine resistance in Kenya, Malawi, and Tanzania. HIV-negative women with a viable singleton pregnancy were randomly assigned (1:1:1) by computer-generated block randomisation, stratified by site and gravidity, to receive monthly IPTp with sulfadoxine–pyrimethamine (500 mg of sulfadoxine and 25 mg of pyrimethamine for 1 day), monthly IPTp with dihydroartemisinin–piperaquine (dosed by weight; three to five tablets containing 40 mg of dihydroartemisinin and 320 mg of piperaquine once daily for 3 consecutive days) plus a single treatment course of placebo, or monthly IPTp with dihydroartemisinin–piperaquine plus a single treatment course of azithromycin (two tablets containing 500 mg once daily for 2 consecutive days). Outcome assessors in the delivery units were masked to treatment group. The composite primary endpoint was adverse pregnancy outcome, defined as fetal loss, adverse newborn baby outcomes (small for gestational age, low birthweight, or preterm), or neonatal death. The primary analysis was by modified intention to treat, consisting of all randomised participants with primary endpoint data. Women who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, NCT03208179. Findings From March-29, 2018, to July 5, 2019, 4680 women (mean age 25·0 years [SD 6·0]) were enrolled and randomly assigned: 1561 (33%; mean age 24·9 years [SD 6·1]) to the sulfadoxine–pyrimethamine group, 1561 (33%; mean age 25·1 years [6·1]) to the dihydroartemisinin–piperaquine group, and 1558 (33%; mean age 24·9 years [6.0]) to the dihydroartemisinin–piperaquine plus azithromycin group. Compared with 335 (23·3%) of 1435 women in the sulfadoxine–pyrimethamine group, the primary composite endpoint of adverse pregnancy outcomes was reported more frequently in the dihydroartemisinin–piperaquine group (403 [27·9%] of 1442; risk ratio 1·20, 95% CI 1·06–1·36; p=0·0040) and in the dihydroartemisinin–piperaquine plus azithromycin group (396 [27·6%] of 1433; 1·16, 1·03–1·32; p=0·017). The incidence of serious adverse events was similar in mothers (sulfadoxine–pyrimethamine group 17·7 per 100 person-years, dihydroartemisinin–piperaquine group 14·8 per 100 person-years, and dihydroartemisinin–piperaquine plus azithromycin group 16·9 per 100 person-years) and infants (sulfadoxine–pyrimethamine group 49·2 per 100 person-years, dihydroartemisinin–piperaquine group 42·4 per 100 person-years, and dihydroartemisinin–piperaquine plus azithromycin group 47·8 per 100 person-years) across treatment groups. 12 (0·2%) of 6685 sulfadoxine–pyrimethamine, 19 (0·3%) of 7014 dihydroartemisinin–piperaquine, and 23 (0·3%) of 6849 dihydroartemisinin–piperaquine plus azithromycin treatment courses were vomited within 30 min. Interpretation Monthly IPTp with dihydroartemisinin–piperaquine did not improve pregnancy outcomes, and the addition of a single course of azithromycin did not enhance the effect of monthly IPTp with dihydroartemisinin–piperaquine. Trials that combine sulfadoxine–pyrimethamine and dihydroartemisinin–piperaquine for IPTp should be considered