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

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