Association of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection With Maternal Mortality and Neonatal Birth Outcomes in Botswana by Human Immunodeficiency Virus Status.

OBJECTIVE: To evaluate the combined association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) infection on adverse birth outcomes in an HIV-endemic region. METHODS: The Tsepamo Study abstracts data from antenatal and obstetric records in government maternity wards across Botswana. We assessed maternal mortality and adverse birth outcomes for all singleton pregnancies from September 2020 to mid-November 2021 at 13 Tsepamo sites among individuals with documented SARS-CoV-2 screening tests and known HIV status. RESULTS: Of 20,410 individuals who gave birth, 11,483 (56.3%) were screened for SARS-CoV-2 infection; 4.7% tested positive. People living with HIV were more likely to test positive (144/2,421, 5.9%) than those without HIV (392/9,030, 4.3%) (P=.001). Maternal deaths occurred in 3.7% of those who had a positive SARS-CoV-2 test result compared with 0.1% of those who tested negative (adjusted relative risk [aRR] 31.6, 95% CI 15.4-64.7). Maternal mortality did not differ by HIV status. The offspring of individuals with SARS-CoV-2 infection experienced more overall adverse birth outcomes (34.5% vs 26.6%; aRR 1.2, 95% CI 1.1-1.4), severe adverse birth outcomes (13.6% vs 9.8%; aRR 1.2, 95% CI 1.0-1.5), preterm delivery (21.4% vs 13.4%; aRR 1.4, 95% CI 1.2-1.7), and stillbirth (5.6% vs 2.7%; aRR 1.7 95% CI 1.2-2.5). Neonates exposed to SARS-CoV-2 and HIV infection had the highest prevalence of adverse birth outcomes (43.1% vs 22.6%; aRR 1.7, 95% CI 1.4-2.0). CONCLUSION: Infection with SARS-CoV-2 at the time of delivery was associated with 3.7% maternal mortality and 5.6% stillbirth in Botswana. Most adverse birth outcomes were worse among neonates exposed to both SARS-CoV-2 and HIV infection.

Impact of prophylactic antimalarials in pregnant women living with Human Immunodeficiency Virus on birth outcomes in Botswana.

OBJECTIVES: Until late 2015, Botswana recommended preventive treatment for pregnant women in malarial regions with chloroquine and proguanil (CP). The guideline change provided an opportunity to evaluate CP and adverse birth outcomes. METHODS: The Tsepamo Study performed birth outcomes surveillance at large delivery centres throughout Botswana. We evaluated adverse birth outcomes from 2015 to 2017 at three hospitals where 93% of CP use was recorded. Outcomes included neonatal death (NND), small for gestational age (SGA), very SGA, stillbirth (SB), preterm delivery (PTD) and very PTD. Logistic regression analysis (unadjusted and adjusted) was conducted for each adverse birth outcome. RESULTS: During the study period, 5883 (26%) of 23,033 deliveries were exposed to CP, with the majority (65%) in the most malaria-endemic region. At this site, there was a trend or an association between CP use and reduction of three adverse birth outcomes: PTD (aOR 0.85, 95% CI 0.76-0.96), vPTD (aOR 0.83, 95% CI 0.68-1.01) and NND (aOR 0.65, 95% CI 0.42-1.00). However, at the least malaria-endemic site, the association was in the opposite direction for SB (aOR 1.54, 95% CI 1.08-2.22), SGA (aOR 1.24, 95% CI 1.06-1.44) and vSGA (aOR 1.42, 95% CI 1.14-1.77). The association between CP and reduced PTD was present among women without HIV (aOR 0.77, 95% CI 0.67-0.89) but not among women with HIV (aOR 1.09, 95% CI 0.78-1.35). CONCLUSIONS: Antimalarial prophylaxis was associated with improved birth outcomes in the most malaria-endemic region of Botswana, but not elsewhere. This finding supports current WHO guidance to use prophylaxis strategies among pregnant women in highly malaria-endemic regions. Further studies of the risks and benefits of specific antimalarial regimens in pregnancy are warranted, particularly in areas with lower incidence of malaria.

Iron, folic acid, and multiple micronutrient supplementation strategies during pregnancy and adverse birth outcomes in Botswana.

BACKGROUND: Antenatal multiple micronutrient supplementation (MMS) with iron, folic acid, and other micronutrients might improve birth outcomes, but it is not currently universally recommended by WHO. METHODS: In this observational cohort study, we surveyed pregnancies for adverse birth outcomes at eight hospitals from July, 2014, to July, 2018, and 18 hospitals from August, 2018, to December, 2020, in Botswana to assess four routine supplementation strategies in women presenting before 24 weeks' gestation: folic acid only, iron only, iron and folic acid supplementation (IFAS), and MMS. Women with singleton pregnancies; a known HIV status, age, and delivery site; haemoglobin measured within 7 days of presenting to antenatal care; and weight measured within 31 days of presenting to care were included in our analysis. Data were abstracted from the maternity obstetric record (a record of antenatal care) at the time of birth from all women giving birth at selected hospitals throughout the country. We estimated risk differences overall and in key subgroups, adjusting for demographic and clinical factors. FINDINGS: Between July 6, 2014, and Dec 8, 2020, 96 341 eligible women (21 659 [22·5%] of whom had HIV) were included in the study. 36 334 (37·7%) women initiated iron only supplementation, 1133 (11·8%) initiated folic acid only supplementation, 23 101 (24·0%) initiated IFAS, and 31 588 (32·8%) women initiated MMS. Women who initiated iron only and folic acid only supplementation had higher risks of stillbirth, preterm birth, very preterm birth, low and very low birthweight, and neonatal death compared with women who received IFAS (adjusted risk differences for iron only supplementation vs IFAS ranged from 0·22% [95% CI 0·04 to 0·40] for neonatal death to 2·39% [1·78 to 3·00] for preterm birth; and adjusted risk differences for folic acid only supplementation vs IFAS ranged from 0·77% [-0·80 to 2·34] for neonatal death to 5·75% [1·38 to 10·13] for preterm birth), with greater difference in women with HIV and those aged 35 years and older. Compared with IFAS, women who initiated MMS had lower risks of preterm and very preterm births, and low and very low birthweight (adjusted risk differences ranged from -0·50% [-0·77 to 0·23] for very preterm birth to -1·06% [-1·69 to -0·42] for preterm birth). INTERPRETATION: Nationwide data from Botswana support improved birth outcomes with MMS compared with IFAS. FUNDING: National Institutes of Health, National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases.

Limited surface examination to evaluate potential teratogens in a resource-limited setting.

BACKGROUND: To determine the frequency of malformations that would be identified in the limited surface examination of a newborn by the delivering nurse midwife in a resource-limited setting. METHODS: The limited surface examination will identify visible external anomalies, but not abnormalities inside the mouth, most heart defects, undescended testes, inguinal hernias, hip dysplasia, peripheral vascular anomalies, and some internal anomalies. The findings in a malformations surveillance program, involving 289,365 births in Boston, have been used to establish the prevalence rate of malformations that would be identified and not identified. In African countries, the number of anomalies to be identified should also be reduced by excluding polydactyly, postaxial, type B, a common minor finding, from the list of potential malformations. RESULTS: Of note, 2.05% (n = 5,941) of the 289,365 births surveyed had one or more malformations. The abnormalities that would have been missed, using surface exam alone, accounted for 0.5% of all of malformations identified and reduced the overall prevalence rate of malformations to 1.5%. In addition, excluding all infants with isolated postaxial polydactyly, type B reduced the expected prevalence rate of malformations to 1.3% in unexposed newborn infants. CONCLUSION: A limited surface examination can detect the majority of malformations among newborn infants.

Maternal anemia and preterm birth among women living with HIV in the United States.

BACKGROUND: Women living with HIV (WLHIV) have a higher prevalence of anemia than women without HIV, possibly related to the effects of HIV and antiretroviral medications. OBJECTIVES: To estimate the prevalence of anemia in the third trimester of pregnancy and the effect of anemia on preterm births in WLHIV in the longitudinal, US-based Pediatric HIV/AIDS Cohort Study (PHACS). METHODS: During the third trimester, we obtained up to three 24-hour dietary recalls to estimate daily intakes of nutrients and measured serum concentrations of iron, vitamin B6, vitamin B12, zinc, folate, ferritin, total iron-binding capacity (TIBC), and high sensitivity C-reactive protein. Third trimester anemia was defined as hemoglobin < 11 g/d and iron-deficiency anemia (IDA) was defined as low ferritin, high TIBC, and low transferrin saturation. A preterm birth was defined as birth at < 37 completed weeks of gestation, regardless of etiology. We fit separate modified Poisson regression models for each outcome (anemia, preterm birth) and each main exposure, adjusted for confounders, and report adjusted prevalence ratios (aPR) and 95% CIs. RESULTS: Of the 267 WLHIV, 50% were anemic in the third trimester, of whom 43.5% (n = 57/131) had IDA. On average, women with anemia were younger, were more likely to be black, started antiretroviral medications in the second trimester, had a low CD4 count (<200 cells/mm3) early in pregnancy, and were less likely to meet recommended intakes for iron, B6, and folate. The prevalence of anemia was greater in WLHIV with a low CD4 count (aPR = 1.65; 95% CI: 1.20-2.27) and high HIV viral load (>10,000 copies/mL; aPR = 1.38; 95% CI: 1.02-1.87). In total, 16% of women delivered preterm. Anemia was associated with a 2-fold (aPR = 2.04; 95% CI: 1.12-3.71) higher prevalence of preterm births. CONCLUSIONS: Anemia is common in pregnant WLHIV, highlighting the need to address the underlying factors and clinical outcomes of anemia in this population.

Compassionate Use of Remdesivir in Pregnant Women With Severe Coronavirus Disease 2019.

BACKGROUND: Remdesivir is efficacious for severe coronavirus disease 2019 (COVID-19) in adults, but data in pregnant women are limited. We describe outcomes in the first 86 pregnant women with severe COVID-19 who were treated with remdesivir. METHODS: The reported data span 21 March to 16 June 2020 for hospitalized pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection and room air oxygen saturation ≤94% whose clinicians requested remdesivir through the compassionate use program. The intended remdesivir treatment course was 10 days (200 mg on day 1, followed by 100 mg for days 2-10, given intravenously). RESULTS: Nineteen of 86 women delivered before their first dose and were reclassified as immediate "postpartum" (median postpartum day 1 [range, 0-3]). At baseline, 40% of pregnant women (median gestational age, 28 weeks) required invasive ventilation, in contrast to 95% of postpartum women (median gestational age at delivery 30 weeks). By day 28 of follow-up, the level of oxygen requirement decreased in 96% and 89% of pregnant and postpartum women, respectively. Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. Remdesivir was well tolerated, with a low incidence of serious adverse events (AEs) (16%). Most AEs were related to pregnancy and underlying disease; most laboratory abnormalities were grade 1 or 2. There was 1 maternal death attributed to underlying disease and no neonatal deaths. CONCLUSIONS: Among 86 pregnant and postpartum women with severe COVID-19 who received compassionate-use remdesivir, recovery rates were high, with a low rate of serious AEs.

Adverse Birth Outcomes in Botswana Among Women With Vertically or Horizontally Acquired Human Immunodeficiency Virus.

BACKGROUND: Women with vertically acquired HIV (VHIV) may have a greater risk of adverse birth outcomes than women with horizontally acquired HIV (HHIV). METHODS: The Tsepamo study performed birth outcomes surveillance at 8 government delivery sites in Botswana from July 2014 through March 2019. Pregnant women diagnosed with HIV before their 11th birthday received VHIV status, and other women had HHIV. Small for gestational age (SGA), preterm delivery (PTD), stillbirth, and neonatal death were compared using χ2 and Fisher's exact tests. Log-binomial regression models determined risk ratios (RRs). RESULTS: VHIV women (n = 402) aged 15-27 years were identified over 4 years of surveillance and compared with HHIV women (n = 8465) of the same age. VHIV women were more likely to use nevirapine (NVP)-based antiretroviral treatment (ART) in pregnancy and to have SGA and very SGA infants, but less likely to have very PTD infants. In unadjusted analyses, VHIV women had a higher risk of any adverse birth outcome combined (RR = 1.21, 95% confidence interval [CI], 1.08-1.36). After adjusting for potential confounders, particularly use of NVP-based regimens, the risk of adverse birth outcomes among VHIV and HHIV women was similar. CONCLUSIONS: NVP-based ART is a primary and modifiable risk factor for adverse birth outcomes. Updating ART regimens could improve birth outcomes for women with HIV.

Mid-trimester cervical length not associated with HIV status among pregnant women in Botswana.

OBJECTIVE: HIV-infected women on antiretroviral therapy have a higher risk of preterm birth than HIV-uninfected women in Botswana. To better understand the mechanism for preterm birth among HIV-infected women, we evaluated whether mid-trimester cervical length differed by HIV status as cervical shortening is associated with an increased risk for preterm birth. METHODS: We conducted a prospective cohort study among pregnant women receiving care at the Scottish Livingstone Hospital in Molepolole, Botswana. Consecutive women referred for routine obstetrical ultrasound were consented and enrolled if between 22w0d and 24w6d by ultrasound biometry. Blinded to maternal HIV status, an obstetrician measured transvaginal cervical length using standardized criteria. Cervical length, as well as the proportion of women with a short cervix (<25mm), were compared among HIV-infected and HIV-uninfected women. The acceptability of transvaginal ultrasound was also evaluated. RESULTS: Between April 2016 and April 2017, 853 women presenting for obstetric ultrasound were screened, 187 (22%) met eligibility criteria, and 179 (96%) were enrolled. Of those enrolled, 50 (28%) were HIV-infected (86% on antiretroviral therapy), 127 (71%) were HIV-uninfected, and 2 (1%) had unknown HIV status. There was no significant difference in mean cervical length between HIV-infected and HIV-uninfected women (32mm vs 31mm, p = 0.21), or in the proportion with a short cervix (10% vs 14%, p = 0.44). Acceptability data was available for 115 women who underwent a transvaginal ultrasound exam. Of these, 112 of 115 (97%) women deemed the transvaginal scan acceptable. CONCLUSIONS: The increased risk of preterm birth observed among HIV-infected women receiving antiretroviral therapy in Botswana is unlikely associated with mid-trimester cervical shortening. Further research is needed to understand the underlying mechanism for preterm birth among HIV-infected women.

Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana.

BACKGROUND: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies. METHODS: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals. RESULTS: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87). CONCLUSIONS: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.).

The aetiology of diarrhoea, pneumonia and respiratory colonization of HIV-exposed infants randomized to breast- or formula-feeding.

BACKGROUND: Diarrhoea and pneumonia are common causes of childhood death in sub-Saharan Africa but there are few studies describing specific pathogens. OBJECTIVES: The study aimed to describe the pathogens associated with diarrhoea, pneumonia and oropharyngeal colonization in children born to HIV-infected women (HIV-exposed infants). METHODS: The Mashi Study randomized 1200 HIV-infected women and their infants to breastfeed for 6 months with ZDV prophylaxis or formula-feed with 4 weeks of ZDV. Children were tested for HIV by PCR at 1, 4, 7, 9 and 12 months and by ELISA at 18 months. Pre-defined subsets of children were sampled during episodes of diarrhoea (n = 300) and pneumonia (n = 85). Stool was tested for bacterial pathogens, rotavirus and parasites. Children with pneumonia underwent bacterial blood culture, and testing of nasopharyngeal aspirates for viral pathogens by PCR. Oropharyngeal swabs were collected from a consecutive subset of 561 infants at the routine 3-month visit for bacterial culture. RESULTS: The median age (range) at sampling was 181 days for diarrhoea (0-730) and 140 days for pneumonia (2-551). Pathogens were identified in 55 (18%) children with diarrhoea and 32 (38%) with pneumonia. No differences in pathogens by child HIV status (HIV-infected vs HIV-uninfected) or feeding strategy were identified. Campylobacter was the most common diarrhoeal pathogen (7%). Adenovirus (22%) and other viruses (19%) were the primary pathogens isolated during pneumonias. More formula-fed infants had oropharyngeal colonization by pathogenic Gram-negative bacteria (16.8% vs 6.2%, P = 0.003), which was associated with a non-significant increased risk of pneumonia (OR 2.2, 95% CI 0.8-5.7). CONCLUSION: A trend toward oropharyngeal bacterial colonization was observed in formula-fed infants. Although viruses were most commonly detected during pneumonia, respiratory colonization by Gram-negative bacteria may have contributed to pneumonia in formula-fed infants.