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Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for malaria prevention in HIV-negative pregnant women, but it is contraindicated in HIV-infected women taking daily cotrimoxazole prophylaxis (CTXp) because of potential added risk of adverse effects associated with taking two antifolate drugs simultaneously. We studied the safety and efficacy of mefloquine (MQ) in women receiving CTXp and long-lasting insecticide treated nets (LLITNs). A total of 1,071 HIV-infected women from Kenya, Mozambique, and Tanzania were randomized to receive either three doses of IPTp-MQ (15 mg/kg) or placebo given at least one month apart; all received CTXp and a LLITN. IPTp-MQ was associated with reduced rates of maternal parasitemia (risk ratio [RR], 0.47 [95% CI 0.27-0.82]; p=0.008), placental malaria (RR, 0.52 [95% CI 0.29-0.90]; p=0.021), and reduced incidence of non-obstetric hospital admissions (RR, 0.59 [95% CI 0.37-0.95]; p=0.031) in the intention to treat (ITT) analysis. There were no differences in the prevalence of adverse pregnancy outcomes between groups. Drug tolerability was poorer in the MQ group compared to the control group (29.6% referred dizziness and 23.9% vomiting after the first IPTp-MQ administration). HIV viral load at delivery was higher in the MQ group compared to the control group (p=0.048) in the ATP analysis. The frequency of perinatal mother to child transmission of HIV was increased in women who received MQ (RR, 1.95 [95% CI 1.14-3.33]; p=0.015). The main limitation of the latter finding relates to the exploratory nature of this part of the analysis. An effective antimalarial added to CTXp and LLITNs in HIV-infected pregnant women can improve malaria prevention, as well as maternal health through reduction in hospital admissions. However, MQ was not well tolerated, limiting its potential for IPTp and indicating the need to find alternatives with better tolerability to reduce malaria in this particularly vulnerable group. MQ was associated with an increased risk of mother to child transmission of HIV, which warrants a better understanding of the pharmacological interactions between antimalarials and antiretroviral drugs. ClinicalTrials.gov NCT 00811421; Pan African Clinical Trials Registry PACTR 2010020001813440 Please see later in the article for the Editors' Summary.

\"Fertility and Pregnancy: An Epidemiologic Perspective offers an overview of human reproduction - how it works, and what causes it to go wrong. Weaving together history, biology, obstetrics, pediatrics, demography, infectious diseases, molecular genetics, and evolutionary biology, Allen Wilcox brings a fresh coherence to the epidemiologic study of reproduction and pregnancy. Along the way, he provides entertaining anecdotes, superb graphs, odd tidbits, and occasional humor that bring the topic to life.\"--BOOK JACKET.

The cornerstone of malaria prevention in pregnancy, intermittent preventive treatment (IPTp) with sulfadoxine–pyrimethamine, is contraindicated in women with HIV who are receiving co-trimoxazole prophylaxis. We assessed whether IPTp with dihydroartemisinin–piperaquine is safe and effective in reducing the risk of malaria infection in women with HIV receiving co-trimoxazole prophylaxis and antiretroviral drugs. For this randomised, double-blind, placebo-controlled clinical trial, women with HIV attending the first antenatal care clinic visit, resident in the study area, and with a gestational age up to 28 weeks were enrolled at five sites in Gabon and Mozambique. Participants were randomly assigned (1:1) to receive either IPTp with dihydroartemisinin–piperaquine at each scheduled antenatal care visit plus daily co-trimoxazole (intervention group) or placebo at each scheduled antenatal care visit plus daily co-trimoxazole (control group). Randomisation was done centrally via block randomisation (block sizes of eight), stratified by country. IPTp was given over 3 days under direct observation by masked study personnel. The number of daily IPTp tablets was based on bodyweight and according to the treatment guidelines set by WHO (target dose of 4 mg/kg per day [range 2–10 mg/kg per day] of dihydroartemisinin and 18 mg/kg per day [range 16–27 mg/kg per day] of piperaquine given once a day for 3 days). At enrolment, all participants received co-trimoxazole (fixed combination drug containing 800 mg trimethoprim and 160 mg sulfamethoxazole) for daily intake. The primary study outcome was prevalence of peripheral parasitaemia detected by microscopy at delivery. The modified intention-to-treat population included all randomly assigned women who had data for the primary outcome. Secondary outcomes included frequency of adverse events, incidence of clinical malaria during pregnancy, and frequency of poor pregnancy outcomes. All study personnel, investigators, outcome assessors, data analysts, and participants were masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT03671109. From Sept 18, 2019, to Nov 26, 2021, 666 women (mean age 28·5 years [SD 6·4]) were enrolled and randomly assigned to the intervention (n=332) and control (n=334) groups. 294 women in the intervention group and 308 women in the control group had peripheral blood samples taken at delivery and were included in the primary analysis. Peripheral parasitaemia at delivery was detected in one (<1%) of 294 women in the intervention group and none of 308 women in the control group. The incidence of clinical malaria during pregnancy was lower in the intervention group than in the control group (one episode in the intervention group vs six in the control group; relative risk [RR] 0·12, 95% CI 0·03–0·52, p=0·045). In a post-hoc analysis, the composite outcome of overall malaria infection (detected by any diagnostic test during pregnancy or delivery) was lower in the intervention group than in the control group (14 [5%] of 311 women vs 31 [10%] of 320 women; RR 0·48, 95% CI 0·27–0·84, p=0·010). The frequency of serious adverse events and poor pregnancy outcomes (such as miscarriages, stillbirths, premature births, and congenital malformations) did not differ between groups. The most frequently reported drug-related adverse events were gastrointestinal disorder (reported in less than 4% of participants) and headache (reported in less than 2% of participants), with no differences between study groups. In the context of low malaria transmission, the addition of IPTp with dihydroartemisinin–piperaquine to co-trimoxazole prophylaxis in pregnant women with HIV did not reduce peripheral parasitaemia at delivery. However, the intervention was safe and associated with a decreased risk of clinical malaria and overall Plasmodium falciparum infection, so it should be considered as a strategy to protect pregnant women with HIV from malaria. European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) and Medicines for Malaria Venture. For the Portuguese and French translations of the abstract see Supplementary Materials section.

Cardiovascular disease complicates 1–4% of pregnancies — with a higher prevalence when including hypertensive disorders — and is the leading cause of maternal death. In women with known cardiovascular pathology, such as congenital heart disease, timely counselling is possible and the outcome is fairly good. By contrast, maternal mortality is high in women with acquired heart disease that presents during pregnancy (such as acute coronary syndrome or aortic dissection). Worryingly, the prevalence of acquired cardiovascular disease during pregnancy is rising as older maternal age, obesity, diabetes mellitus and hypertension become more common in the pregnant population. Management of cardiovascular disease in pregnancy is challenging owing to the unique maternal physiology, characterized by profound changes to multiple organ systems. The presence of the fetus compounds the situation because both the cardiometabolic disease and its management might adversely affect the fetus. Equally, avoiding essential treatment because of potential fetal harm risks a poor outcome for both mother and child. In this Review, we examine how the physiological adaptations during pregnancy can provoke cardiometabolic complications or exacerbate existing cardiometabolic disease and, conversely, how cardiometabolic disease can compromise the adaptations to pregnancy and their intended purpose: the development and growth of the fetus.In this Review, Roos-Hesselink and colleagues describe how the physiological adaptations during pregnancy can induce cardiometabolic complications or an exacerbation of existing cardiometabolic disease, and discuss the epidemiology, pathophysiology, diagnosis and management of cardiometabolic diseases acquired or presenting during pregnancy, including hypertensive disorders, gestational diabetes mellitus, thromboembolic disorders and peripartum cardiomyopathy.

The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death. In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit. A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P = 0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events. Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.).

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. 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. 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. 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. European & Developing Countries Clinical Trials Partnership 2, supported by the EU, and the UK Joint-Global-Health-Trials-Scheme of the Foreign, Commonwealth and Development Office, Medical Research Council, Department of Health and Social Care, Wellcome, and the Bill-&-Melinda-Gates-Foundation.