Veronica Ades

Impact of Sulfadoxine-Pyrimethamine Resistance on Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy at Clearing Infections and Preventing Low Birth Weight

BACKGROUND Owing to increasing sulfadoxine-pyrimethamine (SP) resistance in sub-Saharan Africa, monitoring the effectiveness of intermittent preventive therapy in pregnancy (IPTp) with SP is crucial. METHODS Between 2009 and 2013, both the efficacy of IPTp-SP at clearing existing peripheral malaria infections and the effectiveness of IPTp-SP at reducing low birth weight (LBW) were assessed among human immunodeficiency virus-uninfected participants in 8 sites in 6 countries. Sites were classified as high, medium, or low resistance after measuring parasite mutations conferring SP resistance. An individual-level prospective pooled analysis was conducted. RESULTS Among 1222 parasitemic pregnant women, overall polymerase chain reaction-uncorrected and -corrected failure rates by day 42 were 21.3% and 10.0%, respectively (39.7% and 21.1% in high-resistance areas; 4.9% and 1.1% in low-resistance areas). Median time to recurrence decreased with increasing prevalence of Pfdhps-K540E. Among 6099 women at delivery, IPTp-SP was associated with a 22% reduction in the risk of LBW (prevalence ratio [PR], 0.78; 95% confidence interval [CI], .69-.88; P < .001). This association was not modified by insecticide-treated net use or gravidity, and remained significant in areas with high SP resistance (PR, 0.81; 95% CI, .67-.97; P = .02). CONCLUSIONS The efficacy of SP to clear peripheral parasites and prevent new infections during pregnancy is compromised in areas with >90% prevalence of Pfdhps-K540E. Nevertheless, in these high-resistance areas, IPTp-SP use remains associated with increases in birth weight and maternal hemoglobin. The effectiveness of IPTp in eastern and southern Africa is threatened by further increases in SP resistance and reinforces the need to evaluate alternative drugs and strategies for the control of malaria in pregnancy.

Maternal nutritional status predicts adverse birth outcomes among HIV-infected rural Ugandan women receiving combination antiretroviral therapy.

Objective Maternal nutritional status is an important predictor of birth outcomes, yet little is known about the nutritional status of HIV-infected pregnant women treated with combination antiretroviral therapy (cART). We therefore examined the relationship between maternal BMI at study enrollment, gestational weight gain (GWG), and hemoglobin concentration (Hb) among 166 women initiating cART in rural Uganda. Design Prospective cohort. Methods HIV-infected, ART-naïve pregnant women were enrolled between 12 and 28 weeks gestation and treated with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor-based combination regimen. Nutritional status was assessed monthly. Neonatal anthropometry was examined at birth. Outcomes were evaluated using multivariate analysis. Results Mean GWG was 0.17 kg/week, 14.6% of women experienced weight loss during pregnancy, and 44.9% were anemic. Adverse fetal outcomes included low birth weight (LBW) (19.6%), preterm delivery (17.7%), fetal death (3.9%), stunting (21.1%), small-for-gestational age (15.1%), and head-sparing growth restriction (26%). No infants were HIV-infected. Gaining <0.1 kg/week was associated with LBW, preterm delivery, and a composite adverse obstetric/fetal outcome. Maternal weight at 7 months gestation predicted LBW. For each g/dL higher mean Hb, the odds of small-for-gestational age decreased by 52%. Conclusions In our cohort of HIV-infected women initiating cART during pregnancy, grossly inadequate GWG was common. Infants whose mothers gained <0.1 kg/week were at increased risk for LBW, preterm delivery, and composite adverse birth outcomes. cART by itself may not be sufficient for decreasing the burden of adverse birth outcomes among HIV-infected women. Trial Registration Clinicaltrials.gov NCT00993031

Intermittent Preventive Therapy with Sulfadoxine-Pyrimethamine for Malaria in Pregnancy: A Cross-Sectional Study from Tororo, Uganda

Background Intermittent preventive treatment during pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is widely recommended in sub-Saharan Africa to reduce the risk of malaria and improve birth outcomes. However, there are reports that the efficacy of IPTp with SP is waning, especially in parts of Africa where antimalarial resistance to this drug has become widespread. Methodology/Principal Findings We conducted a cross-sectional study of 565 HIV-uninfected women giving birth at Tororo District Hospital in southeastern Uganda. The primary objective of the study was to measure associations between use of SP during pregnancy from antenatal records and the risk of adverse outcomes including placental malaria, low birth weight, maternal parasitemia and maternal anemia. The proportion of women who reported taking 0, 1, 2, and 3 doses of SP during pregnancy was 5.7%, 35.8%, 56.6% and 2.0% respectively. Overall, the prevalence of placental malaria was 17.5%, 28.1%, and 66.2% by placental smear, PCR, and histopathology, respectively. In multivariate analyses controlling for potential confounders, ≥2 doses of SP was associated with non-significant trends towards lower odds of placental malaria by placental smear (OR = 0.75, p = 0.25), placental malaria by PCR (OR = 0.93, p = 0.71), placental malaria by histopathology (OR = 0.75, p = 0.16), low birth weight (OR = 0.63, p = 0.11), maternal parasitemia (OR = 0.88, p = 0.60) and maternal anemia (OR = 0.88, p = 0.48). Using a composite outcome, ≥2doses of SP was associated with a significantly lower odds of placental malaria, low birth weight, maternal parasitemia, or maternal anemia (OR = 0.52, p = 0.01). Conclusions/Significance In this area of Uganda with intense malaria transmission, the prevalence of placental malaria by histopathology was high even among women who reported taking at least 2 doses of SP during pregnancy. The reported use of ≥2 doses of SP was not associated with protection against individual birth and maternal outcome measures but did protect against a composite measure of any adverse outcome.

Lopinavir/Ritonavir-Based Antiretroviral Treatment (ART) Versus Efavirenz-Based ART for the Prevention of Malaria Among HIV-Infected Pregnant Women

BACKGROUND Human immunodeficiency virus (HIV)-infected pregnant women are at increased risk of malaria and its complications. In vitro and in vivo data suggest that the HIV protease inhibitors lopinavir/ritonavir may have potent antimalarial activity. We sought to evaluate whether lopinavir/ritonavir-based antiretroviral therapy (ART) reduced the risk of placental malaria. METHODS HIV-infected, ART-naive pregnant women were enrolled between gestational weeks 12 and 28 and randomly assigned to receive lopinavir/ritonavir-based or efavirenz-based ART. Women received daily trimethoprim-sulfamethoxazole prophylaxis and insecticide-treated bed nets at enrollment and were followed up to 1 year after delivery. The primary outcome was placental malaria, defined by the detection of malaria parasites, using microscopy or polymerase chain reaction (PCR) analysis of placental blood specimens. Secondary outcomes included placental malaria, defined by histopathologic results; adverse birth outcomes; incidence of malaria; and prevalence of asymptomatic parasitemia. Analyses were done using an intention-to-treat approach. RESULTS Of 389 subjects randomly assigned to a treatment group, 377 were followed through to delivery. There was no significant difference in the risk of placental malaria, as defined by thick smear or PCR findings, between the lopinavir/ritonavir-based and efavirenz-based ART arms (7.4% vs 9.8%; P = .45). Similarly, there were no differences in secondary outcomes between the 2 treatment arms. CONCLUSIONS Lopinavir/ritonavir-based ART did not reduce the risk of placental or maternal malaria or improve birth outcomes, compared with efavirenz-based ART. CLINICAL TRIALS REGISTRATION NCT00993031.

Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy.

Background:Protease inhibitor–based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART. Methods:This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12–28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim–sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression. Results:Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth. Conclusions:LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

Efficacy and Safety of Lopinavir/ritonavir- versus Efavirenz-based Antiretroviral Therapy in HIV-Infected Pregnant Ugandan Women

Objective:Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4+ cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda. Design:Randomized clinical trial. Methods:We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ⩽400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduce placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naive pregnant women at 12–28 weeks gestation and any CD4+ cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum. Results:The median age of the 389 study participants was 29 years; median CD4+ cell count was 370 cells/&mgr;l. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P < 0.001). At 48 weeks postpartum, 91.0% of women on efavirenz and 88.4% on lopinavir/ritonavir had viral suppression (P = 0.49). Grade 1 or 2 gastrointestinal adverse events were higher among women on lopinavir/ritonavir versus efavirenz. Only two infants acquired HIV (both in the lopinavir/ritonavir arm), and HIV-free infant survival was similar between study arms: 92.9% (lopinavir/ritonavir) versus 97.2% (efavirenz) (P = 0.10). Conclusion:Virologic suppression at delivery was higher with an efavirenz versus lopinavir/ritonavir-based regimen. However, women in both arms achieved high levels of virologic suppression through 1 year postpartum and the risk of transmission to infants was low.

Safety, pharmacokinetics and efficacy of artemisinins in pregnancy

Malaria in pregnancy can lead to serious maternal and fetal morbidity and mortality. Access to the most effective antimalarials in pregnancy is essential. Resistance to current therapies is high for all antimalarial therapies except artemisinins. Artemisinin-based combination therapy is current the first line of malaria treatment recommended by the WHO for children, adults and pregnant women in second or third trimester. Due to potential embryotoxicity of artemisinins identified in animal studies, artemisinins are not considered safe for use in first trimester of pregnancy. Artemisinins are more rapidly metabolized in pregnant women, but it is not clear whether this reduces efficacy. Most studies show very high cure rates for pregnant women. Areas for further research include the safety profile in first trimester of pregnancy, the effect of HIV infection on artemisinin use in pregnancy, the relationship between the pharmacokinetic profile and efficacy, the effect of newly emerging artemisinin resistance on treatment in pregnancy and the use of artemisinin-based combination therapy for intermittent preventive treatment in pregnancy.

Neonatal mortality in HIV-exposed infants born to women receiving combination antiretroviral therapy in Rural Uganda.

As human immunodeficiency virus (HIV)-infected women gain access to combination antiretroviral therapy throughout sub-Saharan Africa, a growing number of infants are being born HIV-exposed but uninfected. Data about neonatal mortality and the impact of premature delivery, in this population are limited. We describe the 28-day mortality outcomes in a cohort of HIV-exposed infants who had ultrasound-confirmed gestational age in rural Uganda. There were 13 deaths among 351 infants, including 9 deaths in the perinatal period. Premature delivery was a strong predictor of mortality. The prevention of HIV transmission to infants is now possible in rural low-resource settings but the frequency of neonatal death among HIV-exposed infants remains extremely high, calling for new comprehensive interventions to reduce mortality in this growing population.

Empowering women to control post-partum haemorrhage

www.thelancet.com Vol 375 February 6, 2010 459 misoprostol use in Nepal and Indonesia. Estimates for the effi cacy of both oxytocin and misoprostol in preventing haemor rhage were taken from a meta-analysis (fewer deaths are consequently predicted due to the link between haemorrhage and death). Ronsmans and Huang also suggest that we overestimate deaths from postpartum haemorrhage and sepsis. But the data they cite concerns all Africa and not sub-Saharan Africa, where incidence and case-fatality rates are probably higher (see page 8 of our webappendix). Further, Seale and colleagues have argued that maternal sepsis in sub-Saharan Africa is grossly underestimated. Yusuf Ahmed and colleagues correct ly point out that many maternal deaths in sub-Saharan Africa are from infectious diseases other than genital tract infections—eg, malaria, tuberculosis, or other HIV-related disorders; these diseases are indeed a considerable burden on maternal health. We would like to clarify that our estimates relating to infection pertain only to puerperal sepsis, defi ned by WHO as “infection of the genital tract” in the 42 days after birth. Our estimates for both the incidence and case fatality of puerperal sepsis are derived from WHO estimates for sub-Saharan Africa (see pages 10–11 of our webappendix), and not from estimates of puerperal infection, which would include malaria and other infectious diseases. Thus the estimated eff ect of oral antibiotics in pre venting deaths from puerperal sepsis does not assume any eff ect on other infectious diseases. As discussed briefl y in the conclusion of our paper, the mathematical model could be adapted to consider maternal deaths from other causes; the limiting factor is the availability of evidence to use in estimating plausible values of the model parameters. We agree with Braunholtz and colleagues that legitimate questions remain about the feasibility of sustainable community interventions; this is precisely why we advocated the careful evaluation of such strategies and why we welcome Metin Gülmezoglu and João Paulo Souza’s response. Braunholtz and colleagues commend our openness. We encourage others who use our model to make the parameter estimates used and the reasoning behind these choices publicly available when presenting fi ndings. A dedicated webpage has been constructed on which to publish such material. In addition to its primary function, our model provides a framework for exploring the policy implications of uncertainty in incidence and case fatality rates, achievable coverage of com munity interventions, and plausible increases in health-facility delivery. Given the unquestioned importance of reducing maternal mortality, but diff ering opinions as to how, open and rational debate is not just welcome but urgently required.

On Female Genital Cutting: Factors to be Considered When Confronted With a Request to Re-infibulate

According to the World Health Organization, female genital cutting affects millions of girls and women worldwide, particularly on the African continent and in the Middle East. This paper presents a plausible, albeit hypothetical, clinical vignette and then explores the legal landscape as well as the ethical landscape physicians should use to evaluate the adult patient who requests re-infibulation. The principles of non-maleficence, beneficence, justice, and autonomy are considered for guidance, and physician conscientious objection to this procedure is discussed as well. Analyses of law and predominant principles of bioethics fail to yield a clear answer regarding performing female genital cutting or re-infibulation on an adult in the United States. Physicians should consider the patient’s physical, mental, and social health when thinking about female genital cutting and should understand the deep-rooted cultural significance of the practice.