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In 1967, two toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (FIRSV) in the United States died from enhanced RSV disease (ERD), a severe form of illness resulting from aberrant priming of the antiviral immune response during vaccination. Up to 80% of immunized children subsequently exposed to wild-type virus were hospitalized. These events hampered RSV vaccine development for decades. Here, we provide a characterization of the clinical, immunopathological, and transcriptional signature of fatal human ERD, outlining evidence for safety evaluation of RSV vaccines and a framework for understanding disease enhancement for pathogens in general.

Background: Severity of human metapneumovirus (hMPV) lower respiratory illness (LRTI) is considered similar to that observed for respiratory syncytial virus (RSV). However, differences in severity between these pathogens have been noted, suggesting the degree of illness may vary in different populations. Moreover, a potential association between hMPV and asthma also suggests that hMPV may preferentially affect asthmatic subjects., Methods: In a population-based surveillance study in children aged <2 years admitted for severe LRTI in Argentina, nasopharyngeal aspirates were tested by RT-PCR for hMPV, RSV, influenza A, and human rhinovirus., Results: Of 3947 children, 383 (10%) were infected with hMPV. The hospitalization rate for hMPV LRTI was 2.26 per 1000 children (95% confidence interval [CI], 2.04-2.49). Thirty-nine (10.2%) patients infected with hMPV experienced life-threatening disease (LTD; 0.23 per 1000 children; 95% CI, .16-.31/1000), and 2 died (mortality rate 0.024 per 1000; 95% CI, .003-.086). In hMPV-infected children birth to an asthmatic mother was an increased risk for LTD (odds ratio, 4.72; 95% CI, 1.39-16.01). We observed a specific interaction between maternal asthma and hMPV infection affecting risk for LTD., Conclusions: Maternal asthma increases the risk for LTD in children <2 years old hospitalized for severe hMPV LRTI., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness., Methods: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible., Results: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed., Conclusions: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Efforts to better understand the risk factors associated with respiratory failure (RF) and fatal lower respiratory tract infection (LRTI) in premature children in developing countries are necessary to elaborate evidenced-based preventive interventions. We aim to characterize the burden of respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) LRTI in premature children and determine risk factors for RF and fatal illness in a vulnerable population., Methods: This is a prospective, population-based, cross-sectional study. Subjects with severe LRTI were enrolled during respiratory season. Risk factors for RF and death in premature infants were investigated., Results: A total of 664 premature children participated. Infant's hospitalization rate due to LRTI was 82.6/1000 (95% confidence interval [CI], 68.6-96.7/1000). Infant's RSV and hMPV rates were 40.9/1000 (95% CI, 36.3-45.6/1000) and 6.6/1000 (95% CI, 3.9-9.2/1000), respectively. The RF rate was 8.2/1000 (95% CI, 4.9-11.5/1000). The LRTI mortality was 2.2/1000 (95% CI, 0.7-3.7/1000); for RSV, the rate was 0.8/1000 (95% CI, 0-1.7/1000) with a case-fatality ratio of 1.8%. Never breastfeeding, malnutrition, younger than 6 months, congenital heart disease, and lower hematocrit were risk factors for RF. Experiencing pneumonia, pneumothorax, sepsis, or apnea were clinical determinants of poor outcomes., Conclusions: Premature children under 2 years old in vulnerable environments experience RF and death more often than term counterparts. Modifiable risk factors associated with poor outcomes should prompt evidence-based interventions., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Retrospective observational studies suggest that transmission of Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for preconceptional treatment to reduce parasitic load. The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300 mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. A short and low dose BZN treatment might reduce major side effects and increase compliance, but its efficacy to reduce T. cruzi parasitic load compared to the standard 60d/300 mg course is not yet established. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed., Methods and Design: We are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150 mg/day (30d/150 mg) vs. BZN 60d/300 mg. We will recruit not previously treated T. cruzi seropositive women with a live birth during the postpartum period in Argentina, randomize them at 6 months postpartum, and follow them up with the following specific aims: Specific aim 1: to measure the effect of BZN 30d/150 mg compared to 60d/300 mg preconceptional treatment on parasitic load measured by the frequency of positive Polymerase Chain Reaction (PCR) (primary outcome) and by real-time quantitative PCR (qPCR), immediately and 10 months after treatment. Specific aim 2: to measure the frequency of serious adverse events and/or any adverse event leading to treatment interruption., Trial Registration: ClinicalTrials.gov . Identifier: NCT03672487 . Registered 14 September 2018.

Background: Despite international recommendations, coverage of syphilis testing in pregnant women and treatment of those found seropositive remains limited in sub-Saharan Africa. We assessed whether combining the provision of supplies with a behavioural intervention was more effective than providing supplies only, to improve syphilis screening and treatment during antenatal care., Methods: In this 18-month, cluster randomised controlled trial, we randomly assigned (1:1) 26 urban antenatal care clinics in Kinshasa, Democratic Republic of the Congo, and Lusaka, Zambia, to receive a behavioural intervention (opinion leader selection, academic detailing visits, reminders, audits and feedback, and supportive supervision) plus supplies for syphilis testing and treatment (intervention group) or to receive supplies only (control group). The primary outcomes were proportion of pregnant women who had syphilis screening out of the total who attended the clinic; and the proportion of women who had treatment with benzathine benzylpenicillin out of those who tested positive for syphilis at their first antenatal care visit. This trial is registered at ClinicalTrials.gov, number NCT02353117., Findings: The 18-month study period was Feb 1, 2016, to July 14, 2017. 18 357 women were enrolled at the 13 intervention clinics and 17 679 women were enrolled at the 13 control clinics at their first antenatal care visit. Syphilis screening was done in a median of 99·9% (IQR 99·0-100·0) of women in the intervention clinics and 93·8% (85·0-98·9) in the control clinics (absolute difference 6·1% [95% CI 1·1-14·1]; p=0·00092). Syphilis treatment at the first visit was done in a median of 100% (IQR 99·7-100·0) of seropositive women in intervention clinics and 43·2% (2·6-83·2) of seropositive women in control clinics (absolute difference 56·8% [12·8-99·0]; p=0·0028)., Interpretation: A behavioural intervention, together with the provision of supplies, can lead to more than 95% of women being screened and treated for syphilis. The sole provision of supplies is sufficient to reach such levels of screening coverage but is not sufficient to ensure high levels of treatment., Funding: Bill & Melinda Gates Foundation., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Reducing deaths from hypertensive disorders of pregnancy is a global priority. Low dietary calcium might account for the high prevalence of pre-eclampsia and eclampsia in low-income countries. Calcium supplementation in the second half of pregnancy is known to reduce the serious consequences of pre-eclampsia; however, the effect of calcium supplementation during placentation is not known. We aimed to test the hypothesis that calcium supplementation before and in early pregnancy (up to 20 weeks' gestation) prevents the development of pre-eclampsia METHODS: We did a multicountry, parallel arm, double-blind, randomised, placebo-controlled trial in South Africa, Zimbabwe, and Argentina. Participants with previous pre-eclampsia and eclampsia received 500 mg calcium or placebo daily from enrolment prepregnancy until 20 weeks' gestation. Participants were parous women whose most recent pregnancy had been complicated by pre-eclampsia or eclampsia and who were intending to become pregnant. All participants received unblinded calcium 1·5 g daily after 20 weeks' gestation. The allocation sequence (1:1 ratio) used computer-generated random numbers in balanced blocks of variable size. The primary outcome was pre-eclampsia, defined as gestational hypertension and proteinuria. The trial is registered with the Pan-African Clinical Trials Registry, number PACTR201105000267371. The trial closed on Oct 31, 2017., Findings: Between July 12, 2011, and Sept 8, 2016, we randomly allocated 1355 women to receive calcium or placebo; 331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant, and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks' gestation. Pre-eclampsia occurred in 69 (23%) of 296 participants in the calcium group versus 82 (29%) of 283 participants in the placebo group with pregnancies beyond 20 weeks' gestation (risk ratio [RR] 0·80, 95% CI 0·61-1·06; p=0·121). For participants with compliance of more than 80% from the last visit before pregnancy to 20 weeks' gestation, the pre-eclampsia risk was 30 (21%) of 144 versus 47 (32%) of 149 (RR 0·66, CI 0·44-0·98; p=0·037). There were no serious adverse effects of calcium reported., Interpretation: Calcium supplementation that commenced before pregnancy until 20 weeks' gestation, compared with placebo, did not show a significant reduction in recurrent pre-eclampsia. As the trial was powered to detect a large effect size, we cannot rule out a small to moderate effect of this intervention., Funding: The University of British Columbia, a grantee of the Bill & Melinda Gates Foundation; UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO; the Argentina Fund for Horizontal Cooperation of the Argentinean Ministry of Foreign Affairs; and the Centre for Intervention Science in Maternal and Child Health., (© 2019 This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Numerous deaths in children aged <5 years in the developing world occur at home. Acute respiratory infections (ARIs) are thought to play an important role in these deaths. Risk factors and pathogens linked to fatal episodes remain unclear., Methods: A case-control study among low-income children aged <5 years was performed in Buenos Aires, Argentina, to define risk factors and viral pathogens among those who died of ARI at home., Results: A total of 278 families of children aged <5 years (of whom 104 died and 174 were healthy controls) participated in the study. A total of 87.5% of ARI-associated deaths occurred among infants aged <12 months. The estimated mortality rate due to ARI among infants was 5.02 deaths/1000 live births. Dying at home from ARI was associated with living in a crowded home (odds ratio [OR], 3.73; 95% confidence interval [CI], 1.41-9.88), having an adolescent mother (OR, 4.89; 95% CI, 1.37-17.38), lacking running water in the home (OR, 4.39; 95% CI, 1.11-17.38), incomplete vaccinations for age (OR, 3.39; 95% CI, 1.20-9.62), admission to a neonatal intensive care unit (OR, 7.17; 95% CI, 2.21-23.27), and no emergency department visit during the ARI episode (OR, 72.32; 95% CI, 4.82-1085.6). The at-home death rate due to respiratory syncytial virus infection among infants was 0.26 deaths/100 live births and that due to influenza was 0.07 deaths/1000 live births., Conclusions: Social vulnerabilities underlie at-home mortality due to ARI. Mortality rates due to RSV and influenza virus infection are high among infants at home and are similar to those reported for hospitalized children.

Background: High levels of maternal and newborn mortality and morbidity remain a daunting reality in many low-income countries. Several interventions delivered during antenatal care have been shown to improve maternal and newborn outcomes, but stockouts of medical supplies at point of care can prevent implementation of these services. We aimed to evaluate whether a supply chain strategy based on the provision of kits could improve quality of care., Methods: We did a pragmatic, stepped-wedge, cluster-randomised controlled trial at ten antenatal care clinics in Mozambique. Clinics were eligible if they were not already implementing the proposed antenatal care package; they served at least 200 new pregnant women per year; they had Maternal and Child Health (MCH) nurses; and they were willing to participate. All women attending antenatal care visits at the participating clinics were included in the trial. Participating clinics were randomly assigned to shift from control to intervention on prespecified start dates. The intervention involved four components (kits with medical supplies, a cupboard to store these supplies, a tracking sheet to monitor stocks, and a one-day training session). The primary outcomes were the proportion of women screened for anaemia and proteinuria, and the proportion of women who received mebendazole in the first antenatal care visit. The intervention was delivered under routine care conditions, and analyses were done according to the intention-to-treat principle. This trial is registered with the Pan African Clinical Trial Registry, number PACTR201306000550192., Findings: Between March, 2014, and January, 2016, 218 277 antenatal care visits were registered, with 68 598 first and 149 679 follow-up visits. We found significant improvements in all three primary outcomes. In first visits, 5519 (14·6%) of 37 826 women were screened for anaemia in the control period, compared with 30 057 (97·7%) of 30 772 in the intervention period (adjusted odds ratio 832·40; 99% CI 666·81-1039·11; p<0·0001); 3739 (9·9%) of 37 826 women were screened for proteinuria in the control period, compared with 29 874 (97·1%) of 30 772 in the intervention period (1875·18; 1447·56-2429·11; p<0·0001); and 17 926 (51·4%) of 34 842 received mebendazole in the control period, compared with 24 960 (88·2%) of 28 294 in the intervention period (1·88; 1·70-2·09; p<0·0001). The effect was immediate and sustained over time, with negligible heterogeneity between sites., Interpretation: A supply chain strategy that resolves stockouts at point of care can result in a vast improvement in quality during antenatal care visits, when compared with the routine national process for procurement and distribution of supplies., Funding: Government of Flanders and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction., (© 2017 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this Article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the Article's original URL.)

Background: Congenital syphilis is associated with perinatal deaths, preterm births and congenital malformations. Low rates of syphilis screening during pregnancy and treatment of those found seropositive have been reported in the Democratic Republic of the Congo (DRC) and Zambia. We report the rates on antenatal syphilis screening, the seroprevalence of syphilis infection, and the frequency of antibiotic treatment in pregnant women screened positive for syphilis during their attendance at antenatal care (ANC) clinics in Kinshasa, DRC and Lusaka, Zambia. Methods: Women attending their first ANC were enrolled consecutively during a 9-month period in 16 and 13 ANC clinics in Kinshasa and Lusaka respectively, in the context of the baseline period of a cluster trial. Study personnel collected data on women's characteristics, the syphilis screening practices, the test results, and the frequency of treatment, that were done under routine ANC conditions and registered in the clinic records. Results 4,153 women in Kinshasa and 18,097 women in Lusaka were enrolled. The frequency of screening at the first visit was 59.7% (n= 2,479) in Kinshasa, and 27.8% (n=5,025) in Lusaka. Screening test availability varied. In the periods in which tests were available the screening rates were 92.8% in Kinshasa and 52.0% in Lusaka. The frequency of women screened seropositive was 0.4% (n=10) in Kinshasa and 2.2% (n=109) in Lusaka. Respectively, 10% (n=1) and 11.9% (n= 13) among seropositive women received treatment at the first visit. Conclusions: The results of the study show that screening for syphilis in pregnancy is not universal even when supplies are available. Our ongoing trial will evaluate the impact of a behavioral intervention on changing health providers' practices to increase screening and treatment rates when supplies are available., Competing Interests: No competing interests were disclosed.

Background: Evidence from observational studies suggests an increased risk of HIV acquisition among women using depot medroxyprogesterone acetate (DMPA) contraception., Methods: Within the context of a South African programme to increase women's access to the intrauterine contraceptive device (IUD), we conducted a pragmatic, open-label, parallel-arm, randomised controlled trial (RCT) of the IUD versus injectable progestogen contraception (IPC) at two South African hospitals. The primary outcome was pregnancy; secondary outcomes included HIV acquisition. Consenting women attending termination of pregnancy services were randomised after pregnancy termination between July 2009 and November 2012. Condoms were promoted for the prevention of sexually transmitted infections. Voluntary HIV testing was offered at baseline and at 12 or more months later. Findings on HIV acquisition are reported in this article., Results: HIV acquisition data were available for 1290 initially HIV-negative women who underwent a final study interview at a median of 20 months after randomisation to IPC or an IUD. Baseline group characteristics were comparable. In the IPC group, 545/656 (83%) of participants received DMPA, 96 (15%) received injectable norethisterone enanthate, 14 (2%) received the IUD and one received oral contraception. In the IUD group 609 (96%) received the IUD, 20 (3%) received IPC and 5 (1%) had missing data. According to intention-to-treat analysis, HIV acquisition occurred in 20/656 (3.0%) women in the IPC arm and 22/634 (3.5%) women in the IUD arm (IPC vs IUD, risk ratio 0.88; 95% confidence interval 0.48-1.59; p =0.7)., Conclusions: This sub-study was underpowered to rule out moderate differences in HIV risk, but confirms the feasibility of randomised trial methodology to address this question. Larger RCTs are needed to determine the relative risks of various contraceptive methods on HIV acquisition with greater precision., Trial Registration Number: Pan African Clinical Trials Registry number PACTR201409000880157 (04-09-2014)., Competing Interests: Competing interests: GJH and MS are members of the Evidence for Contraceptive health and HIV Outcomes (ECHO) consortium that is undertaking a multicentre randomised trial of contraceptive methods and HIV acquisition., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization and an important cause of death in infants in the developing world. The relative contribution of social, biologic, and clinical risk factors to RSV mortality in low-income regions is unclear., Objectives: To determine the burden and risk factors for mortality due to RSV in a low-income population of 84,840 infants., Methods: This was a prospective, population-based, cross-sectional, multicenter study conducted between 2011 and 2013. Hospitalizations and deaths due to severe lower respiratory tract illness (LRTI) were recorded during the RSV season. All-cause hospital deaths and community deaths were monitored. Risk factors for respiratory failure (RF) and mortality due to RSV were assessed using a hierarchical, logistic regression model., Measurements and Main Results: A total of 2,588 (65.5%) infants with severe LRTI were infected with RSV. A total of 157 infants (148 postneonatal) experienced RF or died with RSV. RSV LRTI accounted for 57% fatal LRTI tested for the virus. A diagnosis of sepsis (odds ratio [OR], 17.03; 95% confidence interval [CI], 13.14-21.16 for RF) (OR, 119.39; 95% CI, 50.98-273.34 for death) and pneumothorax (OR, 17.15; 95% CI, 13.07-21.01 for RF) (OR, 65.49; 95% CI, 28.90-139.17 for death) were the main determinants of poor outcomes., Conclusions: RSV was the most frequent cause of mortality in low-income postneonatal infants. RF and death due to RSV LRTI, almost exclusively associated with prematurity and cardiopulmonary diseases in industrialized countries, primarily affect term infants in a developing world environment. Poor outcomes at hospitals are frequent and associated with the cooccurrence of bacterial sepsis and clinically significant pneumothoraxes.

Background: Pertussis disease is a growing concern for developing countries. In Argentina, rates of illness and death peaked in 2011. More than 50% of fatalities due to pertussis occurred in infants younger than two months of age, too young for vaccination. In 2012, the government offered immunization with a vaccine containing Tdap to all pregnant women after 20weeks of gestation with the intent of reducing morbidity and mortality in young infants., Methods: Maternal acellular pertussis vaccine impact on reducing infant disease burden was estimated based on data from the Argentinean Health Surveillance System. We divided Argentinean states in two groups experiencing high (>50) and low (⩽50) Tdap vaccine coverage and compared these two groups using a Bayesian structural time-series model. Low coverage regions were used as a control group, and the time series were compared before and after the implementation of the Tdap program., Findings: We observed a relative reduction of 51% (95% CI [-67%, -35%]; p=0.001) in pertussis cases in high coverage states in comparison with the low coverage areas. Analysis of infants between two and six months showed a 44% (95% CI [-66%, -24%]; p=0.001) reduction in illness. Number of deaths was highest in 2011 with 76 fatalities, for an incidence rate of 2.9 per 100,000. Comparing with 2011, rates decreased by 87% to 10 subjects, or 0.9 per 100,000 in 2013., Interpretation: We show an age-dependent protective effect of maternal Tdap immunization in a developing country for infants younger than six months., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Although there is increasing evidence for a relationship between symptomatic Zika virus (ZIKV) maternal infection, and microcephaly, a firm causal relation has yet to be established by epidemiologic studies. Studies also need to be conducted in recently infected settings. Our objectives are to assess the frequency of ZIKV infection during pregnancy in Honduras and the association of microcephaly with ZIKV infection., Methods/design: We will perform a prospective study enrolling pregnant women at their first antenatal visit and following them up until delivery. At the time of enrollment, women will be interviewed to collect socio-demographic data, data needed to locate them for potential additional follow-up, and data about ZIKV symptoms during pregnancy. We will also collect maternal blood as soon as possible after enrollment. A probable maternal ZIKV infection will be defined as positive for maternal ZIKV IgM. A confirmed maternal ZIKV infection will be defined as positive for ZIKV IgM confirmed by plaque reduction neutralization test. Microcephaly at birth will be defined as an occipito-frontal circumference <2SD for sex and gestational age. Our objective is to enroll 2000 pregnant women. In a first step, we will follow a case cohort design and only analyze blood samples for cases and a sub-cohort of 200 women randomly selected. Blood samples for the entire population will be analyzed at a later stage if funds are available., Discussion: This protocol was designed to be implemented with minimal resources. It allows a cohort to be built, which could be a foundation for future in-depth and follow-up studies.

Background: The copper intrauterine device (IUD) is under-utilised in South Africa, where injectable progestin contraception (IPC) dominates contraception usage. There is a lack of robust comparative data on these contraceptive options to inform policy, programs, clinical counseling, and women's choices., Methods: Within the context of a South African program to increase women's access to the IUD, we conducted a pragmatic, open-label, parallel-arm, randomised controlled trial of the IUD versus IPC at two South African hospitals. The target sample size was 7,000 women and the randomisation ratio was 1:1. The random sequence was computer-generated and group allocation was concealed in sealed, opaque, consecutively-numbered envelopes. Counselled, consenting women attending termination of pregnancy services were randomly assigned to IUD or IPC immediately post-termination. Condoms were promoted for the prevention of sexually-transmitted infections. The primary outcome was pregnancy; secondary outcomes were discontinuation, side-effects, and HIV acquisition and disease progression. Pregnancy and discontinuation outcomes are reported here., Results: The trial closed early with 2,493 participants randomised (IUD = 1,247, IPC = 1,246), due to international concerns regarding a possible association between IPC and HIV acquisition. Median follow-up was 20 months; 982 and 1000 participants were followed up in the IUD and IPC groups, respectively. Baseline group characteristics were comparable. Pregnancy occurred significantly less frequently among women allocated to the IUD than IPC: 56/971 (5.8%) versus 83/992 (8.4%), respectively; risk ratio (RR) 0.69, 95% confidence interval (CI) 0.50 to 0.96; P = 0.025. There were more protocol violations in the IUD group; however, discontinuation rates were similar between IUD and IPC groups (141/855 [16.5%] and 143/974 [14.7%], respectively). Women in the IUD group were more likely to discontinue contraceptive use due to abdominal pain or backache and non-specific symptoms, and those in the IPC group due to oligo- or amenorhoea and lack of sexual activity., Conclusions: The IUD was significantly more effective in preventing pregnancy than IPC. Efforts to expand contraception options and improve access to the IUD in settings where it is under-utilised are worthwhile. This trial shows that randomising long-acting, reversible contraceptives is feasible., Trial Registration: Pan African Clinical Trials Registry number PACTR201409000880157 (04-09-2014).

Background: Epidemiological findings suggest that the link between poverty and pre-eclampsia might be dietary calcium deficiency. Calcium supplementation has been associated with a modest reduction in pre-eclampsia, and also in blood pressure (BP)., Methods: This exploratory sub-study of the WHO Calcium and Pre-eclampsia (CAP) trial aims to determine the effect of 500mg/day elemental calcium on the blood pressure of non-pregnant women with previous pre-eclampsia. Non-pregnant women with at least one subsequent follow-up trial visit at approximately 12 or 24weeks after randomization were included., Results: Of 836 women randomized by 9 September 2014, 1st visit data were available in 367 women of whom 217 had previously had severe pre-eclampsia, 2nd visit data were available in 201 women. There was an overall trend to reduced BP in the calcium supplementation group (1-2.5mmHg) although differences were small and not statistically significant. In the subgroup with previous severe pre-eclampsia, the mean diastolic BP change in the calcium group (-2.6mmHg) was statistically larger than in the placebo group (+0.8mmHg), (mean difference -3.4, 95% CI -0.4 to -6.4; p=0.025). The effect of calcium on diastolic BP at 12weeks was greater than in those with non-severe pre-eclampsia (p=0.020, ANOVA analysis)., Conclusions: There is an overall trend to reduced BP but only statistically significant in the diastolic BP of women with previous severe pre-eclampsia. This is consistent with our hypothesis that this group is more sensitive to calcium supplementation, however results need to be interpreted with caution., (Copyright © 2015. Published by Elsevier B.V.)

Background: Maternal mortality remains a daunting problem in Mozambique and many other low-resource countries. High quality antenatal care (ANC) services can improve maternal and newborn health outcomes and increase the likelihood that women will seek skilled delivery care. This study explores the factors influencing provider uptake of the recommended package of ANC interventions in Mozambique., Methods: This study used qualitative research methods including key informant interviews with stakeholders from the health sector and a total of five focus group discussions with women with experience with ANC or women from the community. Study participants were selected from three health centers located in Maputo city, Tete, and Cabo Delgado provinces in Mozambique. Staff responsible for the medicines/supply chain at national, provincial and district level were interviewed. A check list was implemented to confirm the availability of the supplies required for ANC. Deductive content analysis was conducted., Results: Three main groups of factors were identified that hinder the implementation of the ANC package in the study setting: a) system or organizational: include chronic supply chain deficiencies, failures in the continuing education system, lack of regular audits and supervision, absence of an efficient patient record system and poor environmental conditions at the health center; b) health care provider factors: such as limited awareness of current clinical guidelines and a resistant attitude to adopting new recommendations; and c) Users: challenges with accessing ANC, poor recognition amongst women about the purpose and importance of the specific interventions provided through ANC, and widespread perception of an unfriendly environment at the health center., Conclusions: The ANC package in Mozambique is not being fully implemented in the three study facilities, and a major barrier is poor functioning of the supply chain system. Recommendations for improving the implementation of antenatal interventions include ensuring clinical protocols based on the ANC model. Increasing the community understanding of the importance of ANC would improve demand for high quality ANC services. The supply chain functioning could be strengthened through the introduction of a kit system with all the necessary supplies for ANC and a simple monitoring system to track the stock levels is recommended.

Objectives: To determine whether earlier application of the Non-pneumatic Anti-Shock Garment (NASG) at clinic level compared to the referral hospital level reduces maternal morbidity and mortality and recovery time from shock due to severe Obstetric Haemorrhage (OH) and to determine the safety of the NASG when applied at clinic level., Design: A cluster Randomized Controlled Trial (RCT), Setting: Harare and Parirenyatwa Referral Hospitals (RH) in Harare and the twelve Harare City Council clinics that offer maternity care., Subjects: Women who had suffered severe OH at clinic level and were being transferred to a Referral Hospital (RH)., Iterventions: The clinics were randomized into two groups. In the early NASG group eligible women were given the standard management for OH and had the NASG applied at the clinic level before transport to RH. In the control group, eligible women were given the standard management for OH at the clinic level, transferred to the RH, and received the NASG at the RH. All women received equivalent OH/hypovolemic shock management at the RH., Main Outcome Measures: The main outcome measures were maternal mortality and morbidity, blood loss, recovery from shock and the occurrence of side effects whilst in the NASG., Results: There were few maternal deaths and morbidities, and no statistically significant differences between the two groups were noted. Women in the early NASG group spent a statistically significant shorter time in the NASG at referral hospital level (OR 0.64, 95% CI 0.52 - 0.79, p < 0.001) and had a non-significant 40% faster recovery from shock (HR 1.39; 95% CI 0.98-1.97, p=0.07). There were no differences in reported side effects., Conclusion: Earlier NASG application at the clinic level was associated with faster recovery from shock in women who had suffered severe OH and appears safe to use.

Background: Bed rest in hospital or at home is widely recommended for the prevention of preterm birth. This advice is based on the observation that hard work and hard physical activity during pregnancy could be associated with preterm birth and with the idea that bed rest could reduce uterine activity. However, bed rest may have some adverse effects on other outcomes., Objectives: To evaluate the effect of prescription of bed rest in hospital or at home for preventing preterm birth in pregnant women at high risk of preterm birth., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (18 December 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 12), MEDLINE (December 2014), EMBASE (December 2014), LILACS (December 2014), and bibliographies of relevant papers., Selection Criteria: Randomized, cluster-randomized and quasi-randomized controlled trials with reported data that assess clinical outcomes in women at high risk of spontaneous preterm birth who were prescribed bed rest in hospital or at home for preventing preterm birth, and their babies., Data Collection and Analysis: Two review authors independently assessed eligibility, trial quality and extracted data., Main Results: Two studies met the inclusion criteria. One study was not considered for the meta-analysis, since data combined singleton and multiple pregnancies. No differences in any maternal and perinatal outcomes were reported by the authors. This study was at low risk of selection, performance, detection and attrition bias. Only data from one study were included in the meta-analysis (1266 women). This study was at unclear risk of bias for most domains due to lack of reporting. Four hundred and thirty-two women were prescribed bed rest at home and a total of 834 women received a placebo (412) or no intervention (422). Preterm birth before 37 weeks was similar in both groups (7.9% in the intervention group versus 8.5% in the control group; risk ratio (RR) 0.92, 95% confidence interval (CI) 0.62 to 1.37). No other results were reported for any of the other primary or secondary outcomes., Authors' Conclusions: There is no evidence, either supporting or refuting the use of bed rest at home or in hospital, to prevent preterm birth. Although bed rest in hospital or at home is widely used as the first step of treatment, there is no evidence that this practice could be beneficial. Due to the potential adverse effects that bed rest could have on women and their families, and the increased costs for the healthcare system, clinicians should discuss the pros and cons of bed rest to prevent preterm birth. Potential benefits and harms should be discussed with women facing an increased risk of preterm birth. Appropriate research is mandatory. Future trials should evaluate both the effectiveness of bed rest, and the effectiveness of the prescription of bed rest, to prevent preterm birth.

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

Background: Antenatal care (ANC) reduces maternal and perinatal morbidity and mortality directly through the detection and treatment of pregnancy-related illnesses, and indirectly through the detection of women at increased risk of delivery complications. The potential benefits of quality antenatal care services are most significant in low-resource countries where morbidity and mortality levels among women of reproductive age and neonates are higher.WHO developed an ANC model that recommended the delivery of services scientifically proven to improve maternal, perinatal and neonatal outcomes. The aim of this study is to determine the effect of an intervention designed to increase the use of the package of evidence-based services included in the WHO ANC model in Mozambique. The primary hypothesis is that the intervention will increase the use of evidence-based practices during ANC visits in comparison to the standard dissemination channels currently used in the country., Methods: This is a demonstration project to be developed through a facility-based cluster randomized controlled trial with a stepped wedge design. The intervention was tailored, based on formative research findings, to be readily applicable to local prenatal care services and acceptable to local pregnant women and health providers. The intervention includes four components: the provision of kits with all necessary medicines and laboratory supplies for ANC (medical and non-medical equipment), a storage system, a tracking system, and training sessions for health care providers. Ten clinics were selected and will start receiving the intervention in a random order. Outcomes will be computed at each time point when a new clinic starts the intervention. The primary outcomes are the delivery of selected health care practices to women attending the first ANC visit, and secondary outcomes are the delivery of selected health care practices to women attending second and higher ANC visits as well as the attitude of midwives in relation to adopting the practices. This demonstration project is pragmatic in orientation and will be conducted under routine conditions., Discussion: There is an urgent need for effective and sustainable scaling-up approaches of health interventions in low-resource countries. This can only be accomplished by the engagement of the country's health stakeholders at all levels. This project aims to achieve improvement in the quality of antenatal care in Mozambique through the implementation of a multifaceted intervention on three levels: policy, organizational and health care delivery levels. The implementation of the trial will probably require a change in accountability and behaviour of health care providers and we expect this change in 'habits' will contribute to obtaining reliable health indicators, not only related to research issues, but also to health care outcomes derived from the new health care model. At policy level, the results of this study may suggest a need for revision of the supply chain management system. Given that supply chain management is a major challenge for many low-resource countries, we envisage that important lessons on how to improve the supply chain in Mozambique and other similar settings, will be drawn from this study., Trial Registration: Pan African Clinical Trial Registry database. Identification number: PACTR201306000550192.

Background: Intrapartum complications are responsible for approximately half of all maternal deaths, and two million stillbirth and neonatal deaths per year. Prolonged second stage of labour is associated with potentially fatal maternal complications such as haemorrhage and infection and it is a major cause of stillbirth and newborn morbidity and mortality. Currently, the three main options for managing prolonged second stage of labour are forceps, vacuum extractor and caesarean section. All three clinical practices require relatively expensive equipment (e.g., a surgical theatre for caesarean section) and/or highly trained staff which are often not available in low resource settings. The specific aim of the proposed study is to test the safety and feasibility of a new device (Odón device) to effectively deliver the fetus during prolonged second stage of labour. The Odón device is a low-cost technological innovation to facilitate operative vaginal delivery and designed to minimize trauma to the mother and baby. These features combined make it a potentially revolutionary development in obstetrics, particularly for improving intrapartum care and reducing maternal and perinatal morbidity and mortality in low resource settings., Methods/design: This will be a hospital-based, multicenter prospective phase 1 cohort study with no control group. Delivery with the Odón device will be attempted under normal labour and non-emergency conditions on all the women enrolled in the study. One-hundred and thirty pregnant women will be recruited in tertiary care facilities in Argentina. Safety will be assessed by examining maternal and infant outcomes until discharge. Feasibility will be evaluated by observing successful expulsion of the fetal head after one-time application of the device under standardized conditions (full cervical dilation, anterior presentation, +2 station, normal fetal heart rate)., Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR). Identifier: ACTRN12613000141741.

Background: Little information is available about the incidence of complications from vacuum aspiration for first-trimester abortion after cervical preparation with prostaglandin analogues. We compared incidence of complications from vacuum aspiration in women who had had cervical preparation with misoprostol and those who had not., Methods: We did a randomised parallel-group trial at 14 centres in nine countries between Oct 22, 2002, and Sept 24, 2005. Healthy women seeking first-trimester abortion were randomly assigned via a computer-generated randomisation sequence stratified by centre, to receive vaginal administration of either two 200 μg tablets of misoprostol or two placebo tablets 3 h before abortion by vacuum aspiration. Participants and health-care personnel other than staff administering the treatment were masked to group assignment. Follow-up was up to 2 weeks. The primary outcome was one or more complications of vacuum aspiration (cervical tear, uterine perforation, incomplete abortion, uterine re-evacuation, pelvic inflammatory disease, or any other serious adverse event). We included women undergoing treatment and vacuum aspiration in the analysis of immediate complications; whereas, in the analysis of delayed complications, we included only those followed-up. In the analysis of any immediate or delayed complication, we excluded women lost to follow-up. This trial is registered, number ISRCTN85366519., Findings: We randomly assigned 2485 women to the misoprostol group and 2487 to the placebo group. Two women in the misoprostol group did not have vacuum aspiration. 56 women in each group were lost to follow-up. 50 (2%) of 2427 women in the misoprostol group and 74 (3%) of 2431 in the placebo group had one or more complication of vacuum aspiration (relative risk [RR] 0·68, 95% CI 0·47-0·96). No women in the misoprostol group had cervical tears and three had uterine perforations compared with two women in the placebo group who had cervical tears and one who had perforation. 19 (<1%) women given misoprostol and 55 (2%) on placebo had incomplete abortions (0·35, 0·21-0·58), of whom 14 (<1%) versus 48 (2%) needed uterine re-evacuation (0·29, 0·16-0·53). We noted no difference between groups in incidence of pelvic inflammatory disease (30 [1%] vs 25 [1%]; RR 1·20, 0·71-2·04) or other serious adverse events. The main side-effects of misoprostol during the 3 h treatment were abdominal pain (1355 [55%] of 2484 women vs 545 [22%] of 2487 women in the placebo group) and vaginal bleeding (909 [37%] vs 167 [7%])., Interpretation: Cervical preparation with 400 μg of vaginal misoprostol can reduce incidence of complications from vacuum aspiration for first trimester abortion., Funding: UN Development Programme/UN Population Fund/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, WHO, and the Packard Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Active management of the third stage of labour reduces the risk of post-partum haemorrhage. We aimed to assess whether controlled cord traction can be omitted from active management of this stage without increasing the risk of severe haemorrhage., Methods: We did a multicentre, non-inferiority, randomised controlled trial in 16 hospitals and two primary health-care centres in Argentina, Egypt, India, Kenya, the Philippines, South Africa, Thailand, and Uganda. Women expecting to deliver singleton babies vaginally (ie, not planned caesarean section) were randomly assigned (in a 1:1 ratio) with a centrally generated allocation sequence, stratified by country, to placental delivery with gravity and maternal effort (simplified package) or controlled cord traction applied immediately after uterine contraction and cord clamping (full package). After randomisation, allocation could not be concealed from investigators, participants, or assessors. Oxytocin 10 IU was administered immediately after birth with cord clamping after 1-3 min. Uterine massage was done after placental delivery according to local policy. The primary (non-inferiority) outcome was blood loss of 1000 mL or more (severe haemorrhage). The non-inferiority margin for the risk ratio was 1·3. Analysis was by modified intention-to-treat, excluding women who had emergency caesarean sections. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN 12608000434392., Findings: Between June 1, 2009, and Oct 30, 2010, 12,227 women were randomly assigned to the simplified package group and 12,163 to the full package group. After exclusion of women who had emergency caesarean sections, 11,861 were in the simplified package group and 11,820 were in the full package group. The primary outcome of blood loss of 1000 mL or more had a risk ratio of 1·09 (95% CI 0·91-1·31) and the upper 95% CI limit crossed the pre-stated non-inferiority margin. One case of uterine inversion occurred in the full package group. Other adverse events were haemorrhage-related., Interpretation: Although the hypothesis of non-inferiority was not met, omission of controlled cord traction has very little effect on the risk of severe haemorrhage. Scaling up of haemorrhage prevention programmes for non-hospital settings can safely focus on use of oxytocin., Funding: United States Agency for International Development and UN Development Programme/UN Population Fund/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Based on an unusual clinical experience of a teenage boy in child psychotherapy, two conclusions are proposed: (1) that the extremely unhappy, early love affairs that occur in most men's lives serve a valuable function in helping them separate from their mothers sufficiently to be able to realistically relate to appropriate marriage partners, and (2) that some Don Juans start new relationships in order to break them off, rather than the reverse.

Objective: To assess perinatal risks to singleton births after in vitro fertilization (IVF) versus spontaneous conception., Design: Cross-sectional., Setting: A 2006 registry database of the Japan Society of Obstetrics and Gynaecology (JSOG) capturing 5.8% of total births., Patient(s): 53,939 singleton births from spontaneous conceptions and 1,408 singletons after IVF., Intervention(s): None., Main Outcome Measure(s): Perinatal death, low-birth weight (LBW), small for gestational age (SGA), congenital malformation, and sex ratio assessment based on singleton birth cases versus singleton live-born cases., Result(s): In this study, IVF may include intracytoplasmic sperm injection (ICSI), gamete intrafallopian transfer, or IVF followed by zygote intrafallopian transfer. In crude and adjusted analysis, perinatal death, SGA, congenital malformation, and sex ratio were not statistically significantly associated with IVF. The LBW rates were statistically significantly higher in IVF pregnancies, but the association statistically significantly decreased after adjusting for confounding factors. Placental previa, a maternal outcome, was found to be statistically significantly higher in IVF pregnancies., Conclusion(s): No evidence was implicated IVF procedures as dramatically increasing the adjusted risk of perinatal death, LBW, SGA, congenital malformation, or sex ratio when compared with spontaneous conceptions. However, because of sample size limitations, the study cannot exclude small to moderate increases in perinatal deaths or congenital malformations., (Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate if calcium supplementation during pregnancy could have any influence on primary dentition measured as the reduction of dental caries of the child., Design: Individual randomized controlled trial., Setting: One hospital in Rosario, Argentina., Population: Random sample of 195 12-year-old children from a follow-up study of 614 women who were randomized during pregnancy to calcium supplementation or placebo., Methods: An independent researcher blinded to the group where the mothers were assigned performed a dental examination of the children., Main Outcome Measures: Proportion of children with at least one decayed, missing or filled teeth (DMFT/dmft) and mean number of decayed, missing or filled surfaces (DMFS/dmfs) per children., Results: Ninety-eight children were assessed in the calcium supplementation group and 97 in the placebo group. 63.3% of the children whose mother took calcium supplementation had at least one DMFT/dmft compared to 86.6% in the placebo group (<0.001). The children whose mother received the intervention had a 27% reduction in the risk of developing at least one DMFT/dmft (RR: 0.73, CI 95%: [0.62; 0.87])., Conclusions: This study shows a modeling effect of calcium intake during pregnancy on dental caries of the offspring. At around 12 years of age children whose mothers received calcium supplementation when pregnant showed a significant reduction in dental caries.

Objective: To review the use of evidence-based practices in the care of mothers who died or had severe morbidity attending public hospitals in two Latin American countries., Methods: This study is part of a multicenter intervention to increase the use of evidence-based obstetric practice. Data on maternal deaths and women admitted to intensive care units whose deliveries occurred in 24 hospitals in Argentina and Uruguay were analyzed. Primary outcomes were use rates of effective interventions to reduce maternal mortality (MM) and severe maternal morbidity (SMM)., Results: A total of 106 women were included: 26 maternal deaths and 80 women with SMM. Some effective interventions for severe acute hemorrhage had a high use rate, such as blood transfusion (91%) and timely cesarean delivery (75%), while active management of the third stage of labor (25%) showed a lower rate. The overall use rate of effective interventions was 58% (95% CI, 49%-67%). This implies that 42% of the women did not receive one of the effective interventions to reduce MM and SMM., Conclusion: This study shows a low use of effective interventions to reduce MM and SMM in public hospitals in Argentina and Uruguay. Dissemination and implementation of evidence-based practices must be guaranteed to effectively achieve progress on maternal health., (Copyright 2010 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To examine the association between high prepregnancy maternal body mass index (BMI) and the risk of preterm birth (PTB)., Methods: A systematic review of the literature. We included cohorts and case-control studies published since 1968 that examined the association between BMI and PTB of all types, spontaneous (s), elective and with ruptured membranes (PPROM) in three gestational age categories: general (<37 weeks), moderate (32-36 weeks) and very (<32 weeks) PTB., Results: 20,401 citations were screened and 39 studies (1,788,633 women) were included. Preobese (BMI, 25-29.9) and obese I (BMI, 30-34.9) women have a reduced risk for sPTB: AOR = 0.85 (95% CI: 0.80-0.92) and 0.83 (95% CI: 0.75-0.92), respectively. Their risk for moderate PTB was 1.20 (95% CI: 1.04-1.38) and 1.60 (95% CI: 1.32-1.94), respectively. Obese II women (BMI, 35-40) have an increased risk for PTB in general (AOR = 1.33, 95% CI: 1.12-1.57) moderate (AOR = 2.43, 95% CI: 1.46-4.05) and very PTB (AOR = 1.96, 95% CI: 1.66-2.31). Obese III women (BMI > 40) have an even higher risk for very PTB (AOR = 2.27, 95%CI: 1.76-2.94). High BMI does not modify the risk for PPROM and increases the risk for elective PTB., Conclusions: High maternal BMI may have different effects on different types of PTB.

Objective: To propose a tool to assist trialists in making design decisions that are consistent with their trial's stated purpose., Study Design and Setting: Randomized trials have been broadly categorized as either having a pragmatic or explanatory attitude. Pragmatic trials seek to answer the question, "Does this intervention work under usual conditions?," whereas explanatory trials are focused on the question, "Can this intervention work under ideal conditions?" Design decisions make a trial more (or less) pragmatic or explanatory, but no tool currently exists to help researchers make the best decisions possible in accordance with their trial's primary goal. During the course of two international meetings, participants with experience in clinical care, research commissioning, health care financing, trial methodology, and reporting defined and refined aspects of trial design that distinguish pragmatic attitudes from explanatory., Results: We have developed a tool (called PRECIS) with 10 key domains and which identifies criteria to help researchers determine how pragmatic or explanatory their trial is. The assessment is summarized graphically., Conclusion: We believe that PRECIS is a useful first step toward a tool that can help trialists to ensure that their design decisions are consistent with the stated purpose of the trial.

Objective: The protective role of breastfeeding against severe acute lung disease in infants is well established, but its mechanism is unclear. Most hypotheses assume that breastfeeding confers similar passive protection to every infant; however, a few observations have suggested that the benefits of breast milk against severe lung disease may differ according to gender. The objective of this study was to determine whether the effect of breastfeeding on susceptibility to severe acute lung disease among infants at high risk is different for girls and boys., Methods: A cohort was analyzed prospectively by use of 2 different strategies: (1) predictors of first episode of rehospitalization by univariate and multivariate analyses using robust Poisson regression and (2) mean number of rehospitalizations between groups using multiple regression negative binomial models., Results: A total of 119 high-risk, very low birth weight infants were enrolled. Breast milk protected girls but not boys against severe acute lung disease. The interaction between breastfeeding and gender was clinically and statistically significant, even after adjustment for variables that can affect severity of acute lung disease. Disease was most severe in formula-fed girls (versus formula-fed boys)., Conclusions: Breastfeeding decreased the risk for severe acute lung disease in girls but not in boys. These findings suggest that breast milk protection is not universally conferred by passive transfer of humoral immunity (which should be gender indifferent), show that respiratory symptoms may be amenable to nonspecific modulation, and identify nonbreastfed preterm infant girls as an at-risk group for severe acute lung disease.

Background: Implementation of evidence-based obstetrical practices remains a significant challenge. Effective strategies to disseminate and implement such practices are needed., Methods: We randomly assigned 19 hospitals in Argentina and Uruguay to receive a multifaceted behavioral intervention (including selection of opinion leaders, interactive workshops, training of manual skills, one-on-one academic detailing visits with hospital birth attendants, reminders, and feedback) to develop and implement guidelines for the use of episiotomy and management of the third stage of labor or to receive no intervention. The primary outcomes were the rates of prophylactic use of oxytocin during the third stage of labor and of episiotomy. The main secondary outcomes were postpartum hemorrhage and birth attendants' readiness to change their behavior with regard to episiotomies and management of the third stage of labor. The outcomes were measured at baseline, at the end of the 18-month intervention, and 12 months after the end of the intervention., Results: The rate of use of prophylactic oxytocin increased from 2.1% at baseline to 83.6% after the end of the intervention at hospitals that received the intervention and from 2.6% to 12.3% at control hospitals (P=0.01 for the difference in changes). The rate of use of episiotomy decreased from 41.1% to 29.9% at hospitals receiving the intervention but remained stable at control hospitals, with preintervention and postintervention values of 43.5% and 44.5%, respectively (P<0.001 for the difference in changes). The intervention was also associated with reductions in the rate of postpartum hemorrhage of 500 ml or more (relative rate reduction, 45%; 95% confidence interval [CI], 9 to 71) and of 1000 ml or more (relative rate reduction, 70%; 95% CI, 16 to 78). Birth attendants' readiness to change also increased in the hospitals receiving the intervention. The effects on the use of episiotomy and prophylactic oxytocin were sustained 12 months after the end of the intervention., Conclusions: A multifaceted behavioral intervention increased the prophylactic use of oxytocin during the third stage of labor and reduced the use of episiotomy. (ClinicalTrials.gov number, NCT00070720 [ClinicalTrials.gov]; Current Controlled Trials number, ISRCTN82417627 [controlled-trials.com].)., (Copyright 2008 Massachusetts Medical Society.)

There are many systematic reviews of continuing education programmes and educational strategies for quality improvement in health care. Most of the reviewed studies are one-off evaluations rather than impact evaluations with long-term follow-up. There are few systematic reviews of organisational, financial and regulatory interventions, and few high-quality studies. These interventions are probably as or more important than educational strategies, although they are less well evaluated. Few studies have been undertaken in low- and middle-income countries (LMIC) or that address maternal and child health (MCH). Thus, the results of the available studies and reviews need to be interpreted cautiously when applied to LMIC. Interactive workshops, reminders and multifaceted interventions can improve professional practice, and they generally have moderate effects. Educational outreach visits consistently improve prescribing but have variable effects on other behaviours. Audit and feedback interventions have variable effects on professional practice, but most often these are small to moderate effects. Mass-media and patient-mediated interventions may change professional practice. Multifaceted interventions that combine several quality-improvement strategies are also effective but may not be more so than single interventions. While all of these strategies are applicable to MCH in LMIC, the applicability of the results to rural settings, in particular, may be limited. Use of these strategies could exacerbate inequalities, and this should be taken into consideration when planning implementation. Scaling up and sustainability may be difficult to achieve in LMIC contexts and need careful consideration. The use of financial interventions has not been well studied; financial incentives and disincentives may be difficult to use effectively and efficiently, although their impact on practice needs to be considered. Organisational interventions are likely to be important, given that there are often underlying organisational or system problems. Regulatory interventions have not been well evaluated, but may sometimes be both inexpensive and effective. There are no 'magic bullets' or simple solutions for ensuring the quality of health care services. Interventions should be selected or tailored to address the underlying reasons for a failure to deliver effective services. Decision-makers should select the most appropriate interventions for specific problems. This requires a governance structure that clearly assigns responsibility for quality-improvement activities, priority setting, selection and design of interventions, and evaluation.

Background: Calcium supplementation during pregnancy has been shown to reduce the incidence of hypertension in the mother, but the effects on the offspring are uncertain. Assessing the impact on the offspring is very important given the now large body of evidence indicating that blood pressure levels in childhood and young adulthood can be influenced by factors operating during fetal life. We conducted a systematic review of the literature to summarize the evidence supporting an association between maternal dietary calcium intake during pregnancy and blood pressure in the offspring., Methods: A systematic review was performed to identify randomized, quasi-randomized and cohort studies reporting the relationship between offspring blood pressure or incidence of hypertension and levels of maternal dietary calcium intake during pregnancy, either from supplements (i.e. pills) or food. MEDLINE, EMBASE and the Cochrane Library Registry were searched for relevant trials., Results: Two randomized trial and three observational studies were identified and included in this review. In 4 of the 5 studies, loss to follow-up was a serious concern. There was heterogeneity between the studies, particularly those conducted on children below 12 month of age. Results were more consistent among the studies including older children (1 to 9 years) where a higher maternal calcium intake was associated with a reduction of -1.92 mm Hg (95% CI -3.14 to -0.71) in offspring systolic blood pressure. One large randomized trial found a clinically and statistically significant reduction in the incidence of hypertension in 7-year-old children (RR = 0.59, 95% CI 0.39 to 0.90)., Conclusion: There is evidence in the literature to support an association between maternal calcium intake during pregnancy and offspring blood pressure. However, more research is needed to confirm these finding given the small sample sizes and the methodological problems in many of the studies conducted so far. More studies on populations with calcium deficit are also needed. If confirmed, these findings could have important public health implications. Calcium supplementation during pregnancy is simple and inexpensive and may be a way to reduce the risk of hypertension and its sequels in the next generation.

Background: Cesarean section rates show a wide variation among countries in the world, ranging from 0.4 to 40 percent, and a continuous rise in the trend has been observed in the past 30 years. Our aim was to explore the association of cesarean section rates of different countries with their maternal and neonatal mortality and to test the hypothesis that in low-income countries, increasing cesarean section rates were associated with reductions in both outcomes, whereas in high-income countries, such association did not exist., Methods: We performed a cross-sectional multigroup ecological study using data from 119 countries from 1991 to 2003. These countries were classified into 3 categories: low-income (59 countries), medium-income (31 countries), and high-income (29 countries) countries according to an international classification. We assessed the ecological association between national cesarean section rates and maternal and neonatal mortality by fitting multiple linear regression models., Results: Median cesarean section rates were lower in low-income than in medium- and high-income countries. Seventy-six percent of the low-income countries, 16 percent of the medium-income countries, and 3 percent of high-income countries showed cesarean section rates between 0 and 10 percent. Three percent of low-income countries, 36 percent of medium-income countries, and 31 percent of high-income countries showed cesarean section rates above 20 percent. In low-income countries, a negative and statistically significant linear correlation was observed between cesarean section rates and neonatal mortality and between cesarean section rates and maternal mortality. No association was observed in medium- and high-income countries for either neonatal mortality or maternal mortality., Conclusions: No association between cesarean section rates and maternal or neonatal mortality was shown in medium- and high-income countries. Thus, it becomes relevant for future good-quality research to assess the effect of the high figures of cesarean section rates on maternal and neonatal morbidity. For low-income countries, and on confirmation by further research, making cesarean section available for high-risk pregnancies could contribute to improve maternal and neonatal outcomes, whereas a system of care with cesarean section rates below 10 percent would be unlikely to cover their needs.

Background: Miscarriage is pregnancy loss before 23 weeks of gestational age and it happens in 10% to 15% of pregnancies depending on maternal age and parity. It is associated with chromosomal defects in about a half or two thirds of cases. Many interventions have been used to prevent miscarriage but bed rest is probably the most commonly prescribed especially in cases of threatened miscarriage and history of previous miscarriage. Since the etiology of miscarriage in most of the cases is not related to an excess of activity, it is unlikely that bed rest could be an effective strategy to reduce spontaneous miscarriage., Objectives: To evaluate the effect of prescription of bed rest during pregnancy to prevent miscarriage in women at high risk of miscarriage., Search Strategy: We searched the Cochrane Pregnancy and Childbirth Group trials register (July 2004). In addition, we searched The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, POPLINE, LILACS and EMBASE., Selection Criteria: We included all published, unpublished and ongoing randomized trials with reported data which compare clinical outcomes in pregnant women who were prescribed bed rest in hospital or at home for preventing miscarriage compared with alternative care or no intervention., Data Collection and Analysis: Two authors independently assessed the methodological quality of included trials using the methods described in the Cochrane Reviewers' Handbook. Studies were included irrespective of their methodological quality., Main Results: Only two studies including 84 women were identified. There was no statistically significant difference in the risk of miscarriage in the bed rest group versus the no bed rest group (placebo or other treatment) (relative risk (RR) 1.54, 95% confidence interval (CI) 0.92 to 2.58). Neither bed rest in hospital nor bed rest at home showed a significant difference in the prevention of miscarriage. There was a higher risk of miscarriage in those women in the bed rest group than in those in the human chorionic gonadotrophin therapy group with no bed rest (RR 2.50, 95% CI 1.22 to 5.11). It seems that the small number of participants included in these studies is a main factor to make this analysis inconclusive., Authors' Conclusions: There is insufficient evidence of high quality that supports a policy of bed rest in order to prevent miscarriage in women with confirmed fetal viability and vaginal bleeding in first half of pregnancy.

BACKGROUND: A significant proportion of the health care administered to women in Latin American maternity hospitals during labor and delivery has been demonstrated to be ineffective or harmful, whereas effective interventions remain underutilized. The routine use of episiotomies and the failure to use active management of the third stage of labor are good examples. METHODS/DESIGN: The aim of this trial is to evaluate the effect of a multifaceted behavioral intervention on the use of two evidence-based birth practices, the selective use of episiotomies and active management of the third stage of labor (injection of 10 International Units of oxytocin). The intervention is based on behavioral and organizational change theories and was based on formative research. Twenty-four hospitals in three urban districts of Argentina and Uruguay will be randomized. Opinion leaders in the 12 intervention hospitals will be identified and trained to develop and implement evidence-based guidelines. They will then disseminate the guidelines using a multifaceted approach including academic detailing, reminders, and feedback on utilization rates. The 12 hospitals in the control group will continue with their standard in-service training activities. The main outcomes to be assessed are the rates of episiotomy and oxytocin use during the third stage of labor. Secondary outcomes will be perineal sutures, postpartum hemorrhages, and birth attendants' opinions.

Background: Retinopathy of Prematurity (ROP) is a common retinal neovascular disorder of premature infants. It is of variable severity, usually heals with mild or no sequelae, but may progress to blindness from retinal detachments or severe retinal scar formation. This is a preliminary report of the effectiveness and safety of a new and original use of topical ketorolac in preterm newborn to prevent the progression of ROP to the more severe forms of this disease., Methods: From January 2001 to December 2002, all fifty nine preterm newborns with birthweight less than 1250 grams or gestational age less than 30 weeks of gestational age admitted to neonatal intensive care were eligible for treatment with topical ketorolac (0.25 milligrams every 8 hours in each eye). The historical comparison group included all 53 preterm newborns, with the same inclusion criteria, admitted between January 1999 and December 2000., Results: Groups were comparable in terms of weight distribution, Apgar score at 5 minutes, incidence of sepsis, intraventricular hemorrhage and necrotizing enterocolitis. The duration of oxygen therapy was significantly longer in the control group. In the ketorolac group, among 43 children that were alive at discharge, one (2.3%) developed threshold ROP and cryotherapy was necessary. In the comparison group 35 children survived, and six child (17%) needed cryotherapy (Relative Risk 0.14, 95%CI 0.00 to 0.80, p = 0.041). Adjusting by duration of oxygen therapy did not significantly change these results. Adverse effects attributable to ketorolac were not detected., Conclusions: This preliminary report suggests that ketorolac in the form of an ophthalmic solution can reduce the risk of developing severe ROP in very preterm newborns, without producing significant adverse side effects. These results, although promising, should be interpreted with caution because of the weakness of the study design. This is an inexpensive and simple intervention that might ameliorate the progression of a disease with devastating consequences for children and their families. We believe that next logical step would be to assess the effectiveness of this intervention in a randomized controlled trial of adequate sample size.

Background: Latin America has a high rate of caesarean sections. We tested the hypothesis that a hospital policy of mandatory second opinion, based on the best existing scientific evidence, reduces the hospital caesarean section rate by 25%, without increasing maternal and perinatal morbidity and mortality., Methods: 36 hospitals in Argentina (18), Brazil (eight), Cuba (four), Guatemala (two), and Mexico (four), were randomly assigned to intervention or control in a matched pair design. All physicians in the intervention hospitals deciding a non-emergency caesarean section had to follow a policy of mandatory second opinion. The primary outcome was the overall caesarean section rate in the hospitals after a 6-month implementation period. We also assessed women's satisfaction with labour and delivery care and physicians'acceptance of the second opinion policy., Findings: A total of 34 hospitals attending 149?276 deliveries were randomised and completed the protocol. The mandatory second opinion policy was associated with a small but significant reduction in rates of caesarean section (relative rate reduction 7.3%; 95% CI 0.2-14.5), mostly in intrapartum sections (12.6%; 0.6-24.7). Other maternal and neonatal outcomes and women's perceptions and satisfaction with the process of care were similarly distributed between the groups., Interpretation: In hospitals applying this policy of second opinion, 22 intrapartum caesarean sections could be prevented per 1000 deliveries, without affecting maternal or perinatal morbidity, and without affecting mothers' satisfaction with the care process.

Background: Bed rest in hospital or at home is widely recommended for the prevention of preterm birth. This advice is based on the observation that hard work and hard physical activity during pregnancy could be associated with preterm birth and with the idea that bed rest could reduce uterine activity. However, bed rest may have some adverse effects on other outcomes., Objectives: To evaluate the effect of prescription of bed rest in hospital or at home for preventing preterm birth in pregnant women at high risk of preterm birth., Search Strategy: We searched the Cochrane Pregnancy and Childbirth Group trials register (July 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003), MEDLINE (July 2003), LILACS (July 2003), EMBASE (July 2003), POPLINE (July 2003) and bibliographies of relevant papers., Selection Criteria: Randomized and quasi-randomized controlled trials with reported data that assess clinical outcomes in women at high risk of spontaneous preterm birth who were prescribed bed rest in hospital or at home for preventing preterm birth, and their babies., Data Collection and Analysis: Two reviewers independently assessed eligibility, trial quality and extracted data., Main Results: One study met the inclusion criteria (1266 women). This trial has uncertain methodological quality due to lack of reporting. Four hundred and thirty-two women were prescribed bed rest at home and a total of 834 women received a placebo (412) or no intervention (422). Preterm birth before 37 weeks was similar in both groups (7.9% in the intervention group versus 8.5% in the control group), and the relative risk was 0.92 with a 95% confidence interval from 0.62 to 1.37. No other results were available., Reviewer's Conclusions: There is no evidence, either supporting or refuting the use of bed rest at home or in hospital, to prevent preterm birth. Although bed rest in hospital or at home is widely used as the first step of treatment, there is no evidence that this practice could be beneficial. Due to the potential adverse effects that bed rest could have on women and their families, and the increased costs for the healthcare system, clinicians should not routinely advise women to rest in bed to prevent preterm birth. Potential benefits and harms should be discussed with women facing an increased risk of preterm birth. Appropriate research is mandatory. Future trials should evaluate both the effectiveness of bed rest, and the effectiveness of the prescription of bed rest, to prevent preterm birth.

Preeclampsia is a pregnancy-specific condition that increases maternal and infant mortality and morbidity. It is diagnosed by new-onset increased blood pressure and proteinuria during gestation; for many years these markers were the sole targets for study. More recently, increased attention to the multisystemic nature of the syndrome with involvement of almost all organs, activation of coagulation and increased sensitivity to pressor agents has expanded understanding of the disorder. The epidemiology of preeclampsia, being more common in poor women, long ago suggested that nutrients might be involved in the disorder. Numerous conflicting hypotheses were advanced but the testing of these hypotheses has either been done poorly or not at all. Review of the available data indicates very few studies that provide useful insights. In many studies the syndrome is poorly defined and in most studies nutritional data (questionnaires or biomarkers) are obtained on women with the clinical syndrome. In overtly preeclamptic women it is impossible to decipher cause from effect. Nonetheless, current concepts of the genesis of preeclampsia that include endothelial dysfunction, inflammatory activation, oxidative stress and predisposing maternal factors provide targets for well-designed nutritional investigation. In this review the current concepts of the pathogenesis of preeclampsia are reviewed and available data are assessed in light of these concepts. Targets for nutritional investigation based on the current knowledge of pathophysiology are suggested.

Objective: To assess in an animal model the effect of maternal dietary calcium intake during pregnancy on the blood pressure of offspring., Design: Randomised controlled trial., Sample: Ninety-eight 20-week-old female Wistar-Kyoto rats, giving birth to a total of 119 pups that were included in the follow up study., Methods: Rats were randomised to a calcium deficient diet, a diet with the recommended calcium levels, or a diet with calcium content much higher than the recommended levels. After one month on the experimental diet they were bred. After birth, systolic blood pressure in the offspring was measured monthly till 52 weeks of age., Main Outcome Measures: Blood pressure of the offspring., Results: The difference in blood pressure of the offspring between the normal and low maternal calcium group increased 0.49 mmHg per month (95% CI 0.18 to 0.84), 0.38 (0.07 to 0.68) between the low and high calcium group, and 0.12 (-0.20 to 0.43) between the normal and high calcium group. At the end of the follow up (52 weeks of age) blood pressure of the offspring in the deficient calcium group was 12.1 mmHg (95% CI 8.8 to 15.4, P < 0.0001) higher than in the normal calcium group and 7.5 mmHg (95% CI 4.4 to 10.5, P < 0.001) higher than the high calcium group. Blood pressure of the offspring in the high calcium group was 4.3 mmHg (95% CI 1.0 to 7.5, P = 0.01) higher than in the normal calcium group. In a multiple regression model maternal calcium intake during pregnancy was the strongest predictor of blood pressure of the offspring during adulthood., Conclusions: This experiment supports previous studies in humans suggesting a link between calcium intake during pregnancy and blood pressure in the offspring, and provides an animal model to explore the mechanisms involved in such association.