Causes and circumstances of maternal death: A secondary analysis of the community-level Interventions for pre-eclampsia (CLIP) trials cohort

Background: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials.Methods: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12-49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen\u27s κ coefficient.Findings: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193-268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43-0·66]) or InterVA-5 (κ=0·44 [0·30-0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60-0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38-0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27-0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59-0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00-0·15]).Interpretation: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths.Funding: University of British Columbia (grantee of the Bill & Melinda Gates Foundation)

Blood pressure thresholds in pregnancy for identifying maternal and infant risk: A secondary analysis of community-level interventions for pre-eclampsia (CLIP) trial data

Background: Blood pressure measurement is a marker of antenatal care quality. In well resourced settings, lower blood pressure cutoffs for hypertension are associated with adverse pregnancy outcomes. We aimed to study the associations between blood pressure thresholds and adverse outcomes and the diagnostic test properties of these blood pressure cutoffs in low-resource settings.Methods: We did a secondary analysis of data from 22 intervention clusters in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials (NCT01911494) in India (n=6), Mozambique (n=6), and Pakistan (n=10). We included pregnant women aged 15-49 years (12-49 years in Mozambique), identified in their community by trained community health workers, who had data on blood pressure measurements and outcomes. The trial was unmasked. Maximum blood pressure was categorised as: normal blood pressure (systolic blood pressure [sBP] [dBP] Hg), elevated blood pressure (sBP 120-129 mm Hg and dBP Hg), stage 1 hypertension (sBP 130-139 mm Hg or dBP 80-89 mm Hg, or both), non-severe stage 2 hypertension (sBP 140-159 mm Hg or dBP 90-109 mm Hg, or both), or severe stage 2 hypertension (sBP ≥160 mm Hg or dBP ≥110 mm Hg, or both). We classified women according to the maximum blood pressure category reached across all visits for the primary analyses. The primary outcome was a maternal, fetal, or neonatal mortality or morbidity composite. We estimated dose-response relationships between blood pressure category and adverse outcomes, as well as diagnostic test properties.Findings: Between Nov 1, 2014, and Feb 28, 2017, 21 069 women (6067 in India, 4163 in Mozambique, and 10 839 in Pakistan) contributed 103 679 blood pressure measurements across the three CLIP trials. Only women with non-severe or severe stage 2 hypertension, as discrete diagnostic categories, experienced more adverse outcomes than women with normal blood pressure (risk ratios 1·29-5·88). Using blood pressure categories as diagnostic thresholds (women with blood pressure within the category or any higher category vs those with blood pressure in any lower category), dose-response relationships were observed between increasing thresholds and adverse outcomes, but likelihood ratios were informative only for severe stage 2 hypertension and maternal CNS events (likelihood ratio 6·36 [95% CI 3·65-11·07]) and perinatal death (5·07 [3·64-7·07]), particularly stillbirth (8·53 [5·63-12·92]).Interpretation: In low-resource settings, neither elevated blood pressure nor stage 1 hypertension were associated with maternal, fetal, or neonatal mortality or morbidity adverse composite outcomes. Only the threshold for severe stage 2 hypertension met diagnostic test performance standards. Current diagnostic thresholds for hypertension in pregnancy should be retained.Funding: University of British Columbia, the Bill & Melinda Gates Foundation

Does malaria during pregnancy affect the newborn?

Objective: To investigate the effect of malarial infection during pregnancy on the newborn.Methods: A retrospective cohort study was conducted at The Aga Khan University Hospital (AKUH), Karachi, using in-patient hospital records over an 11-year period from 1988 to 1999. The incidence of preterm delivery, low birth weight (LBW) and intrauterine growth retardation (IUGR) in 29 pregnant women with malaria, was compared with that in 66 selected pregnant women without malaria, who delivered at the AKUH during the same time period.Results: Pregnant women with malaria had a 3.1 times greater risk of preterm labor (p=0.14). They were more likely to be anaemic compared to women without malaria (RR=2.9, 95% CI=1.6-5.4) and had a significantly lower mean haemoglobin level (p=0.0001). Maternal malaria was significantly associated with LBW babies (p=0.001). The mean birth weight of infants born to pregnant women with malaria was 461 g less (p=0.0005). No significant association was, however, found between malarial infection during pregnancy and IUGR (p=0.33).CONCLUSION: Malarial infection during pregnancy is associated with poor maternal and fetal outcome. It is significantly associated with maternal anaemia and LBW infants. Appropriate measures must, therefore, be taken to prevent malaria during pregnancy, especially in endemic areas

Economic and cost-effectiveness analysis of the community-level interventions for pre-eclampsia (CLIP) trials in India, Pakistan and Mozambique

Background: The Community-Level Interventions for Pre-eclampsia (CLIP) trials (NCT01911494) in India, Pakistan and Mozambique (February 2014-2017) involved community engagement and task sharing with community health workers for triage and initial treatment of pregnancy hypertension. Maternal and perinatal mortality was less frequent among women who received ≥8 CLIP contacts. The aim of this analysis was to assess the incremental costs and cost-effectiveness of the CLIP intervention overall in comparison to standard of care, and by PIERS (Pre-eclampsia Integrated Estimate of RiSk) On the Move (POM) mobile health application visit frequency.Methods: Included were all women enrolled in the three CLIP trials who had delivered with known outcomes by trial end. According to the number of POM-guided home contacts received (0, 1-3, 4-7, ≥8), costs were collected from annual budgets and spending receipts, with inclusion of family opportunity costs in Pakistan. A decision tree model was built to determine the cost-effectiveness of the intervention (vs usual care), based on the primary clinical endpoint of years of life lost (YLL) for mothers and infants. A probabilistic sensitivity analysis was used to assess uncertainty in the cost and clinical outcomes.Results: The incremental per pregnancy cost of the intervention was US$12.66 (India), US$11.51 (Pakistan) and US$13.26 (Mozambique). As implemented, the intervention was not cost-effective due largely to minimal differences in YLL between arms. However, among women who received ≥8 CLIP contacts (four in Pakistan), the probability of health system and family (Pakistan) cost-effectiveness was ≥80% (all countries).Conclusion: The intervention was likely to be cost-effective for women receiving ≥8 contacts in Mozambique and India, and ≥4 in Pakistan, supporting WHO guidance on antenatal contact frequency.Trial registration number: NCT01911494

Role of community engagement in maternal health in rural Pakistan: Findings from the CLIP randomized trial

Background: Community-based strategies to promote maternal health can help raise awareness of pregnancy danger signs and preparations for emergencies. The objective of this study was to assess change in birth preparedness and complication readiness (BPCR) and pregnant women\u27s knowledge about pre-eclampsia as part of community engagement (CE) activities in rural Pakistan during the Community Level Interventions for Pre-eclampsia (CLIP) Trial.Methods: The CLIP Trial was a cluster randomized controlled trial that aimed to reduce maternal and perinatal morbidity and mortality using CE strategies alongside mobile health-supported care by community health care providers. CE activities engaged pregnant women at their homes and male stakeholders through village meetings in Hyderabad and Matiari in Sindh, Pakistan. These sessions covered pregnancy complications, particularly pre-eclampsia/eclampsia, BPCR and details of the CLIP intervention package. BPCR was assessed using questions related to transport arrangement, permission for care, emergency funds, and choice of facility birth attendant for delivery during quarterly household surveys. Outcomes were assessed via multilevel logistic regression with adjustment for relevant confounders with effects summarized as odds ratios and 95% confidence intervals.Results: There were 15 137 home-based CE sessions with pregnant women and families (n = 46 614) and 695 village meetings with male stakeholders (n = 7784) over two years. The composite outcomes for BPCR and pre-eclampsia knowledge did not differ significantly between trial arms. However, CE activities were associated with improved pre-eclampsia knowledge in some areas. Specifically, pregnant women in the intervention clusters were twice as likely to know that seizures could be a complication of pregnancy (odds ratio (OR) = 2.17, 95% confidence interval (CI) = 1.11, 4.23) and 2.5 times more likely to know that high blood pressure is potentially life-threatening during pregnancy (OR = 2.52, 95% CI = 1.31, 4.83) vs control clusters.Conclusions: The findings suggested that a CE strategy for male and female community stakeholders increased some measures of knowledge regarding complications of pre-eclampsia in low-resource settings. However, the effect of this intervention on long-term health outcomes needs further study.Trial registration: Clinical Trials.gov - INCT01911494

Causes and circumstances of maternal death:a secondary analysis of the Community-Level Interventions for (CLIP) trials cohort

BACKGROUND: Incomplete vital registration systems mean that causes of death during pregnancy and childbirth are poorly understood in low-income and middle-income countries. To inform global efforts to reduce maternal mortality, we compared physician review and computerised analysis of verbal autopsies (interpreting verbal autopsies [InterVA] software), to understand their agreement on maternal cause of death and circumstances of mortality categories (COMCATs) in the Community-Level Interventions for Pre-eclampsia (CLIP) cluster randomised trials. METHODS: The CLIP trials took place in India, Pakistan, and Mozambique, enrolling pregnant women aged 12–49 years between Nov 1, 2014, and Feb 28, 2017. 69 330 pregnant women were enrolled in 44 clusters (36 008 in the 22 intervention clusters and 33 322 in the 22 control clusters). In this secondary analysis of maternal deaths in CLIP, we included women who died in any of the 22 intervention clusters or 22 control clusters. Trained staff administered the WHO 2012 verbal autopsy after maternal deaths. Two physicians (and a third for consensus, if needed) reviewed trial surveillance data and verbal autopsies, and, in intervention clusters, community health worker-led visit data. They determined cause of death according to the WHO International Classification of Diseases-Maternal Mortality (ICD-MM). Verbal autopsies were also analysed by InterVA computer models (versions 4 and 5) to generate cause of death. COMCAT analysis was provided by InterVA-5 and, in India, by physician review of Maternal Newborn Health Registry data. Causes of death and COMCATs assigned by physician review, Inter-VA-4, and InterVA-5 were compared, with agreement assessed with Cohen's κ coefficient. FINDINGS: Of 61 988 pregnancies with successful follow-up in the CLIP trials, 143 maternal deaths were reported (16 deaths in India, 105 in Pakistan, and 22 in Mozambique). The maternal death rate was 231 (95% CI 193–268) per 100 000 identified pregnancies. Most deaths were attributed to direct maternal causes (rather than indirect or undetermined causes as per ICD-MM classification), with fair to good agreement between physician review and InterVA-4 (κ=0·56 [95% CI 0·43–0·66]) or InterVA-5 (κ=0·44 [0·30–0·57]), and InterVA-4 and InterVA-5 (κ=0·72 [0·60–0·84]). The top three causes of death were the same by physician review, InterVA-4, and InterVA-5 (ICD-MM categories obstetric haemorrhage, non-obstetric complications, and hypertensive disorders); however, attribution of individual patient deaths to obstetric haemorrhage varied more between methods (physician review, 38 [27%] deaths; InterVA-4, 69 [48%] deaths; and InterVA-5, 82 [57%] deaths), than did attribution to non-obstetric causes (physician review, 39 [27%] deaths; InterVA-4, 37 [26%] deaths; and InterVA-5, 28 [20%] deaths) or hypertensive disorders (physician review, 23 [16%] deaths; InterVA-4, 25 [17%] deaths; and InterVA-5, 24 [17%] deaths). Agreement for all nine ICD-MM categories was fair for physician review versus InterVA-4 (κ=0·48 [0·38–0·58]), poor for physician review versus InterVA-5 (κ=0·36 [0·27–0·46]), and good for InterVA-4 versus InterVA-5 (κ=0·69 [0·59–0·79]). The most commonly assigned COMCATs by InterVA-5 were emergencies (68 [48%] of 143 deaths) and health systems (62 [43%] deaths), and by physician review (India only) were health systems (seven [44%] of 16 deaths) and inevitability (five [31%] deaths); agreement between InterVA-5 and physician review (India data only) was poor (κ=0·04 [0·00–0·15]). INTERPRETATION: Our findings indicate that InterVA-5 is less accurate than InterVA-4 at ascertaining causes and circumstances of maternal death, when compared with physician review. Our results suggest a need to improve the next iteration of InterVA, and for researchers and clinicians to preferentially use InterVA-4 when recording maternal deaths. FUNDING: University of British Columbia (grantee of the Bill & Melinda Gates Foundation)

A Randomized Trial of Prophylactic Antibiotics for Miscarriage Surgery.

BACKGROUND: Surgical intervention is needed in some cases of spontaneous abortion to remove retained products of conception. Antibiotic prophylaxis may reduce the risk of pelvic infection, which is an important complication of this surgery, particularly in low-resource countries. METHODS: We conducted a double-blind, placebo-controlled, randomized trial investigating whether antibiotic prophylaxis before surgery to complete a spontaneous abortion would reduce pelvic infection among women and adolescents in low-resource countries. We randomly assigned patients to a single preoperative dose of 400 mg of oral doxycycline and 400 mg of oral metronidazole or identical placebos. The primary outcome was pelvic infection within 14 days after surgery. Pelvic infection was defined by the presence of two or more of four clinical features (purulent vaginal discharge, pyrexia, uterine tenderness, and leukocytosis) or by the presence of one of these features and the clinically identified need to administer antibiotics. The definition of pelvic infection was changed before the unblinding of the data; the original strict definition was two or more of the clinical features, without reference to the administration of antibiotics. RESULTS: We enrolled 3412 patients in Malawi, Pakistan, Tanzania, and Uganda. A total of 1705 patients were assigned to receive antibiotics and 1707 to receive placebo. The risk of pelvic infection was 4.1% (68 of 1676 pregnancies) in the antibiotics group and 5.3% (90 of 1684 pregnancies) in the placebo group (risk ratio, 0.77; 95% confidence interval [CI], 0.56 to 1.04; P = 0.09). Pelvic infection according to original strict criteria was diagnosed in 1.5% (26 of 1700 pregnancies) and 2.6% (44 of 1704 pregnancies), respectively (risk ratio, 0.60; 95% CI, 0.37 to 0.96). There were no significant between-group differences in adverse events. CONCLUSIONS: Antibiotic prophylaxis before miscarriage surgery did not result in a significantly lower risk of pelvic infection, as defined by pragmatic broad criteria, than placebo. (Funded by the Medical Research Council and others; AIMS Current Controlled Trials number, ISRCTN97143849.)

Congenital vaginal obstructions: Varied presentation and outcome

Congenital obstructing lesions of vagina, hydrometrocolpos, and hematocolpos, present at a variable time during early childhood and adolescence to different medical and surgical specialties. Twenty-six cases presenting over an 18-years period (1987–2005) were divided into three groups; Group A: neonates (6), Group B: adolescents (18), and Group C: adults (2). Common presentations in neonates (Group A) were abdominal mass (5), neonatal sepsis (3), and respiratory distress (2); whereas abdominal pain (18), voiding dysfunctions (13), and backache (7) were prevalent in adolescents (Group B). Adults (Group C) presented with inability to consummate and infertility (2). Four patients received erroneous treatment; exploratory laparotomy (1) and appendectomy (3). Urinary symptoms and associated urinary abnormalities were present in more than 50% of cases, especially those with complex anomalies. Management included excision of imperforate hymen (16) and transverse vaginal septum (8) through perineal (20) and abdominoperineal approach (4). Patients with urogenital sinus (1) and cloacal malformation (1) had staged reconstruction at 2.5 years of age following preliminary vesicostomy and colostomy at birth. On follow up (range 1–15 years; mean 7) more than 60% patients have menstrual irregularity (11), endometriosis (5), and infertility (4). In conclusion, rarity and variable presentation of congenital vaginal obstructions can lead to delayed diagnosis and erroneous management. A high index of suspicion and cross-sectional imaging help in early diagnosis and associated renal anomalies. A comprehensive management is imperative to preserve the reproductive potentials, as significant proportion of patients may experience sexual difficulties, menstrual irregularity, and infertility

Understanding the context of male and transgender sex work using peer ethnography.

OBJECTIVES: To distinguish between three distinct groups of male and transgender sex workers in Pakistan and to demonstrate how members of these stigmatized groups need to be engaged in the research process to go beyond stated norms of behaviour. METHODS: A peer ethnography study was undertaken in a major city in Pakistan. 15 male and 15 transgender sex workers were trained as peer researchers to each interview three peers in their network. Analysis was based on interviews with peer researchers as well as observation of dynamics during training and analysis workshops. RESULTS: The research process revealed that, within the epidemiological category of biological males who sell sex, there are three sociologically different sexual identities: khusras (transgender), khotkis (feminized males) and banthas (mainstream male identity). Both khusras and khotkis are organised in strong social structures based on a shared identity. While these networks provide emotional and material support, they also come with rigid group norms based on expected "feminine" behaviours. In everyday reality, sex workers showed fluidity in both behaviour and identity according to the situational context, transgressing both wider societal and group norms. The informal observational component in peer ethnography was crucial for the accurate interpretation of interview data. Participant accounts of behaviour and relationships are shaped by the research contexts including who interviews them, at what stage of familiarity and who may overhear the conversation. CONCLUSIONS: To avoid imposing a "false clarity" on categorisation of identity and assumed behaviour, it is necessary to go beyond verbal accounts to document the fluidity of everyday reality