We included 59 studies of 995 records identified, consisting of 141 415 women and 3387 stillbirths. Plasmodium falciparum malaria detected at delivery in peripheral samples increased the odds of stillbirth (odds ratio [OR] 1·81 [95% CI 1·42–2·30]; I 2 =26·1%; 34 estimates), as did P falciparum detected in placental samples (OR 1·95 [1·48–2·57]; I 2 =33·6%; 31 estimates). P falciparum malaria detected and treated during pregnancy was also associated with stillbirth, but to a lesser extent (OR 1·47 [95% CI 1·13–1·92]; 19 estimates). Plasmodium vivax malaria increased the odds of stillbirth when detected at delivery (2·81 [0·77–10·22]; three estimates), but not when detected and treated during pregnancy (1·09 [0·76–1·57]; four estimates). The association between P falciparum malaria in pregnancy and stillbirth was two times greater in areas of low-to-intermediate endemicity than in areas of high endemicity (ratio of ORs 1·96 [95% CI 1·34–2·89]). Assuming all women with malaria are still parasitaemic at delivery, an estimated 20% of the 1 059 700 stillbirths in malaria-endemic sub-Saharan Africa are attributed to P falciparum malaria in pregnancy; the population attributable fraction decreases to 12%, assuming all women with malaria are treated during pregnancy.

We did a systematic review of the association between confirmed malaria in pregnancy and stillbirth. We included population-based cross-sectional, cohort, or case-control studies (in which cases were stillbirths or perinatal deaths), and randomised controlled trials of malaria in pregnancy interventions, identified before Feb 28, 2017. We excluded studies in which malaria in pregnancy was not confirmed by PCR, light microscopy, rapid diagnostic test, or histology. The primary outcome was stillbirth. We pooled estimates of the association between malaria in pregnancy and stillbirth using meta-analysis. We used meta-regression to assess the influence of endemicity. The study protocol is registered with PROSPERO, protocol number CRD42016038742.

P falciparum and P vivax malaria in pregnancy both increase the risk of stillbirth, but to a lesser extent if malaria is treated before delivery. In areas transitioning from high to moderate endemicity, the proportion of stillbirths attributed to malaria in pregnancy is likely to increase due to an increased risk of malaria-associated stillbirth in infected individuals. In sub-Saharan Africa, where the average endemicity is now moderate, one to two in ten stillbirths are attributed to P falciparum malaria in pregnancy, and the risk of malaria-associated stillbirth in infected individuals is likely to increase as endemicity decreases further. There is a pressing need for context-appropriate, evidence-based interventions for malaria in pregnancy in low-endemicity settings.

To our knowledge, this large and comprehensive systematic review and meta-analysis, including data from 59 studies, provides the most accurate estimates of the associations between both P falciparum and P vivax malaria in pregnancy and stillbirth to date. This review also provides the first quantification of the influence of malaria endemicity on this association, which is particularly pertinent as malaria endemicity is declining globally. Using the estimates from this review, we have quantified the number of stillbirths attributed to malaria in pregnancy in malaria-endemic sub-Saharan Africa, assuming initially that no malaria in pregnancy is resolved before delivery, and then assuming that all malaria in pregnancy is treated before delivery.

We searched Scopus, PubMed, and Web of Science for articles published up to Feb 28, 2017, in any language, that reviewed, or estimated a population attributable fraction for, the association between malaria in pregnancy and stillbirth using the search terms “malaria”, “pregnan*”, “still* OR perinatal”, and “review OR attributable”. Before this review, one systematic review had been done for the association between placental Plasmodium falciparum malaria and stillbirth, which pooled associations from nine studies. One study had calculated the population attributable fraction for the contribution of P falciparum malaria in pregnancy in Africa to stillbirth using the estimated association between malaria in pregnancy and stillbirth from a single study-site in Africa. We found no systematic reviews of the association between Plasmodium vivax malaria in pregnancy and stillbirth through our search. No studies had quantified the influence of endemicity on the association between malaria in pregnancy and stillbirth.

We aimed to systematically review and synthesise population studies of pregnant women living in malaria-endemic areas, in which researchers collected data on malaria in pregnancy and stillbirth, to quantify the association between malaria in pregnancy and stillbirth, for both P falciparum and P vivax malaria, detected either during pregnancy or at delivery. We also aimed to assess sources of heterogeneity across studies, particularly endemicity, and to determine population attributable fractions (PAFs) to quantify the contribution of malaria in pregnancy to stillbirth at varying levels of endemicity.

An estimated 2·6 million stillbirths occur worldwide each year, resulting in substantial psychosocial and economic costs.98% of stillbirths occur in resource-limited settings and many are preventable.Annually, 125 million women are at risk of Plasmodium falciparum or Plasmodium vivax malaria in pregnancy.Although P falciparum malaria in pregnancy is recognised as a cause of stillbirth,the association between P falciparum and P vivax malaria in pregnancy and stillbirth has yet to be comprehensively quantified using all available data. Precise estimates of the association between P falciparum and P vivax malaria in pregnancy and stillbirth requires consideration of malaria endemicity; in low-endemicity areas, the effect of malaria in pregnancy might be greater because maternal antimalarial immunity is low.Malaria endemicity is declining worldwide, particularly in Africa,and 76% of women at risk of malaria in pregnancy live in low-endemicity areas outside of Africa where P falciparum and P vivax malaria coexist.Quantification of the contribution of malaria in pregnancy to stillbirth is essential for resource allocation for stillbirth prevention (for malaria or other factors).

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Where appropriate (low between-study variance and more than ten contributing estimates), we assessed bias due to small-study effects with funnel plots and Egger's asymmetry test.We explored heterogeneity using meta-regression to estimate the association between the log-transformed study-specific ORs and prespecified variables (definition of stillbirth, P falciparum endemicity class, first year of enrolment, when women were enrolled during pregnancy, and ultrasound gestational age estimation). We used the pooled ORs for the association between peripheral P falciparum malaria detected at delivery (assuming all malaria in pregnancy goes unresolved) or during pregnancy (assuming all malaria in pregnancy is treated during pregnancy) and stillbirth in areas of low-to-intermediate and high P falciparum endemicity to calculate PAFs for population prevalences between 1% and 50% and between 50% and 100%, respectively. All analyses were done in Stata (version 14). The study protocol is registered with PROSPERO, protocol number CRD42016038742.

We estimated pooled ORs for the association between malaria in pregnancy and stillbirth from random-effects meta-analyses, done separately according to species (P falciparum or P vivax), time of detection (during pregnancy or at delivery), and sample (peripheral or placental). The exposed group for estimates of malaria detected during pregnancy assumes both detection and treatment during pregnancy; however, whether exposed women were malaria-free at delivery is unknown. The exposed group for estimates of malaria detected at delivery includes women who might have been treated during pregnancy (including presumptive treatment), but were parasitaemic at the time of delivery (ie, unresolved malaria). If studies used multiple detection methods, we included the estimate using the most common method within the relevant meta-analysis.

We categorised P falciparum endemicity as low, intermediate, or high using information in the published papers. If there was insufficient information and study enrolment started after 2005, we categorised endemicity using the Malaria Atlas Project Data Explorer (endemicity class [proportion of children aged 2–10 years in the general population infected with P falciparum at any one time in 2010, PfPR] was approximated using the endemicity colour scale as low [<10%], intermediate [≥10% to <50%], or high [≥50%]).

Two independent authors (KAM and MJLS) extracted data using a proforma; discrepancies were resolved by discussion with a third reviewer (FJIF). Authors of studies were contacted and provided a proforma ( appendix p 4 ) to complete if collection of data on malaria in pregnancy and stillbirth or perinatal death was indicated in the methods or results sections, but the association between malaria in pregnancy and stillbirth was not reported. We also contacted authors to clarify information regarding eligibility, and for species-specific estimates. Risk of bias was assessed using the Risk of Bias in Non-randomised Studies—of Interventions (ROBINS-I) tool ( appendix p 5 ).We extracted measures of association and 95% CIs from the most fully adjusted model or calculated odds ratios (ORs) and 95% CIs using cross-tabulated data.

For this systematic review and meta-analysis, we searched Scopus, PubMed, and Web of Science for studies published in any language up to and including Feb 28, 2017, which assessed the association between malaria in pregnancy and birth outcomes, and reported on stillbirth or perinatal death ( appendix p 3 ). We also contacted key researchers in the field for unpublished data. We included population-based, cross-sectional, cohort, or case-control studies (in which cases were stillbirths or perinatal deaths) done in malaria-endemic areas if the association between confirmed malaria in pregnancy and stillbirth or perinatal death could be obtained. We also included groups of randomised controlled trials of malaria in pregnancy interventions in which women received the status-quo intervention when the study was done, or no intervention. We excluded studies in which malaria in pregnancy was not confirmed by PCR, light microscopy, rapid diagnostic test, or histology. The primary outcome was stillbirth. We included studies reporting on perinatal death that were unable to provide data specifically for stillbirth in a secondary analysis of perinatal death. We did not exclude studies on the basis of definitions used to define stillbirth and perinatal death, which vary widely between studies, but instead extracted gestational age thresholds for meta-regression analyses. This review is reported according to the MOOSE guidelinesand the PRISMA guidelines for systematic reviews ( appendix p 2 ).

Despite lower infection rates, PAFs in low-to-intermediate P falciparum endemicity areas were similar to or higher than those in high P falciparum endemicity areas ( appendix p 18 ). In 2015, the PfPRin malaria-endemic Africa was 16·2% (95% CI 14·24–19·02), and 9% of the total population were living in high-endemicity areas.An estimated 1 059 700 stillbirths occurred in sub-Saharan Africa in 2015.Therefore, assuming that all malaria in pregnancy goes unresolved before delivery, an estimated 20·5% (217 026 of 1 059 700) of stillbirths in sub-Saharan Africa would be attributed to P falciparum malaria in pregnancy (range from lower and upper CI limits for OR and prevalence estimates: 11·6% [n=122 713] to 32·2% [n=341 541]; appendix p 18 ). Assuming that all malaria in pregnancy is treated during pregnancy, regardless of symptoms, the PAF in sub-Saharan Africa would be 12·5% (range 4·7–23·6%; n=132 221 [range 50 308–249 608]; appendix p 18 ). The population prevalence of P falciparum is not yet available for regions outside of Africa; we have provided formulas to calculate PAFs at any population prevalence ( appendix p 18 ).

Low-to-intermediate P falciparum endemicity was associated with greater ORs for the association between P falciparum malaria in pregnancy and stillbirth, especially for malaria detected at delivery, compared with high P falciparum endemicity (ratio of ORs during pregnancy 1·62 [95% CI 1·02–2·60]; at delivery (peripheral) 1·96 [1·34–2·89]; at delivery (placental) 2·09 [1·14–3·82]), and endemicity reduced between-study variance ( appendix p 16 ). Studies that provided a gestational age threshold for the definition of stillbirth were associated with greater ORs for the association between P falciparum malaria in pregnancy and stillbirth compared with those that did not provide a threshold ( appendix p 16 ). No other factors were consistently found to influence the associations between P falciparum malaria in pregnancy and stillbirth ( appendix p 16 ).

There were seven estimates from six studies of the association between P vivax malaria in pregnancy and stillbirth (four estimates of P vivax malaria detected in peripheral blood during pregnancy, and three estimates of P vivax malaria detected in peripheral blood at delivery; figure 4 ). Peripheral P vivax malaria was not associated with stillbirth when detected and treated during pregnancy (OR 1·09 [95% CI 0·76–1·57]; I=0%; four estimates), but increased the odds of stillbirth by 2·81 times (95% CI 0·77–10·22; I=62·5%; three estimates) when detected at delivery ( figure 4 ).

LM=light microscopy. MiP=malaria in pregnancy. n=number of stillbirths. N=total number of births. OR=odds ratio. Pooled ORs calculated for malaria detected during pregnancy or at delivery. Detection method was LM in all studies, except for De Beaudrap, 2013 (PCR, LM, rapid diagnostic test or histology at delivery). De Beaudrap, 2013, contributed two estimates: P vivax malaria detected during pregnancy and P vivax malaria detected at delivery. Estimates from Singh, 2014, were not species-specific, but 83% of Plasmodium spp infections in the cohort were P vivax. All studies included all women, regardless of the presence of symptoms. In Singh, 1998, malaria exposure might have also been at delivery, but the study was designed to detect malaria during pregnancy. The magnitude of association was also large in studies with a high proportion of P vivax malaria that did not provide species-specific estimates ( appendix p 21 ).

There were 68 estimates from 48 studies of the association between P falciparum malaria at delivery and stillbirth. Peripheral P falciparum malaria at delivery (34 estimates) was associated with a 1·81 times increase in the odds of stillbirth (95% CI 1·42–2·30, I=26·1%; figure 3 ). Similarly, placental P falciparum malaria at delivery (31 estimates) was associated with a 1·95 times increase in the odds of stillbirth (1·48–2·57, I=33·6%; figure 3 ). There was some evidence of small-study effects for placental detection (p=0·0490), but not for peripheral detection (p=0·3190; appendix p 14 ). The method of malaria diagnosis had a small, but negligible, effect on the association between peripheral P falciparum malaria and stillbirth ( appendix p 10 ). The association between placental P falciparum malaria and stillbirth was greater when malaria was detected by microscopy (OR 2·40 [95% CI 1·60–3·59]), but still present if it was detected by more sensitive methods such as histology (1·53 [1·15–2·04]) and PCR (1·59 [0·88–2·85]; appendix p 10 ).

LM=light microscopy. MiP=malaria in pregnancy. n=number of stillbirths. N=total number of births. OR=odds ratio. Pooled ORs calculated for malaria detected in peripheral blood and placental blood, or either. Detection method was LM for all estimates, except for Braun, 2015 (peripheral) and Valente, 2011—PCR; Ahmed, 2014, Kalilani-Phiri, 2013 (placental), Watson-Jones, 2007 (placental), Okoko, 2002, and Anagnos, 1986—placental histology; Mbonye, 2015—PCR or LM; McGregor, 1983—LM or placental histology; De Beaudrap, 2013—PCR, LM, rapid diagnostic test, or placental histology; Obieche, 2015—LM or rapid diagnostic test; and Taha, 1993—LM or placental histology. McGregor, 1983, contributed two cohorts: women living in rural areas and women living in urban areas. Several cohorts detected malaria in both peripheral and placental samples, so a pooled OR combining placental and peripheral malaria was not estimated. In Arinaitwe, 2013; De Beaudrap, 2013; Huynh, 2011; Ostrowski, 2007; Watson-Jones, 2007; Ayisi, 2003; Sule-Odu, 2002; Axemo, 1995; and Lamikanra, 1993, Plasmodium species was not specified, but assumed to be P falciparum because the studies were done in areas of unstable P vivax transmission and high Duffy negativity. In Taha, 1993, Plasmodium species was not specified, but assumed to be P falciparum because the study was done in an area of unstable P vivax transmission. In Ahmed, 2014, and McGregor, 1983, estimates were not species-specific; however, only 5% (Ahmed) and <1% (McGregor) of all Plasmodium spp infections in the cohort were not P falciparum. Watson-Jones, 2007, reported ORs for active (OR 7·74 [95% CI 1·80–32·70]), active chronic (1·92 [0·50–6·90]), and past chronic placental infection (1·84 [0·60–5·20]), which we pooled to obtain a single OR. All studies included all women, regardless of the presence of symptoms, except for Mbonye, 2015 (asymptomatic women only) and Mbonye 2008 (asymptomatic women only). *Cross-tabulation unknown.

There were 19 estimates from 14 studies of the association between P falciparum malaria detected through screening of all women (ie, regardless of symptoms) and treated during pregnancy and stillbirth. P falciparum malaria detected and treated during pregnancy (19 estimates) was associated with a 1·47 times increase in the odds of stillbirth (95% CI 1·13–1·92; I=23·5%; figure 2 ). There was no evidence of small-study effects (p=0·763; appendix p 14 ). The pooled OR from a meta-analysis including only estimates for malaria diagnosed by light microscopy was similar (OR 1·48 [95% CI 1·11–1·97], I=27·7%; appendix p 10 ). P falciparum malaria detected and treated during pregnancy was not associated with stillbirth in a meta-analysis of three studies that contributed estimates for HIV-positive women specifically (0·97 [0·23–4·06], I=0%); all women in these populations were given either antiretroviral drugs, intermittent preventive treatment for malaria in pregnancy, or daily co-trimoxazole throughout pregnancy. The association between P falciparum malaria detected and treated during pregnancy was lower in a subgroup of nine estimates for malaria detected and treated before 30 weeks' gestation (OR 1·25 [0·95–1·79], I=18·7%) than in a subgroup of 12 estimates for malaria detected at any time, or an unspecified time, during pregnancy (1·57 [1·06–2·34], I=34·7%; appendix p 15 ).

CMX=co-trimoxazole. IPTp-SP=intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine. LM=light microscopy. MiP=malaria in pregnancy. n=number of stillbirths. N=total number of births. OR=odds ratio. Detection method was LM for all estimates, except for Klement, 2014 (either LM or placental histology) and De Beaudrap, 2013 (PCR, LM, or rapid diagnostic test). Klement, 2014, contributed two cohorts: HIV-positive women receiving IPTp-SP and HIV-positive women receiving CMX. Luntamo, 2010, contributed two cohorts: HIV-positive women receiving IPTp-SP and HIV-negative women receiving IPTp-SP. In Huynh, 2011, Plasmodium species was not specified, but assumed to be P falciparum because the study was done in an area of unstable P vivax transmission and high Duffy negativity. In De Beaudrap, 2013, estimates were not species-specific; however, only 4·5% of all Plasmodium spp infections in the cohort were not P falciparum. In Klement, 2014, and Singh, 1998, malaria exposure might have also been at delivery (included in this meta-analysis because separate estimates were not provided for malaria during pregnancy and malaria at delivery, and the studies were designed to detect malaria during pregnancy). Klement, 2014, used rapid diagnostic tests if LM was not available. Briand, 2009, provided estimates for malaria detected at enrolment (about 22 weeks; OR 0·82 [95% CI 0·048–13·99]), and malaria detected at the second IPTp administration visit (about 31 weeks; 3·03 [0·37–24·48]), which we pooled to obtain a single OR. A meta-analysis of the association between symptomatic P falciparum malaria detected during pregnancy and stillbirth is in the appendix (p 20 ; pooled OR 1·80 [95% CI 1·31–2·47]). *Cross-tabulation unknown.

46 of the 59 included studies were done in Africa, ten were done in Asia, and two were done in the Americas ( table ). Of 51 studies in which P falciparum endemicity could be confidently classified (using information provided in the published papers in 42 of the studies, and using Malaria Atlas Project data in nine of the studies), most were done in settings of high P falciparum endemicity (24 [47%] of 51 studies) or intermediate P falciparum endemicity (18 [35%] of 51 studies), and only nine (18%) were done in settings of low P falciparum endemicity ( table ). Studies done in settings of low or intermediate P falciparum endemicity were pooled into one low-to-intermediate group in subsequent meta-regression analyses because of the limited number of studies in the low-endemicity group. Six (10%) of 59 studies contributed P vivax-specific estimates. Half of the studies (30 [51%] of 59 studies) provided a gestational age to define stillbirth: eight studies used 20 weeks, five studies used 22 weeks, two studies used 24 weeks, 14 studies used 28 weeks, and one study used 32 weeks. The stillbirth proportion in women with no malaria in pregnancy (determined from the most sensitive diagnostic method from each study; case-control studies excluded) varied considerably between studies, ranging from 0% to 8% (median 2·17% [25–75th percentile 1·09–3·88, minimum to maximum 0–8·33], I=90%; appendix p 13 ).

We identified 995 records, and 455 records were potentially relevant after screening titles and abstracts ( figure 1 ). After full-text reviews, 332 articles were excluded ( appendix p 7 ), 29 articles met the inclusion criteria for stillbirth, and 85 potentially met the inclusion criteria for stillbirth. Contact with 85 authors yielded a further 34 studies that met the inclusion criteria for stillbirth. Four more studies were identified that met the inclusion criteria following contact with 71 key researchers. 59 studies were included in our primary review of the association between malaria in pregnancy and stillbirth; eight studies were included in a secondary review of the association between malaria in pregnancy and perinatal death ( appendix p 8 ).

*Key researchers were identified systematically using the references of a review of malaria in pregnancy,and through our search; the four studies identified through contact with key researchers rather than our systematic search were Natureeba, 2014; Mbonye, 2015; Gutman, 2015; and Moore, 2017. †Citations and reasons for exclusion are given in the appendix (p 7) . ‡Including seven studies that met the inclusion criteria for perinatal death before author contact.

Discussion

To our knowledge, this large and comprehensive systematic review and meta-analysis provides the most accurate estimates of the association between malaria in pregnancy and stillbirth to date. P falciparum and P vivax malaria in pregnancy detected at delivery increased the odds of stillbirth. For malaria detected during pregnancy, the magnitude of the association was reduced for P falciparum and eliminated for P vivax, compared with malaria detected at delivery; we assume this difference in magnitude was due to treatment before delivery and irrespective of symptoms. Associations between P falciparum malaria in pregnancy and stillbirth were two times greater in low-to-intermediate P falciparum endemicity areas than in high-endemicity areas, suggesting that the risk of malaria-associated stillbirth in infected women will increase as malaria endemicity declines. In areas transitioning from high to moderate endemicity, the proportion of stillbirths attributed to malaria in pregnancy in the population is likely to increase due to the individual-level increase in the association between malaria in pregnancy and stillbirth. These findings have major implications for policies and resource allocation for stillbirth prevention.

81 Lawn JE

Blencowe H

Waiswa P

et al. Stillbirths: rates, risk factors, and acceleration towards 2030. We estimated that 217 026 stillbirths are attributed to P falciparum malaria in pregnancy in malaria-endemic sub-Saharan Africa (20% of all stillbirths in sub-Saharan Africa). This estimate is similar to the estimate obtained by Lawn and colleagues,which used the association between peripheral P falciparum malaria detected at delivery and stillbirth derived from one study site in Africa, and did not consider the effect of endemicity or the contribution of malaria in pregnancy occurring outside of Africa. These PAFs use associations between P falciparum malaria in pregnancy detected at delivery and stillbirth, thereby assuming that no malaria in pregnancy is resolved with antimalarial treatment before delivery. If all cases of malaria in pregnancy were treated during pregnancy, irrespective of the presence of symptoms, the PAF would be substantially reduced (from 20% to 12% of all stillbirths in sub-Saharan Africa, corresponding to a difference of 88 767 stillbirths). High coverage of intermittent presumptive treatment with an effective antimalarial could achieve this reduction. Population prevalences of P falciparum and P vivax infection in other regions are not yet available; instead we have provided equations to calculate PAFs at any population prevalence. PAFs will probably be underestimated at lower population prevalences because we could not estimate the association in areas of low P falciparum endemicity specifically because there were few studies in these settings. Our classification of P falciparum endemicity was crude because endemicity reporting is not standardised, and is often imprecise. Over a million stillbirths occurred in southern and southeast Asia and Oceania in 2015, which is dominated by low-endemicity areas. Therefore, tens of thousands of stillbirths outside of Africa could also be attributed to malaria in pregnancy; this cannot be ignored.

82 van Geertruyden J-P

Thomas F

Erhart A

D'Alessandro U The contribution of malaria in pregnancy to perinatal mortality. 81 Lawn JE

Blencowe H

Waiswa P

et al. Stillbirths: rates, risk factors, and acceleration towards 2030. , 83 Frøen JF

Gordijn SJ

Abdel-Aleem H

et al. Making stillbirths count, making numbers talk—issues in data collection for stillbirths. The major strengths of this review were the inclusion of 59 studies (50 more than a previous reviewof placental P falciparum malaria and stillbirth), and the assessment of both P vivax and P falciparum malaria, and malaria detected both during pregnancy and at delivery. Stillbirth is rarely a primary outcome of malaria in pregnancy studies because of its rarity. We were able to include many studies that did not report the association between malaria in pregnancy and stillbirth, despite collecting the necessary data, through correspondence with the authors of 85 studies. This approach increased the number of included studies from 29 to 59, and reduced the risk of publication bias. Many studies were excluded because stillbirth was not mentioned in the methods or results sections, although it seems unlikely that moderately sized studies on malaria in pregnancy would report zero stillbirths. Therefore, we also contacted key researchers in the field to request data from malaria in pregnancy studies that had collected, but not reported, stillbirth data. Despite these measures, we found some evidence of small-study effects. Stillbirth is a sensitive indicator of maternal health and quality of care; future population studies of malaria in pregnancy should ensure that stillbirths are reported (including their definition), even if there are none.

84 Chico RM

Mayaud P

Ariti C

Mabey D

Ronsmans C

Chandramohan D Prevalence of malaria and sexually transmitted and reproductive tract infections in pregnancy in sub-Saharan Africa: a systematic review. 85 Rijken MJ

Rijken JA

Papageorghiou AT

et al. Malaria in pregnancy: the difficulties in measuring birthweight. There are some limitations in this analysis. Malaria in pregnancy was detected using different methods that vary in terms of sensitivity and specificity, and it was not possible to correct for this variability because we did not have individual patient data for the studies that provided adjusted estimates. There was a paucity of data on P vivax malaria in pregnancy, resulting in wide confidence intervals. Most estimates were not adjusted for confounding ( appendix p 5 ), because of the rarity of stillbirth and because we gave the option for authors to provide cross-tabulated data. We were able to assess the association between malaria in pregnancy and stillbirth in a subgroup of HIV-positive cohorts. However, there are many other infections, particularly sexually transmitted infections such as syphilis,that are highly prevalent in malaria-endemic settings and strongly associated with stillbirth, which might have modified or confounded estimates of the association between malaria in pregnancy and stillbirth. Rapid and inexpensive point-of-care tests that increase capacity for malaria in pregnancy studies to actively detect both malaria and other infections are needed to elucidate interactions. The threshold used to differentiate fetal deaths as miscarriages or stillbirths varied, and was only provided for 44% of studies; studies that provided a gestational age threshold, which can be indicative of study quality, reported greater magnitudes of association. Studies should ensure that the definition of stillbirth, as well as the method of gestational age estimation, is reported to facilitate data synthesis.Some of the largest studies included in this review provided ORs derived from regression modelling with adjustment for confounding variables. For this reason, and because the OR approximates the risk ratio when the outcome is rare, PAFs were calculated using pooled ORs rather than pooled risk ratios.

This review provides the most accurate quantification of the association between malaria in pregnancy and stillbirth to date, and for the first time, quantifies the influence of malaria endemicity on this association. Our findings suggest that detection and treatment of malaria in pregnancy before delivery, irrespective of symptoms, results in a lower risk of malaria-associated stillbirth and should be encouraged. In areas of stable transmission in Africa, insecticide-treated nets and intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine are recommended to reduce the burden of malaria in pregnancy; efforts to increase coverage should be continued. However, only prevention of malaria in pregnancy will avert the association between treated malaria in pregnancy and stillbirth. In areas of low endemicity outside of Africa where the association between malaria in pregnancy and stillbirth is greater, there are no recommended interventions for malaria in pregnancy, and little context-appropriate evidence. These findings are particularly relevant as malaria endemicity is declining in Africa, and justify more studies of the burden of both P falciparum and P vivax malaria in pregnancy in low-endemicity settings, and the need for context-appropriate interventions irrespective of endemicity.