Effect of Plasmodium falciparum sulfadoxine-pyrimethamine resistance on the effectiveness of intermittent preventive therapy for malaria in pregnancy in Africa: a systematic review and meta-analysis.

BACKGROUND: Resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine threatens the antimalarial effectiveness of intermittent preventive treatment during pregnancy (IPTp) in sub-Saharan Africa. We aimed to assess the associations between markers of sulfadoxine-pyrimethamine resistance in P falciparum and the effectiveness of sulfadoxine-pyrimethamine IPTp for malaria-associated outcomes. METHODS: For this systematic review and meta-analysis, we searched databases (from Jan 1, 1990 to March 1, 2018) for clinical studies (aggregated data) or surveys (individual participant data) that reported data on low birthweight (primary outcome) and malaria by sulfadoxine-pyrimethamine IPTp dose, and for studies that reported on molecular markers of sulfadoxine-pyrimethamine resistance. Studies that involved only HIV-infected women or combined interventions were excluded. We did a random-effects meta-analysis (clinical studies) or multivariate log-binomial regression (surveys) to obtain summarised dose-response data (relative risk reduction [RRR]) and multivariate meta-regression to explore the modifying effects of sulfadoxine-pyrimethamine resistance (as indicated by Ala437Gly, Lys540Glu, and Ala581Gly substitutions in the dhps gene). This study is registered with PROSPERO, number 42016035540. FINDINGS: Of 1097 records screened, 57 studies were included in the aggregated-data meta-analysis (including 59 457 births). The RRR for low birthweight declined with increasing prevalence of dhps Lys540Glu (ptrend=0·0060) but not Ala437Gly (ptrend=0·35). The RRR was 7% (95% CI 0 to 13) in areas of high resistance to sulfadoxine-pyrimethamine (Lys540Glu ≥90% in east and southern Africa; n=11), 21% (14 to 29) in moderate-resistance areas (Ala437Gly ≥90% [central and west Africa], or Lys540Glu ≥30% to <90% [east and southern Africa]; n=16), and 27% (21 to 33) in low-resistance areas (Ala437Gly <90% [central and west Africa], or Lys540Glu <30% [east and southern Africa]; n=30; ptrend=0·0054 [univariate], I2=69·5%). The overall RRR in all resistance strata was 21% (17 to 25). In the analysis of individual participant data from 13 surveys (42 394 births), sulfadoxine-pyrimethamine IPTp was associated with reduced prevalence of low birthweight in areas with a Lys540Glu prevalence of more than 90% and Ala581Gly prevalence of less than 10% (RRR 10% [7 to 12]), but not in those with an Ala581Gly prevalence of 10% or higher (pooled Ala581Gly prevalence 37% [range 29 to 46]; RRR 0·5% [-16 to 14]; 2326 births). INTERPRETATION: The effectiveness of sulfadoxine-pyrimethamine IPTp is reduced in areas with high resistance to sulfadoxine-pyrimethamine among P falciparum parasites, but remains associated with reductions in low birthweight even in areas where dhps Lys540Glu prevalence exceeds 90% but where the sextuple-mutant parasite (harbouring the additional dhps Ala581Gly mutation) is uncommon. Therapeutic alternatives to sulfadoxine-pyrimethamine IPTp are needed in areas where the prevalence of the sextuple-mutant parasite exceeds 37%. FUNDING: US Centers for Disease Control and Prevention, the Malaria in Pregnancy Consortium (funded through a grant from the Bill & Melinda Gates Foundation to the Liverpool School of Tropical Medicine), Worldwide Antimalarial Resistance Network, European and Developing Countries Clinical Trials Partnership.

Maternal smoking during pregnancy and offspring overweight: is there a dose-response relationship? An individual patient data meta-analysis.

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

Parental smoking and childhood obesity: higher effect estimates for maternal smoking in pregnancy compared with paternal smoking--a meta-analysis.

BACKGROUND: Some studies reported similar effect estimates for the impact of maternal smoking in pregnancy and paternal smoking on childhood obesity, whereas others suggested higher effects for maternal smoking. We performed a meta-analysis to compare the effect of in utero exposure to maternal smoking and that of paternal or household smoking exposure in utero or after birth with mutual adjustment. METHODS: Meta-analysis of observational studies identified in MEDLINE, EMBASE and Web of Knowledge published in 1900-2013. Study inclusion criterion was assessment of the association of maternal smoking during pregnancy and paternal or household smoking (anyone living in the household who smokes) at any time with childhood overweight and obesity. The analyses were based on all studies with mutually adjusted effect estimates for maternal and paternal/household smoking applying a random-effects model. RESULTS: Data for 109,838 mother/child pairs were reported in 12 studies. The pooled odds ratios (ORs) for overweight 1.33 [95% confidence interval (CI) 1.23;1.44] (n=6, I2=0.00%) and obesity 1.60 (95% CI 1.37;1.88) (n=4, I2=32.47%) for maternal smoking during pregnancy were higher than for paternal smoking: 1.07 (95% CI 1.00;1.16) (n=6, I2=41.34%) and 1.23 (95% CI 1.10;1.38) (n=4, I2=14.61%), respectively. Similar estimates with widely overlapping confidence limits were found for maternal smoking during pregnancy and childhood overweight and obesity: 1.35 (95% CI 1.20;1.51) (n=3, I2=0.00%) and 1.28 (95% CI 1.07;1.54) (n=3, I2=0.00%) compared with household smoking 1.22 (95% CI 1.06;1.39) (n=3, I2=72.14%) and 1.31 (95% CI 1.15;1.50)] (n=3, I2=0.00%). CONCLUSIONS: Higher effect estimates for maternal smoking in pregnancy compared with paternal smoking in mutually adjusted models may suggest a direct intrauterine effect.

Asthma in children in relation to pre-term birth and fetal growth restriction.

To assess the impact of parental asthma on risk of pre-term birth (PTB) and intrauterine growth restriction, and their subsequent association with childhood asthma. Three sequential cross-sectional surveys were conducted in 1993 (3,746), 1998 (1,964) and 2006 (1,074) in the same 15 schools among 5-11 year old children in Merseyside using the same respiratory health questionnaire completed by parents (sample size in brackets). Between 1993 and 2006, prevalence of PTB varied between 12.4 and 15.2 %, and of small for gestational age (SGA or growth restricted) babies between 2.1 and 4.6 %, and maternal asthma prevalence between 8.1 and 13.4 %. For the combined surveys mothers with asthma were more likely to have a PTB than non-asthmatic mothers (OR 1.39, 95 % CI 1.10-1.95, p < 0.001), and in the 2006 survey were more likely to have an SGA baby. 40.9 % of PTBs of asthmatic mothers developed doctor diagnosed asthma compared to 34.3 % for term babies (adjusted OR 1.65, 1.34-2.04, p < 0.001). The corresponding estimates for the symptom triad of cough, wheeze and breathlessness were 19.4 and 17.6 % (adjusted OR 1.78, 0.79-3.98). Conversely SGA babies were less likely to develop doctor diagnosed asthma (adjusted OR 0.49, 0.27-0.90, p < 0.021), or the symptom triad of cough, wheeze and breathlessness (adjusted OR 0.22, 0.05-0.97, p < 0.043), whether or not the mother was asthmatic. Maternal asthma is an independent risk factor for PTB which predisposes to childhood asthma. Intrauterine growth restriction was protective against childhood asthma.

Zinc erythrocyte protoporphyrin as marker of malaria risk in pregnancy - a retrospective cross-sectional and longitudinal study.

BACKGROUND: The effects of iron interventions and host iron status on infection risk have been a recurrent clinical concern, although there has been little research on this interaction in pregnant women. METHODS: Cross-sectional and longitudinal analyses were undertaken to determine the association of whole blood zinc erythrocyte protoporphyrin (ZPP) with malaria parasitaemia in pregnant women attending antenatal and delivery care at Montfort and Chikwawa Hospitals, Shire Valley, Malawi. Prevalence of antenatal, delivery and placental malaria was assessed in relation to maternal ZPP levels. The main outcome measures were prevalence of peripheral and placental Plasmodium falciparum parasitaemia and odds ratios of malaria risk. RESULTS: A total of 4,103 women were evaluated at first antenatal visit, of whom at delivery 1327 were screened for peripheral and 1285 for placental parasitaemia. Risk of malaria at delivery (peripheral or placental) was higher in primigravidae (p < 0.001), and lower (peripheral) with use of intermittent preventive anti-malarials during pregnancy (p < 0.001). HIV infection was associated with increased malaria parasitaemia (p < 0.02, peripheral or placental). Parasitaemia prevalence was lower in women with normal ZPP levels compared to those with raised concentrations at both first antenatal visit (all gravidae, p = 0.048, and at delivery (all gravidae, p < 0.001; primigravidae, p = 0.056). Between first antenatal visit and delivery women who transitioned from raised (at first antenatal visit) to normal ZPP values (at delivery) had lower peripheral parasitaemia prevalence at delivery compared to those who maintained normal ZPP values at both these visits (all gravidae: 0.70, 95%CI 0.4-1.1; primigravidae: 0.3, 0.1-0.8). In regression analysis this difference was lost with inclusion of HIV infection in the model. CONCLUSIONS: Raised ZPP concentrations in pregnancy were positively associated with P. falciparum parasitaemia and were probably secondary to malaria inflammation, rather than indicating an increased malaria risk with iron deficiency. It was not possible from ZPP measurements alone to determine whether iron deficiency or repletion alters malaria susceptibility in pregnancy.

Parental compliance--an emerging problem in Liverpool community child health surveys 1991-2006.

BACKGROUND: Compliance is a critical issue for parental questionnaires in school based epidemiological surveys and high compliance is difficult to achieve. The objective of this study was to determine trends and factors associated with parental questionnaire compliance during respiratory health surveys of school children in Merseyside between 1991 and 2006. METHODS: Four cross-sectional respiratory health surveys employing a core questionnaire and methodology were conducted in 1991, 1993, 1998 and 2006 among 5-11 year old children in the same 10 schools in Bootle and 5 schools in Wallasey, Merseyside. Parental compliance fell sequentially in consecutive surveys. This analysis aimed to determine the association of questionnaire compliance with variation in response rates to specific questions across surveys, and the demographic profiles for parents of children attending participant schools. RESULTS: Parental questionnaire compliance was 92% (1872/2035) in 1991, 87.4% (3746/4288) in 1993, 78.1% (1964/2514) in 1998 and 30.3% (1074/3540) in 2006. The trend to lower compliance in later surveys was consistent across all surveyed schools. Townsend score estimations of socio-economic status did not differ between schools with high or low questionnaire compliance and were comparable across the four surveys with only small differences between responders and non-responders to specific core questions. Respiratory symptom questions were mostly well answered with fewer than 15% of non-responders across all surveys. There were significant differences between mean child age, maternal and paternal smoking prevalence, and maternal employment between the four surveys (all p < 0.01). Out-migration did not differ between surveys (p = 0.256) with three quarters of parents resident for at least 3 years in the survey areas. CONCLUSION: Methodological differences or changes in socio-economic status of respondents between surveys were unlikely to explain compliance differences. Changes in maternal employment patterns may have been contributory. This analysis demonstrates a major shift in community parental questionnaire compliance over a 15 year period to 2006. Parental questionnaire compliance must be factored into survey designs and methodologies.

Childhood obesity and parental smoking as risk factors for childhood ADHD in Liverpool children.

ADHD prevalence has risen in parallel with rising prevalence of pregnancy smoking and childhood obesity. The objective was to determine the epidemiological association of pregnancy smoking and childhood obesity with ADHD. A cross-sectional community study was conducted in 2006 using a parental questionnaire. A total of 1,074 schoolchildren aged 5-11 years were enrolled from 15 primary schools in a lower socio-economic area of Merseyside. ADHD was defined by the question "does your child have Attention Deficit Hyperactivity Disorder, (ADHD), which has been diagnosed by a doctor?" The prevalence estimates for childhood obesity, maternal smoking during pregnancy and childhood ADHD were 14.9% (116/777), 28.0% (269/955), and 3.4% (32/945), respectively. ADHD prevalence increased fivefold in children with obesity (RR, 4.80, 95% CI 2.2-10.4, P < 0.001) and more than twofold in children of mothers who smoked during pregnancy (RR, 2.44, 95% CI 1.2-4.9, P = 0.02). Regression analysis adjusting for obesity, overweight, maternal smoking during pregnancy, heavy maternal smoking, household member smoking during pregnancy, doctor-diagnosed asthma, preterm birth, and low birthweight showed significant independent associations of ADHD prevalence with obesity (AOR, 4.66, 95% CI 1.57-13.89, P = 0.006) and pregnancy smoking (AOR, 3.19, 95% CI 1.08-9.49, P = 0.04). There was a positive dose-response association of ADHD with the number of maternal cigarettes smoked during pregnancy. Measures to reduce both smoking among pregnant women and childhood obesity might reduce prevalence of childhood ADHD.

Reduced risk for placental malaria in iron deficient women.

BACKGROUND: Nutritional iron deficiency may limit iron availability to the malaria parasite reducing infection risk, and/or impair host immunity thereby increasing this risk. In pregnant women, there is evidence of an adverse effect with iron supplementation, but the few reported studies are strongly confounded. METHODS: A case control study in pregnant Malawian women was undertaken in Chikhwawa southern Malawi in order to describe iron status in relation to placental malaria controlling for several confounding factors. Pregnancy characteristics were obtained and a blood sample at delivery. A full blood count was performed and serum ferritin and transferrin receptor quantified by enzyme-linked immunoassay. DNA analysis was used to identify genetic polymorphisms for ABO phenotype, hemoglobin HbS, and glucose -6 phosphate dehydrogenase deficiency. Placental tissue was obtained and malaria histology classified as active, past or no malaria infection. RESULTS: 112 cases with placental malaria were identified and 110 women with no evidence of placental infection. Iron deficiency was less frequent in women with placental Plasmodium falciparum infection. In those with acute, chronic or past placental infections the odds ratio for iron deficiency was 0.4, 95% CI 0.2-0.8, p = 0.01; for acute and chronic infections 0.4, 0.2-0.8, p = 0.006; for acute infection 0.3, 0.1-0.7, p = 0.001. The association was greater in multigravidae. CONCLUSION: Women with either acute, or acute and chronic placental malaria were less likely to have iron deficiency than women without placental malaria infection There is a priority to establish if reversing iron deficiency through iron supplementation programs either prior to or during pregnancy enhances malaria risk.

Dose response association of pregnancy cigarette smoke exposure, childhood stature, overweight and obesity.

BACKGROUND: The combined dose response effects of pregnancy cigarette smoke exposure on childhood overweight, obesity and short stature have not been reported. METHOD: A community based cross-sectional survey of 3038 children aged 5-11 years from 15 primary schools in Merseyside, UK. Self-completed parental questionnaires were used for family characteristics, socio-economic status and parental smoking practices. Children were measured for height and weight and z-scores calculated for parental smoking categories. RESULTS: Of 689 (34.0%) mothers who smoked during pregnancy 50.5% smoked ten or more cigarettes daily (heavy smokers). Children of maternal non-smokers had prevalence estimates for overweight, obesity and short stature of 25, 9.6 and 3.2%, respectively. Prevalence estimates were higher in children of mothers who were heavy smokers during pregnancy, 31.5% (P = 0.001), 15.6% (P < 0.001) and 5.5% (P = 0.001), respectively. Mean height for age z-scores was lower among heavy maternal (P < 0.001) and paternal smokers (P < 0.01) compared to non-smokers. Childhood overweight, obesity or short stature were all associated with heavy maternal smoking during pregnancy (all P < 0.001). Mean body mass index (BMI) z-scores were higher in boys of mothers who smoked (P = 0.043). The adjusted odds ratio for short stature in children of heavy maternal smokers was 2.76 (95% CI 1.21-6.33) and 4.28 (1.37-13.37) if both parents were heavy smokers. The adjusted OR for obesity in children of maternal smokers was 1.61(1.19-2.18). The population attributable risk for short stature was 8.8% (1.1-22.7) for heavy maternal smokers. CONCLUSION: A dose-response association was observed between pregnancy smoking exposure, short stature and obesity.

Parental smoking and increased likelihood of female births.

BACKGROUND: A recent decline in the male:female (M:F) sex ratio may relate to pregnancy cigarette smoke exposure. AIM: To assess trends and cigarette exposure dose-response effects on the sex ratio. SUBJECTS AND METHODS: A retrospective analysis was carried out of deliveries at the Liverpool Women's Hospital between 1998 and 2003, and of deliveries reported in community surveys from the same area in 1998 and 2006. RESULTS: For the hospital sample, the M:F sex ratio was 1.14 if no parent smoked, and 0.77 when both parents smoked during the mother's pregnancy (p < 0.001). Heavy maternal smokers (>10 cigarettes per day) were more likely to deliver a female baby than light smokers (p < 0.001). Smoking was associated with increased likelihood of female birth controlling for birth year, socio-economic status, alcohol exposure, maternal haemoglobin and body mass index (adjusted OR: 1.41, 95% CI 1.12-1.92, p < 0.001). In the community sample controlling for socio-economic status the ratios were 1.13 (95% CI 1.03-1.24, p = 0.015) in 1998 and 1.31 (95% CI 1.16-1.48, p < 0.001) in 2006. Secular trends showed decreasing ratios in hospital and community samples for both smokers and non-smokers. CONCLUSION: Pregnancy cigarette smoking increased the proportion of female births with evidence for a dose-response association.

Trends in prevalence of childhood and parental asthma in Merseyside, 1991-2006.

BACKGROUND: To determine changes in prevalence of parental and childhood asthma in Merseyside between 1991 and 2006. METHODS: Four standardized cross-sectional respiratory surveys using a parent-completed questionnaire were completed in 1991 (n = 1171), 1993 (n = 2368) 1998 (n = 1964) and in 2006 (n = 1074) among primary school children attending the same schools in lower socio-economic areas of Merseyside. Main outcome measures were prevalence of doctor diagnosed asthma (DDA) and the symptom triad of cough, wheeze and breathlessness (C+W+B+). RESULTS: Between 1991 and 1998 prevalence of DDA increased (P < 0.001), but in 2006 this decreased from 29.8 to 19.4% (P < 0.001). Prevalence of C+W+B+ increased from 7.8 to 8.0% by 1998, then decreased to 6.7% in 2006 (P = 0.39). Between 1998 and 2006, childhood hospital admissions for respiratory illness decreased from 11.3 to 9.7% (P = 0.23). During this period paternal asthma prevalence increased from 8.6 to 10.7% (P = 0.001) and maternal asthma from 11.2 to 13.4% (P = 0.09). CONCLUSIONS: An increase in the prevalence of DDA and asthmatic respiratory symptoms occurred in children prior to 1998, but this had decreased by 2006. Prevalence of parental asthma increased during the same period.