Exposure to indoor air pollution and adverse pregnancy outcomes in low and middle-income countries: a systematic review and meta-analysis

Introduction Exposure to indoor air pollution such as biomass fuel and particulate matter is a significant cause of adverse pregnancy outcomes. However, there is limited information about the association between indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries. Therefore, this meta-analysis aimed to determine the association between indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries. Methods International electronic databases such as PubMed, Science Direct, Global Health, African Journals Online, HINARI, Semantic Scholar, and Google and Google Scholar were used to search for relevant articles. The study was conducted according to the updated Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A random effect model at a 95% confidence interval was used to determine the association between indoor air pollution exposure and adverse pregnancy outcomes using STATA version 14. Funnel plot and Higgs I2 statistics were used to determine the publication bias and heterogeneity of the included studies, respectively. Results A total of 30 articles with 2,120,228 study participants were included in this meta-analysis. The pooled association between indoor air pollution exposure and at least one adverse pregnancy outcome was 15.5% (95%CI: 12.6–18.5), with significant heterogeneity (I2 = 100%; p < 0.001). Exposure to indoor air pollution increased the risk of small for gestational age by 23.7% (95%CI: 8.2–39.3) followed by low birth weight (17.7%; 95%CI: 12.9–22.5). Exposure to biomass fuel (OR = 1.16; 95%CI: 1.12–1.2), particulate matter (OR = 1.28; 95%CI: 1.25–1.31), and kerosene (OR = 1.38; 95%CI: 1.09–1.66) were factors associated with developing at least one adverse pregnancy outcomes. Conclusions We found that more than one in seven pregnant women exposed to indoor air pollution had at least one adverse pregnancy outcome. Specifically, exposure to particulate matter, biomass fuel, and kerosene were determinant factors for developing at least one adverse pregnancy outcome. Therefore, urgent comprehensive health intervention should be implemented in the area to reduce adverse pregnancy outcomes.

Introduction: Exposure to indoor air pollution such as biomass fuel and particulate matter is a significant cause of adverse pregnancy outcomes.However, there is limited information about the association between indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries.Therefore, this meta-analysis aimed to determine the association between indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries.
Methods: International electronic databases such as PubMed, Science Direct, Global Health, African Journals Online, HINARI, Semantic Scholar, and Google and Google Scholar were used to search for relevant articles.The study was conducted according to the updated Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.A random e ect model at a % confidence interval was used to determine the association between indoor air pollution exposure and adverse pregnancy outcomes using STATA version .Funnel plot and Higgs I statistics were used to determine the publication bias and heterogeneity of the included studies, respectively.
Results: A total of articles with , , study participants were included in this meta-analysis.The pooled association between indoor air pollution exposure and at least one adverse pregnancy outcome was .% ( %CI: .-. ), with significant heterogeneity (I = %; p < .

Introduction
Exposure to indoor air pollution is a persistent public health problem in the 21st century globally.The World Health Organization (WHO) released a report in 2022 indicating that around 3.2 million people die each year as a result of exposure to indoor air pollution.Of this death, more than 237,000 of them were under five children age (1).Exposure to indoor air pollution continues to be the leading cause of adverse pregnancy outcomes such as low birth weight, preterm birth, stillbirth, and neonatal mortality, which could need urgent intervention (2).According to the WHO report of 2019, about 20 million infants were born with low birth weight (LBW) whereas 15 million infants were preterm birth (3).
The magnitudes of adverse pregnancy outcomes are more prevalent in low-income countries because the majority of communities rely on biomass fuel for cooking and heating (4).Evidence from the recent global burden disease released in 2017 indicates that 60.9 million disability-adjusted life years were reported in low and middle-income countries as a result of exposure to air pollution (5).For instance, the odds of stillbirth adverse pregnancy outcomes were 23 times higher among lowincome countries than high-income countries (6), which highlights urgent interventions needed.Beyond adverse pregnancy outcomes, exposure to indoor air pollution has a significant effect on cognitive and economic status; which was lost 6.1% of Gross Domestic Product (GDP) in 2022 alone (7).
Various studies have investigated the association between exposure to indoor air pollution and adverse pregnancy outcomes in different parts of the country (4,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).However, the findings from these studies have been inconclusive and varied, which could hinder the implementation of effective intervention strategies to reduce adverse pregnancy outcomes.For instance, studies conducted in Ethiopia (18), Peru (19), and Zambia (20) showed that exposure to indoor air pollution increased the risk of small for gestational age, stillbirth, and miscarriages whereas a nonsignificant association with neonatal death (18).However, studies conducted in India (13) Indonesia (21) and Bangladesh ( 22) also showed that there is a significant association between exposure to indoor air pollution and neonatal death and low birth weight.
Moreover, exposure to indoor air pollution and all types of adverse pregnancy outcomes were not pertinently investigated in low and middle-income countries.In addition to this, the previous systematic reviews and meta-analyses on exposure to indoor air pollution did not assess exposures to biomass fuel and particulate matter (PM 10 and PM 2.5 ) together, which could underestimate the magnitude of adverse pregnancy outcomes (23-25).Therefore, the objective of this systematic review and meta-analysis aimed to determine the pooled prevalence of adverse pregnancy outcomes among pregnancy women exposure to indoor air pollution in low and middle-income countries.The results from this metaanalysis will provide essential evidence that can inform adverse pregnancy outcomes control program planners, policymakers, and healthcare providers.This evidence will be valuable in designing and implementing evidence-based interventions aimed at reducing the burden of stillbirth, low birth weight, small gestational age, and preterm birth, neonatal and prenatal mortality.outcome", "birth weight", "low birth weight", "low birthweight", "premature birth", "premature infant", "fetal growth retardation", "fetal development", "gestational age", "small for gestational age", "small gestational age", "fetal mortality", "fetal death", "perinatal mortality", "stillbirth", "embryo loss", "spontaneous abortion", "congenital abnormalities", "neural tube defects", "low and middle income country", "low income country", "middle income country", low and middle income countries".
All key terms were combined using the Boolean operators "AND" or "OR" as appropriate.The search was carried out up to December 1, 2023, by four authors independently (CD, YS, AE, and SDK).

Inclusion and exclusion criteria
In this meta-analysis, we included observational studies (cross-sectional, case-control, and cohort studies) on indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries.Studies published between 2000 and December 1, 2023, were included in the meta-analysis.However, qualitative studies, unretrievable studies, editorial letters, studies with poor methodological quality, and studies that did not report the outcome of interest were excluded from the metaanalysis.

Outcome assessment
The primary outcome of the study was to estimate the pooled association between indoor pollution exposure and adverse pregnancy outcomes in low and middle-income countries, calculated by dividing the number of adverse pregnancy outcomes by the total sample size and multiplying by 100.sample size.Five reviewers (LA, CD, FD, MA, and AM) screened the relevant articles for eligibility, and the quality of each article was evaluated using the Joana Brigg Institute (JBI) critical appraisal checklist (27).The quality of each study was independently assessed by the four authors (CD, AAT, AK, and NK), with scores measured on a scale of 100%.A quality score of <50% was used to include articles for further analysis (28, 29).In the case of any discrepancies encountered during the quality assessment, the mean score was computed from the evaluations of all reviewers to address and resolve any differences.

Statistical analysis and synthesis
DerSimonian and Liard's method of random effect model was used to determine the pooled association between indoor air pollution exposure and adverse pregnancy outcomes using STATA 14 (30).The Higgs I 2 statistic model was used to determine the heterogeneity of the included studies, with values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively (31).A p-value of less than 0.05 was considered indicative of the presence of heterogeneity.The publication bias was assessed using a funnel plot and Egger's test with a p-value less than 0.05 suggesting a publication bias (32).
Subgroup analysis was carried out based on various study characteristics such as sample size (large or small), year of publication (2020 and after or before 2020), quality of the study (high or low quality), and study setting (nationwide, healthcare facility or community level).Moreover, a sensitivity analysis was also performed to assess the influence of a single study on the pooled prevalence estimates.

Operational definition
Low birth weight: a birth weight of <2,500 g (33).Stillbirth: "a baby who dies after 28 weeks of pregnancy but before or during birth" (34).
Neonatal death: "deaths among live births during the first 28 completed days of life" (35).
Small for gestational age: those smaller in size than normal for their gestational age, most commonly defined as a weight below the 10th percentile for the gestational age (37).

Study selection
Using an international electronic database, a total of 2,002 articles was identified.Out of these, 296 duplicate articles were excluded using the Endnote reference manager and 817 articles were excluded based on their titles and abstracts.Besides, 10 articles were also excluded based on the quality assessment and outcomes of the interest.Finally, 30 full-text articles were eligible for this meta-analysis (Figure 1).

FIGURE
Forest plot of the pooled association between indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries, .

Association between indoor air pollution exposure and adverse pregnancy outcomes
Our analysis of the 30 included studies revealed significant heterogeneity among them (I 2 = 100%; p < 0.001).Hence, DerSimonian and Liard's method of random effect model was carried out to estimate the pooled association between exposure to indoor air pollution and adverse pregnancy outcomes.The results of the random effect model indicated the pooled prevalence of at least one adverse pregnancy outcome was 15.55% (95% CI: 12.61-18.49)(Figure 2).
Meta-analysis showed that there is a significant association between indoor air pollution exposure and adverse pregnancy outcomes.The high pooled prevalence of adverse pregnancy outcomes was small for gestational age (23.77%) followed by low birth weight (17.74%).The pooled prevalence of preterm birth among pregnant women exposed to indoor air pollution was 16.56%.Likewise, there is a significant association between indoor air pollution exposure and stillbirth (6.11%) (Table 2).

Publication bias assessment
A funnel plot was used to determine the publication bias, revealing an asymmetric distribution that strongly indicated the presence of publication bias (Figure 3).Further, statistical analysis employing the Egger regression test verified the absence of publication bias (p = 0.159).Similarly, the publication bias was also carried out using a funnel plot and statistical Egger test for low birth weight.The finding showed there was an asymmetric distribution that strongly indicated the presence of publication bias (Figure 4).However, the Egger regression test confirmed the absence of publication bias (p = 0.191).
Besides, the publication bias was also determined for small gestational age, preterm birth, and neonatal death using a funnel plot (Supplementary material 1).The Egger regression test confirmed the absence of publication bias among included studies for small gestational age (p = 0929) and preterm birth (p = 0.891), neonatal death (p = 0.322).

Subgroup analysis
To pinpoint the source of heterogeneity among included studies (I 2 = 100%, p < 0.001), subgroup analysis was conducted based on study setting (nationwide, healthcare facility or community), sample size (small or large), quality of the study (high or low) and year of publication (2020 and after or before 2020).

Sensitivity analysis
A sensitivity analysis was performed to evaluate the impact of individual studies on the overall pooled estimate of adverse pregnancy outcomes, and the results indicated that no single study exerted a significant effect (Figure 5).Similarly, we also evaluate the impact of individual studies on the overall pooled estimate of low birth weight, small for gestational age, preterm birth, neonatal death, and stillbirth, and the findings suggest that there is no evidence of a single study's effect on the overall pooled prevalence (Supplementary material 2).

FIGURE
Sensitivity analysis of the pooled association between indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries, .
The association between particulate matter exposure and adverse pregnancy outcomes was determined based on four studies (20,39,47,56).Two of the included studies had a positive association (39, 47), while negative association in the remaining two studies (20,56).The odds of adverse pregnancy outcomes were 1.28 times higher among pregnant women who had particulate matter exposure than those who had no exposure (OR = 1.28; 95% CI: 1.25-1.31),with significant heterogeneity (I 2 = 70.1%;p = 0.018) (Table 4).
Similarly, the association between kerosene exposure and adverse pregnancy outcomes was determined based on the finding of two studies (13, 44).There is a significant association in one study (44) and a non-significant in another study (13).Metaanalysis showed that the pregnant women who had kerosene exposure were 37% times more likely to have adverse pregnancy outcomes than counterparts (OR = 1.37; 95%CI: 1.09-1.66)(Table 4).

Discussion
This systematic review and meta-analysis aimed to determine the association between indoor air pollution exposure and adverse pregnancy outcomes in low and middle-income countries.The overall pooled prevalence of at least one adverse pregnancy outcome was found to be 15.5% (95% CI: 12.61-18.49);with extreme heterogeneity among included studies (I 2 = 100; p < 0.001).Specifically, exposure to indoor air pollution increased the risk of small gestational age by 23.7% (95%CI: 8.25-39.3),stillbirth (6.11%; 95%CI: 3.58-8.65),and neonatal mortality (2.48%; 95%CI: 1.37-3.60).This finding is corroborated by recent systematic reviews and meta-analyses (5,58,59).This is mainly due to exposure to carbon monoxide, particulate matter, and highly polluting biomass fuel could enhance the burden of adverse pregnancy outcomes (55).
There seems to be evidence that exposure to indoor air pollution has a significant contribution to stillbirth outcomes (2), which is consistent with the current meta-analysis.Similarly, our finding was supported by a recent study conducted in Ethiopia (18), which indicates that there is an association between exposure to indoor pollution and stillbirth.This might be due to the pregnant women being exposed to high-polluting indoor air pollution, which could contribute to a significant association with adverse pregnancy outcomes (stillbirth) (18).

FIGURE
Forest plot of odds ratio for the association between biomass fuel exposure and adverse pregnancy outcome, .
The current meta-analysis showed that one in six neonates could experience low birth weight (17.7%; 95%CI: 12.97-22.52),which is consistent with previous study conducted in Sub-Saharan Africa (14%) (60).The current finding was also supported by the previous meta-regression analysis of 204 countries (25), which indicates that exposure to ambient and household indoor air pollution PM 2.5 increased the risk of all low birth weight by 15.6%.This is mainly due to exposure to high polluting air pollution especially, anthropogenic particulates (PM 2.5 ) harmful to child health and growth, leading to low birth weight The odds of at least one adverse pregnancy outcome were 1.16 times higher among women who used high-polluting biomass fuel than those who used non-polluting biomass.Pregnant women exposed to highly polluting biomass fuels (namely, firewood and kerosene) have statistically significant factors for infants with low birth weight showing that low birth weight infants were sixteen percent times as likely to be born mothers exposed to high polluting biomass fuel than counterparts; which is consistent with the recent studies conducted by Kadam et al. (61).Increased exposure time to indoor air pollutants such as particulate matter, carbon monoxide, and sulfur dioxide has a significant impact on the growth and development of the fetus and subsequently low birth weight (62).The association between exposure to indoor air pollution and low birth weight is also established study done in developing countries (62).Therefore, mitigation measures such as cooking outdoors, decreasing exposure time, and improving the ventilation system with chimneys might play a significant role in decreasing adverse pregnancy outcomes (63).The pooled prevalence of preterm birth was found to be 16.56%; these high pregnancy outcomes might be due to the exposure to highly polluting biomass fuel than non-polluting fuel; which is supported by a study conducted in East India (57).The odds of at least adverse pregnancy outcomes were 1.28 times higher among pregnant women exposed to particulate matter than those not exposed to particulate matter.The current finding was also consistent with a study conducted in Ohio, which indicates that pregnancy women exposure to high particulate matter (PM 2.5 ) could increase the risk of preterm by 1.19 (64).A recent metaanalysis also confirmed that exposure to particulate matter (PM 2.5 ) could increase the risk of preterm birth by 1.10 (65).This is mainly because cooking with highly polluting biomass fuel in poorly ventilated homes generates high concentrations of particulate matter (10).Hence, it is important to reduce exposure time to household air pollution may be crucial for the reduction of adverse pregnancy outcomes.
In this meta-analysis, we found that there is a significant association between exposure to indoor air pollution and neonatal mortality.The pooled prevalence of neonatal mortality was found to be 2.48%, with extreme heterogeneity (I 2 = 99.9%;p < 0.001).This finding was in line with studies conducted in Bangladesh (43) and Pakistan (66).This finding was also supported by a study conducted in five world regions (67), which indicates that exposure to indoor air pollution increased the risk of neonatal mortality by 1.24 (95% CI: 1.14-1.34).This is mainly due to exposure to air pollution, which entails potential hazards for their neonates like lower birth weight, preterm birth, and lung developmental defects causing onset of respiratory diseases and reduced lung function in children (68)(69)(70).Because neonates need more air intake for survival and therefore inhale excessive oxygen as compared to children; air polluted with unwanted contaminants enters their lungs and provokes consequent deaths (70).It is also well documented that exposure to air pollution has a significant and positive association with neonatal mortality, particularly in low and middle-income countries (71).

Limitations and strengths of the study
The study followed the updated preferred reporting items for systematic review and meta-analysis.In this meta-analysis, all types of adverse pregnancy outcomes as a result of exposure to indoor air pollution were pertinently assessed.One of the limitations of this meta-analysis was that it did not establish causality between independent and dependent variables since the majority of the included studies were cross-sectional and casecontrol study designs.

Conclusions
We found that there was a significant association between indoor air pollution exposure and adverse pregnancy outcomes.The pooled adverse pregnancy outcomes among women exposed to indoor air pollution were found to be high; which calls for urgent interventions, particularly in low and middle-income countries, where cooking with biomass fuels is common.Therefore, the Ministry of Health, healthcare workers, and other concerned bodies should provide comprehensive public health intervention to reduce adverse pregnancy outcomes.Besides, mechanistic studies are needed to understand the underlying mechanisms of association between exposure to indoor air pollution and adverse pregnancy outcomes.Further studies on the toxicological effect on indoor air pollution (particulate matter, biomass fuel, kerosene) are needed to verify these findings.

FIGURE
FIGUREPRISMA flow diagram of the included studies for the systematic review and meta-analysis of exposure to indoor air pollution and adverse pregnancy outcomes in low and middle-income countries, .
meta-analysis to estimate the association between exposure to indoor air pollution and adverse pregnancy outcomes in low and middle-income countries, .
TABLE Pooled adverse pregnancy outcomes among pregnancy women exposed to indoor air pollution in low and middle-income countries, .
, five African countries (India, Pakistan, Guatemala,FIGUREFunnel plot of the pooled prevalence of at least one adverse pregnancy outcomes in low and middle-income countries, .FIGUREFunnel plot of the pooled association between indoor air pollution exposure and low birth weight in low and middle-income countries, .
TABLE The pooled factors associated with at least one adverse pregnancy outcome in low and middle-income countries, .