Wildfire smoke exposure during pregnancy and perinatal, obstetric, and early childhood health outcomes: A systematic review and meta-analysis.

BACKGROUND: Maternal exposure to air pollution during pregnancy is associated with adverse birth outcomes, although less is known for wildfire smoke. This systematic review evaluated the association between maternal exposure to wildfire smoke during pregnancy and the risk of perinatal, obstetric, and early childhood health outcomes. METHODS: We searched CINAHL Complete, Ovid/EMBASE, Ovid/MEDLINE, ProQuest, PubMed, Scopus, Web of Science, and Google Scholar to identify relevant epidemiological observational studies indexed through September 2023. The screening of titles, abstracts, and full-texts, data extraction, and risk of bias assessment was performed by pairs of independent reviewers. RESULTS: Our systematic search yielded 28,549 records. After duplicate removal, we screened 14,009 studies, identifying 31 for inclusion in the present review. Data extraction highlighted high methodological heterogeneity between studies, including a lack of geographic variation. Approximately 56.5% and 16% originated in the United States and Brazil, respectively, and fewer in other countries. Among the studies, wildfire smoke exposure during pregnancy was assessed using distance of residence from wildfire-affected areas (n = 15), measurement of air pollutant concentration during wildfires (n = 11), number of wildfire records (n = 3), aerosol index (n = 1), and geographic hot spots (n = 1). Pooled meta-analysis for birthweight and low birthweight were inconclusive, likely due to low number of methodologically homogenous studies. However, the reviewed studies provided suggestive evidence for an increased risk of birthweight reduction, low birthweight, preterm birth, and other adverse health outcomes. CONCLUSIONS: This review identified 31 studies evaluating the impacts of maternal wildfire smoke exposure on maternal, infant, and child health. Although we found suggestive evidence of harm from exposure to wildfire smoke during pregnancy, more methodologically homogenous studies are required to enable future meta-analysis with greater statistical power to more accurately evaluate the association between maternal wildfire smoke and adverse birth outcomes and other health outcomes.

Maternal Pertussis Vaccination, Infant Immunization, and Risk of Pertussis.

OBJECTIVES: Following the introduction of jurisdictional maternal pertussis vaccination programs in Australia, we estimated maternal vaccine effectiveness (VE) and whether maternal pertussis vaccination modified the effectiveness of the first 3 primary doses of pertussis-containing vaccines. METHODS: We conducted a population-based cohort study of 279 418 mother-infant pairs using probabilistic linkage of administrative health records in 3 Australian jurisdictions. Infants were maternally vaccinated if their mother had a documented pertussis vaccination ≥14 days before birth. Jurisdictional immunization records were used to identify receipt of the first 3 infant doses of pertussis-containing vaccines. Infant pertussis infections were identified using notifiable disease records. VE was estimated using Cox proportional hazard models. RESULTS: Pertussis was administered during 51.7% (n = 144 429/279 418) of pregnancies, predominantly at 28-31 weeks' gestation. VE of maternal pertussis vaccination declined from 70.4% (95% confidence interval [CI], 50.5-82.3) among infants <2 months old to 43.3% (95% CI, 6.8-65.6) among infants 7-8 months old and was not significant after 8 months of age. Although we observed slightly lower VE point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% CI, 0.61-3.39). CONCLUSIONS: Pertussis vaccination near 28 weeks' gestation was associated with lower risk of infection among infants through 8 months of age. Although there was some evidence of lower effectiveness of infant vaccination among maternally vaccinated infants, this did not appear to translate to greater risk of disease.

Association between maternal influenza vaccination and neurodevelopmental disorders in childhood: a longitudinal, population-based linked cohort study.

OBJECTIVE: To assess the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and the risk of a diagnosis of a neurodevelopmental disorder in early childhood. DESIGN: Retrospective cohort study. SETTING: Population-based birth registry linked with health administrative databases in Western Australia (WA). PARTICIPANTS: Singleton, liveborn children born between 1 April 2012 and 1 July 2016 in WA. EXPOSURE: Receipt of seasonal IIV during pregnancy obtained from a state-wide antenatal vaccination database. MAIN OUTCOME MEASURES: Clinical diagnosis of a neurodevelopmental disorder was recorded from hospital inpatient and emergency department records. We used Cox proportional hazard regression, weighted by the inverse-probability of treatment (vaccination), to estimate the hazard ratio (HR) of neurodevelopmental disorders associated with in utero exposure to seasonal IIV. RESULTS: The study included 140 514 children of whom, 15 663 (11.2%) were exposed to seasonal IIV in utero. The prevalence of neurodevelopmental disorders was 5.4%, including mental or behavioural (0.4%), neurological (5.1%), seizure (2.2%) and sleep disorders (2.7%). Maternal IIV was not associated with increased risk of neurodevelopmental disorders (HR 1.00; 95% CI 0.91 to 1.08). Children exposed in the first trimester had a lower risk of seizure disorders (adjusted HR [aHR] 0.73; 95% CI 0.54 to 0.998), and preterm children exposed any time during pregnancy had a lower risk of sleep disorders (aHR 0.63; 95% CI 0.41 to 0.98). CONCLUSIONS: We did not observe increased risk of neurodevelopmental disorders following in utero exposure to seasonal IIV. Although we observed some evidence for lower risk of seizure and sleep disorders, additional studies are required to confirm.

Timing and temporal trends of influenza and pertussis vaccinations during pregnancy in three Australian jurisdictions: The Links2HealthierBubs population-based linked cohort study, 2012-2017.

BACKGROUND: Antenatal inactivated influenza (IIV) and pertussis-containing vaccines (dTpa) offer protection against severe respiratory infections for pregnant women and infants <6 months of age. Both vaccines are recommended in pregnancy; however, little is known about temporal or jurisdictional trends and predictors of uptake. AIMS: To identify gaps and predictors of IIV and/or dTpa vaccinations in Australian pregnancies from 2012 to 2017. MATERIALS AND METHODS: We conducted a probabilistically linked, multi-jurisdictional population-based cohort study, drawing from perinatal data collections and immunisation databases. We used a generalised linear mixed model with a random effect term to account for clustering of multiple pregnancies within mothers, to calculate vaccination uptake, and identify predictors of uptake by maternal demographic, pregnancy, and health characteristics. RESULTS: Of 591 868 unique pregnancies, IIV uptake was 15%, dTpa 27% and 12% received both vaccines. Pertussis vaccinations in First Nations pregnancies were 20% lower than non-Indigenous pregnancies; dTpa was strongly associated with IIV uptake (risk ratio (RR): 8.60, 95% CI 8.48-8.73). This trend was temporally and jurisdictionally consistent. First Nations women were more likely to have had IIV in pregnancy before the introduction of dTpa in the pregnancy program: (RR: 1.48, 95% CI 1.40-1.57), but less likely after dTpa implementation (RR: 0.78, 95% CI 0.76-0.80). CONCLUSIONS: Inequity in vaccine uptake between First Nations and non-Indigenous pregnancies, and dismal rates of vaccination in pregnancy overall need urgent review, particularly before the next influenza pandemic or pertussis outbreak. If antenatal dTpa is driving IIV uptake, changes in antenatal healthcare practices are needed to ensure vaccines are offered equitably and optimally to protect against infection.

The effects of birth spacing on early childhood development in high-income nations: A systematic review.

Objective: This study aimed to systematically review the literature on the associations between birth spacing and developmental outcomes in early childhood (3-10 years of age). Studies examining the associations between interpregnancy intervals and child development outcomes during and beyond the perinatal period have not been systematically reviewed. Methods: We searched Ovid/MEDLINE, Global Health, PsycINFO, EMBASE, CINAHL Plus, Educational Source, Research Starters, ERIC, Scopus, PubMed, Social Science Research Network database, and ProQuest's Social Sciences Databases for relevant articles published between 1 January 1989 and 25 June 2021. Studies published in English, conducted in populations residing in high-income countries with any measure of birth spacing, and child development outcomes among children aged <10 years were included. Two authors independently assessed the eligibility of studies and extracted data on the study design, setting and population, birth spacing, outcomes, and results. Results: The search yielded 1,556 records, of which seven studies met the inclusion criteria. Five of these seven studies used birth intervals as the exposure measure. Definitions of exposure differed between the studies. Three studies reported an association between short birth spacing and poorer child development outcomes, and two studies reported an association between long birth spacing and poorer child development outcomes. Conclusion: Currently, limited evidence suggests that the adverse effects of sub-optimal birth spacing are observable beyond infancy.

Neuropsychiatric outcomes in offspring after fetal exposure to maternal influenza infection during pregnancy: A systematic review.

Increasing evidence suggests that influenza infection in pregnancy may disrupt fetal neurodevelopment. The impact of maternal influenza infection on offspring neuropsychiatric health has not been comprehensively reviewed. We systematically reviewed comparative studies evaluating associations between maternal influenza infection and neuropsychiatric health outcomes in offspring. We searched MEDLINE, EMBASE, CINAHL, and Web of Science for articles published until January 7, 2022. Included were English studies evaluating neuropsychiatric outcomes in offspring aged > 6 months born to women with and without influenza during pregnancy, defined as clinical or laboratory-confirmed influenza illness, or being pregnant during pandemics/epidemics. Of 12,010 records screened, 42 studies were included. Heterogeneity in study design, exposures, and outcome definitions precluded meta-analyses. Four of 14 studies assessing schizophrenia reported adjusted ratio estimates from 0.5 to 8.2; most 95% CIs contained the null value; study quality was high in three of four. Two studies reported an increased risk of schizophrenia with influenza exposure any time during pregnancy (adjusted incidence rate ratio 8.2, 95% CI: 1.4-48.8; adjusted odds ratio 1.3, 95% CI: 1.2-1.5); another reported a reduced risk with first-trimester exposure (adjusted risk ratio 0.5, 95% CI: 0.3-0.9). Seven studies of autism spectrum disorder reported adjusted ratio estimates from 0.9 to 4.0; all 95% CIs included the null value; study quality was high in four. No conclusions could be drawn about the association between exposure to maternal influenza and neuropsychiatric outcomes due to the limited quantity and quality of available research. Large observational studies with long-term follow-up are required to investigate these associations.

Diabetic and Hypertensive Disorders Following Miscarriage: A Protocol for Systematic Review and Meta-Analysis.

(1) Background: Miscarriages occur in approximately 15-25% of all pregnancies. There is limited evidence suggesting an association between history of miscarriage and the development of diabetic and hypertensive disorders in women. This systematic review aims to collate the existing literature and provide up to date epidemiological evidence on the topic. (2) Methods: We will search CINAHL Plus, Ovid/EMBASE, Ovid/MEDLINE, ProQuest, PubMed, Scopus, Web of Science, and Google Scholar, using a combination of medical subject headings, keywords, and search terms, for relevant articles related to the association between miscarriage and the risk of diabetic and hypertensive disorders. Cross-sectional, case-control, nested case-control, case-cohort, and cohort studies published from inception to April 2022 will be included in the search strategy. Three reviewers will independently screen studies and the risk of bias will be assessed using the Joanna Briggs Institute Critical Appraisal tool. Where the data permit, a meta-analysis will be conducted. (3) Results: The results of this systematic review will be submitted to a peer-reviewed journal for publication. (4) Conclusions: The findings of this systematic review will instigate efforts to manage and prevent reproductive, cardiovascular, and metabolic health consequences associated with miscarriages.

The risk of major structural birth defects associated with seasonal influenza vaccination during pregnancy: A population-based cohort study.

INTRODUCTION: Seasonal inactivated influenza vaccine (IIV) is routinely recommended during pregnancy to protect both mothers and infants from complications following influenza infection. While previous studies have evaluated the risk of major structural birth defects in infants associated with prenatal administration of monovalent pandemic IIV, fewer studies have evaluated the risk associated with prenatal seasonal IIV. METHODS: We conducted a population-based cohort study of 125,866 singleton births between 2012 and 2016 in Western Australia. Birth registrations were linked to the state's registers for congenital anomalies and a state prenatal vaccination database. We estimated prevalence ratios (PR) of any major structural birth defect and defects by organ system. Vaccinated pregnancies were defined as those with a record of IIV in the first trimester. Inverse probability treatment weighting factored for baseline probability for vaccination. A Bonferroni correction was applied to account for multiple comparisons. RESULTS: About 3.9% of births had a major structural birth defect. Seasonal IIV exposure during the first trimester was not associated with diagnosis of any major structural birth defect diagnosed within 1 month of birth (PR 0.98, 95% CI: 0.77, 1.28) or within 6 years of life (PR 1.02, 95% CI: 0.78, 1.35). We identified no increased risk in specific birth defects associated with seasonal IIV. CONCLUSION: Based on registry data for up to 6 years of follow-up, results suggest there is no association between maternal influenza vaccination and risk of major structural birth defects. These results support the safety of seasonal IIV administration during pregnancy.

Maternal influenza vaccination and child mortality: Longitudinal, population-based linked cohort study.

Influenza vaccination is recommended to protect mothers and their infants from influenza. Few studies have evaluated the association between maternal influenza vaccination and child mortality. We aimed to evaluate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and mortality among young children. This longitudinal, population-based cohort study included 191,247 maternal-child pairs in Western Australia between April 2012 and December 2017. Maternal vaccine information was obtained from a state-wide antenatal vaccination database. Mortality was defined as a record of a death registration. We used Cox proportional hazard models, weighted by the inverse-probability of treatment (vaccination), to estimate the hazard ratio of child mortality associated with in utero exposure to seasonal IIV. This study found no association between in utero exposure to seasonal IIV and mortality through age five years.

Prenatal influenza vaccination and allergic and autoimmune diseases in childhood: A longitudinal, population-based linked cohort study.

BACKGROUND: Few studies have evaluated the effect of maternal influenza vaccination on the development of allergic and autoimmune diseases in children beyond 6 months of age. We aimed to investigate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and subsequent diagnosis of allergic and autoimmune diseases. METHODS AND FINDINGS: This longitudinal, population-based linked cohort study included 124,760 singleton, live-born children from 106,206 mothers in Western Australia (WA) born between April 2012 and July 2016, with up to 5 years of follow-up from birth. In our study cohort, 64,169 (51.4%) were male, 6,566 (5.3%) were Aboriginal and/or Torres Strait Islander children, and the mean age at the end of follow-up was 3.0 (standard deviation, 1.3) years. The exposure was receipt of seasonal IIV during pregnancy. The outcomes were diagnosis of an allergic or autoimmune disease, including asthma and anaphylaxis, identified from hospital and/or emergency department (ED) records. Inverse probability of treatment weights (IPTWs) accounted for baseline probability of vaccination by maternal age, Aboriginal and/or Torres Strait Islander status, socioeconomic status, body mass index, parity, medical conditions, pregnancy complications, prenatal smoking, and prenatal care. The models additionally adjusted for the Aboriginal and/or Torres Strait Islander status of the child. There were 14,396 (11.5%) maternally vaccinated children; 913 (6.3%) maternally vaccinated and 7,655 (6.9%) maternally unvaccinated children had a diagnosis of allergic or autoimmune disease, respectively. Overall, maternal influenza vaccination was not associated with diagnosis of an allergic or autoimmune disease (adjusted hazard ratio [aHR], 1.02; 95% confidence interval [CI], 0.95 to 1.09). In trimester-specific analyses, we identified a negative association between third trimester influenza vaccination and the diagnosis of asthma (n = 40; aHR, 0.70; 95% CI, 0.50 to 0.97) and anaphylaxis (n = 36; aHR, 0.67; 95% CI, 0.47 to 0.95).We did not capture outcomes diagnosed in a primary care setting; therefore, our findings are only generalizable to more severe events requiring hospitalization or presentation to the ED. Due to small cell sizes (i.e., <5), estimates could not be determined for all outcomes after stratification. CONCLUSIONS: In this study, we observed no association between in utero exposure to influenza vaccine and diagnosis of allergic or autoimmune diseases. Although we identified a negative association of asthma and anaphylaxis diagnosis when seasonal IIV was administered later in pregnancy, additional studies are needed to confirm this. Overall, our findings support the safety of seasonal inactivated influenza vaccine during pregnancy in relation to allergic and autoimmune diseases in early childhood and support the continuation of current global maternal vaccine programs and policies.

Longitudinal, population-based cohort study of prenatal influenza vaccination and influenza infection in childhood.

BACKGROUND: Influenza vaccination is recommended to protect mothers and their infants from influenza infection. Few studies have evaluated the health impacts of in utero exposure to influenza vaccine among children more than six months of age. METHODS: We used probabilistically linked administrative health records to establish a mother-child cohort to evaluate the risk of influenza and acute respiratory infections associated with maternal influenza vaccination. Outcomes were laboratory-confirmed influenza (LCI) and hospitalization for influenza or acute respiratory infection (ARI). Adjusted hazard ratios (aHRs) accounted for child's Aboriginal status and were weighted by the inverse-probability of treatment. RESULTS: 14,396 (11.5%) children were born to vaccinated mothers. Maternally vaccinated infants aged < 6 months had lower risk of LCI (aHR: 0.33; 95% CI: 0.13, 0.85), influenza-associated hospitalization (aHR: 0.39; 95% CI: 0.16, 0.94) and ARI-associated hospitalization (aHR: 0.85; 95% CI: 0.77, 0.94) compared to maternally unvaccinated infants. With the exception of an increased risk of LCI among children aged 6 months to < 2 years old following first trimester vaccination (aHR: 2.28; 95% CI: 1.41, 3.69), there were no other differences in the risk of LCI, influenza-associated hospitalization or ARI-associated hospitalization among children aged > 6 months. CONCLUSION: Study results show that maternal influenza vaccination is effective in preventing influenza in the first six months and had no impact on respiratory infections after two years of age.

Interpregnancy interval and hypertensive disorders of pregnancy: A population-based cohort study.

BACKGROUND: Despite extensive research on risk factors and mechanisms, the extent to which interpregnancy interval (IPI) affects hypertensive disorders of pregnancy in high-income countries remains unclear. OBJECTIVES: To examine the association between IPI and hypertensive disorders of pregnancy in a high-income country setting using both within-mother and between-mother comparisons. METHODS: A retrospective population-based cohort study was conducted among 103 909 women who delivered three or more consecutive singleton births (n = 358 046) between 1980 and 2015 in Western Australia. We used conditional Poisson regression with robust variance, matching intervals of the same mother and adjusted for factors that vary within-mother across pregnancies, to investigate the association between IPI categories (reference 18-23 months), and the risk of hypertensive disorders of pregnancy. For comparison with previous studies, we also applied unmatched Poisson regression (between-mother analysis). RESULTS: The incidence of preeclampsia and gestational hypertension during the study period was 4%, and 2%, respectively. For the between-mother comparison, mothers with intervals of 6-11 months had lower risk of preeclampsia with adjusted relative risk (RR) 0.92 (95% confidence interval [CI] 0.85, 0.98) compared to reference category of 18-23 months. With the within-mother matched design, we estimated a larger effect of long IPI on risk of preeclampsia (RR 1.29, 95% CI 1.18, 1.42 for 60-119 months; and RR 1.30, 95% CI 1.10, 1.53 for intervals ≥120 months) compared to 18-23 months. Short IPIs were not associated with hypertensive disorders of pregnancy. CONCLUSIONS: In our cohort, longer IPIs were associated with increased risk of preeclampsia. However, there was insufficient evidence to suggest that short IPIs (<6 months) increase the risks of hypertensive disorders of pregnancy.

Early Childhood Health Outcomes Following In Utero Exposure to Influenza Vaccines: A Systematic Review.

CONTEXT: Vaccination during pregnancy is an effective strategy for preventing infant disease; however, little is known about early childhood health after maternal vaccination. OBJECTIVES: To systematically review the literature on early childhood health associated with exposure to influenza vaccines in utero. DATA SOURCES: We searched CINAHL Plus, Embase, Medline, Scopus, and Web of Science for relevant articles published from inception to July 24, 2019. STUDY SELECTION: We included studies published in English reporting original data with measurement of in utero exposure to influenza vaccines and health outcomes among children <5 years of age. DATA EXTRACTION: Two authors independently assessed eligibility and extracted data on study design, setting, population, vaccines, outcomes, and results. RESULTS: The search yielded 3647 records, of which 9 studies met the inclusion criteria. Studies examined infectious, atopic, autoimmune, and neurodevelopmental outcomes, and all-cause morbidity and mortality. Authors of 2 studies reported an inverse association between pandemic influenza vaccination and upper respiratory tract infections, gastrointestinal infections, and all-cause hospitalizations; and authors of 2 studies reported modest increased association between several childhood disorders and pandemic or seasonal influenza vaccination, which, after adjusting for confounding and multiple comparisons, were not statistically significant. LIMITATIONS: Given the small number of studies addressing similarly defined outcomes, meta-analyses were deemed not possible. CONCLUSIONS: Results from the few studies in which researchers have examined outcomes in children older than 6 months of age did not identify an association between exposure to influenza vaccines in utero and adverse childhood health outcomes.

Effect of interpregnancy interval on gestational diabetes: a retrospective matched cohort study.

PURPOSE: To examine the association between interpregnancy interval (IPI) and gestational diabetes using both within-mother and between-mother comparisons. METHODS: A retrospective cohort study of 103,909 women who delivered three or more consecutive singleton births (n = 358,046) between 1 January 1980 and 31 December 2015 in Western Australia. The association between IPI and gestational diabetes was estimated using conditional logistic regression, matching pregnancies to the same mother and adjusted for factors that vary within-mother across pregnancies. For comparison with previous studies, we also applied unmatched logistic regression (between-mother analysis). RESULTS: The conventional between-mother analysis resulted in adjusted odds ratios (aOR) of 1.13 (95% CI, 1.06-1.21) for intervals of 24-59 months and 1.51 (95% CI, 1.33-1.70) for intervals of 120 or more months, compared with IPI of 18-23 months. In addition, short IPIs were associated with lower odds of gestational diabetes with (aOR: 0.89; 95% CI, 0.82-0.97) for 6-11 months and (aOR: 0.92; 95% CI, 0.85-0.99) for 12-17-month. In comparison, the adjusted within-mother matched analyses showed no statistically significant association between IPIs and gestational diabetes. All effect estimates were attenuated using the within-mother matched model. CONCLUSION: Our findings do not support the hypothesis that short IPI (<6 months) increases the risk of gestational diabetes and suggest that observed associations in previous research might be attributable to confounders that vary between mothers.

'Links2HealthierBubs' cohort study: protocol for a record linkage study on the safety, uptake and effectiveness of influenza and pertussis vaccines among pregnant Australian women.

INTRODUCTION: Pregnant women and infants are at risk of severe influenza and pertussis infection. Inactivated influenza vaccine (IIV) and diphtheria-tetanus-acellular pertussis vaccine (dTpa) are recommended during pregnancy to protect both mothers and infants. In Australia, uptake is not routinely monitored but coverage appears sub-optimal. Evidence on the safety of combined antenatal IIV and dTpa is fragmented or deficient, and there remain knowledge gaps of population-level vaccine effectiveness. We aim to establish a large, population-based, multi-jurisdictional cohort of mother-infant pairs to measure the uptake, safety and effectiveness of antenatal IIV and dTpa vaccines in three Australian jurisdictions. This is a first step toward assessing the impact of antenatal vaccination programmes in Australia, which can then inform government policy with respect to future strategies in national vaccination programmes. METHODS AND ANALYSIS: 'Links2HealthierBubs' is an observational, population-based, retrospective cohort study established through probabilistic record linkage of administrative health data. The cohort includes births between 2012 and 2017 (~607 605 mother-infant pairs) in jurisdictions with population-level antenatal vaccination and health outcome data (Western Australia, Queensland and the Northern Territory). Perinatal data will be the reference frame to identify the cohort. Jurisdictional vaccination registers will identify antenatal vaccination status and the gestational timing of vaccination. Information on maternal, fetal and child health outcomes will be obtained from hospitalisation and emergency department records, notifiable diseases databases, developmental anomalies databases, birth and mortality registers. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Western Australian Department of Health, Curtin University, the Menzies School of Health Research, the Royal Brisbane and Women's Hospital, and the West Australian Aboriginal Health Ethics Committees. Research findings will be disseminated in peer-reviewed journals, at scientific meetings, and may be incorporated into communication materials for public health agencies and the public.

Effects of interpregnancy interval on pregnancy complications: protocol for systematic review and meta-analysis.

INTRODUCTION: Interpregnancy interval (IPI) is the length of time between a birth and conception of the next pregnancy. Evidence suggests that both short and long IPIs are at increased risk of adverse pregnancy and perinatal outcomes. Relatively less attention has been directed towards investigating the effect of IPI on pregnancy complications, and the studies that have been conducted have shown mixed results.This systematic review will aim to provide an update to the most recent available evidence on the effect of IPI on pregnancy complications. METHOD AND ANALYSIS: We will search electronic databases such as Ovid/MEDLINE, EMBASE, CINAHL, Scopus, Web of Science and PubMed to identify peer-reviewed articles on the effects of IPI on pregnancy complications. We will include articles published from start of indexing until 12 February 2018 without any restriction to geographic setting. We will limit the search to literature published in English language and human subjects. Two independent reviewers will screen titles and abstracts and select full-text articles that meet the eligibility criteria. The Newcastle-Ottawa tool will be used to assess quality of observational studies. Where data permit, meta-analyses will be performed for individual pregnancy complications. A subgroup analyses by country categories (high-income vs low and middle-income countries) based on World Bank income group will be performed. Where meta-analysis is not possible, we will provide a description of data without further attempt to quantitatively pool results. ETHICS AND DISSEMINATION: Formal ethical approval is not required as primary data will not be collected. The results will be published in peer-reviewed journals and presented at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42018088578.