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Epidemiology
Original research
Maternal modifiable factors and risk of congenital heart defects: systematic review and causality assessment
  1. Judith C Gomersall1,
  2. Vivienne M Moore1,
  3. Renae C Fernandez2,
  4. Lynne C Giles3,
  5. Luke E Grzeskowiak4,
  6. Michael J Davies5,
  7. Alice R Rumbold6
  1. 1School of Public Health and Lifecourse and Intergenerational Health Research Group, The University of Adelaide, Adelaide, South Australia, Australia
  2. 2Robinson Research Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, South Australia, Australia
  3. 3School of Public Health, The University of Adelaide, Adelaide, South Australia, Australia
  4. 4Women and Kids Theme, South Australian Health and Medical Research Institute and College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
  5. 5The Robinson Research Institute and Lifecourse and Intergenerational Health Research Group, The University of Adelaide, Adelaide, South Australia, Australia
  6. 6Women and Kids Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
  1. Correspondence to Dr Judith C Gomersall; judith.gomersall{at}adelaide.edu.au

Abstract

Objective Primary prevention strategies are critical to reduce the global burden of congenital heart defects (CHDs); this requires robust knowledge of causal agents. We aimed to review associations between CHDs and maternal advanced age, obesity, diabetes, hypertension, smoking and alcohol consumption and assess the causal nature of the associations.

Design Systematic review of reviews with application of a Bradford Hill criteria score-based causal assessment system.

Data sources We searched PubMed, Embase and Episteminokos (January 1990–April 2023).

Eligibility criteria Systematic reviews of original epidemiological studies reporting association (relative risk) between one or more of the above maternal factors and CHDs overall (any type) in subsequent offspring.

Data extraction and synthesis Two independent reviewers selected eligible reviews, assessed the risk of bias and assigned the strength of evidence for causality.

Results There was strong evidence of a causal relationship between CHDs and maternal obesity (prepregnancy and early pregnancy) and pre-existing diabetes (six of seven Bradford Hill criteria met). For pre-existing hypertension (strength and biological gradient not met), and advanced age (strength, consistency and biological gradient not met), causal evidence was moderate. Evidence for the causal contribution of gestational diabetes, gestational hypertension, smoking and alcohol consumption was weak (strength, consistency, temporality and biological gradient not met).

Conclusions CHDs can be reduced with stronger action to reduce maternal obesity and pre-existing diabetes prevalence. Investigating environmental exposures that have received limited attention, such as air pollutants and chemical exposures, is important to further inform prevention.

  • risk factors
  • primary prevention
  • systematic review
  • congenital heart disease

Data availability statement

Data are available on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2023-082961

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • This is the first systematic review of associations between modifiable maternal factors and congenital heart defects to assess causality and rank priorities for primary prevention strategy.

    • We performed a comprehensive search of relevant databases to identify relevant associations.

    • We used best practice systematic review methodology and an established method (Bradford Hill) to assess the weight of evidence for the causal nature of associations.

    • Unknown risk of publication bias is a limitation as reviews published in languages other than English and reviews in the grey literature were not eligible.

    Introduction

    Congenital heart defects (CHDs) are the most common class of congenital anomalies.1 Live birth prevalence is 8–10 cases per 1000.1 2 The impacts of CHDs on children, their families, the health system and society are wide-ranging. They are a leading cause of child mortality, often require complex treatment and are associated with long-term cardiovascular and neurological morbidity for afflicted children.3 4 Having a child with a CHD can be distressing for the whole family, with negative effects on parent mental health and family functioning.5 6 Over the last two decades, advancements in medical technology have greatly improved the rate of survival of children with critical CHD and led to a high proportion of individuals with CHD having near-normal life expectancy.5–7 Thus, adverse health and economic impacts associated with this class of congenital anomalies are becoming more evident, and a strategy to mitigate risks associated with CHDs is a priority for global health policy.7

    Genetic factors are present in 15%–40% of CHD cases.8 For the remaining, environmental and chemical exposures are implicated, although causes are often not well understood.9 10 In 2007, the American Heart Association published a scientific statement on non-inherited CHDs risk factors which identified maternal rubella, phenylketonuria, pre-existing diabetes mellitus (PDM), indomethacin for tocolysis and exposures to thalidomide, vitamin A congeners or retinoid, as definitive risk factors.11

    Subsequently, there has been a marked expansion in research examining CHD susceptibility, with a focus on reporting risks associated with maternal diseases and lifestyle.12 This is drawn from observational studies, as it is unethical to obtain causal evidence through experimental studies. Limited attention has been paid to assessing causality.12 However, inference of causation from observational studies has been achieved without human trials (eg, for thalidomide). Employing a comparable established strategy for imputing causation from observational studies of CHDs is crucial to target investment into areas that will have the greatest impact on CHDs reduction. Recent contributions in causal assessment13–16 and systematic review methodology17 18 facilitate implementing such an approach.

    Therefore, here, we present a systematic review of CHDs risks associated with select, prevalent modifiable maternal factors (advanced maternal age, obesity, diabetes mellitus, hypertension, cigarette smoking and alcohol use) and assess causality using established criteria.

    Methods

    This systematic review was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions,19 with modifications for undertaking a review of exposures and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.20 The review protocol was not registered, however, it was approved, prospectively, by a panel of experts.

    Eligibility criteria

    Systematic reviews of original epidemiological studies published January 1990–April 2023 in English reporting associations (risk ratio (RR) or OR, summary or single study, adjusted or unadjusted) between one or more of the above maternal factors and CHDs overall (any specific type) in subsequent offspring were included. Our included factors are modifiable, prevalent, routinely collected and characterised by the debate over appropriate recommendations for women in the periconception period. Non-peer-reviewed systematic reviews were excluded (eg, those conducted for government or committees not published). See online supplemental table S1 for further details about the review eligibility criteria.

    Search and study selection

    To identify relevant systematic reviews, we systematically searched the databases PubMed, Embase and Epistemonikos, from database inception to 28 April 2023 (three searches, initial on 14 April 2021, with top-ups on 27 May 2022 and 28 April 2023). The database selection was informed by which combination of bibliographic databases is most efficient to retrieve systematic reviews in overviews of reviews.21 We scanned included reviews to identify potentially relevant records not retrieved by the primary search. Database search strategies are in online supplemental material S1.

    Two authors independently selected reviews for inclusion. Disagreements were resolved through consensus after discussion and consultation with a third author if necessary.

    Data collection and analysis

    Two authors independently extracted characteristics and data from the included reviews using a prespecified data extraction form tailored for this review. Characteristics extracted from the included reviews were: review title and authors; publication date, search dates and date review was last assessed as up to date; the number of included studies and number of participants in the studies and their characteristics (eg, countries where the studies were conducted, inclusion criteria); quality of the included studies (risk of bias and certainty as reported by reviewers); exposures and comparators (referents) relevant to this review; definition of the CHDs overall outcome (and whether this outcome was the primary or secondary outcome); any other characteristics relevant to assess review quality.

    Statistical data extracted were: summary associations (including for eg, RRs, ORs, with 95% CI), the number of studies and participants contributing data, and statistics required for risk of bias assessments (eg, heterogeneity and publication bias statistics). When meta-analyses were not performed, we extracted single study results. We did not contact authors for unpublished information and data.

    One author assessed the risk of bias of each included systematic review using the Risk of Bias in Systematic Reviews tool22 with a second independently verifying the assessments.

    We summarised associations by factor in narrative and tables, applied select Bradford Hill (BH) criteria13 to assess the causal nature of associations and followed the score-based system used in two recent reviews of epidemiologic evidence17 18 to classify the strength of causal evidence.

    We assessed the BH criteria strength, consistency, temporality, biological gradient, plausibility, analogy and coherence. From the original Hill criteria, the specificity criterion was deemed non-applicable given known multifactorial causes of CHDs, and the experimental evidence criterion was deemed non-applicable as ethical considerations prevent the study of the maternal factors as the cause of disease under controlled conditions. We awarded 1 point for criterion satisfaction and rated overall scores 6–7, 4–5, 0–3 as strong, moderate or weak evidence of causality, respectively. We used knowledge gathered in purposive database searches to make plausibility, analogy and coherence judgments.

    Required for BH criterion satisfaction:

    • Strength of association—relative risk ≥2 with precision (we followed Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group recommendations).14

    • Consistency of association—≥50% of included studies showed an association in the expected direction (we studied forest plots). When summary associations were reported without forest plots, we relied on the GRADE method14 23 that focuses on unexplained inconsistency indicated by the I2 heterogeneity statistic, and we required I2≤50% in most associations, including the one based on pooling data from the largest number of studies for criterion met.

    • Temporality—included studies for the association established a temporal direction by design.

    • Biological gradient—≥50% of tests for a dose–response relationship either showed a statistically significant trend or an apparent change in the magnitude of effect in the expected direction.

    • Plausibility—Possible mechanisms underlying a causal relationship between the maternal factor (exposure) and CHDs in subsequent offspring exist.

    • Analogy—Analogous relationships exist.

    • Coherence of evidence—The association does not conflict with existing knowledge about CHDs and the maternal factor (eg, no conflicting patterns in prevalence and distribution).

    For factors with strong causal evidence, we estimated the population attributable fraction (PAF) of CHD cases (range based on the lowest and highest pooled risk estimates reported). We used the Levin’s formula as used previously,24 which requires the RR estimate for the influence of the factor on CHDs, and the prevalence of the risk factor. For each factor, we calculated PAF estimates of CHD cases, one assuming the lowest RR indicated by our systematic review data, and the other assuming the highest. For maternal factor prevalence, we used the most recent robust global estimates we could identify in the literature, specifically 16.3% for obesity periconception24 and 1% for pregestational diabetes mellitus.25

    Patient and public involvement

    None as this systematic review used study-level data and no individual-level data or participants were involved.

    Results

    From 3724 records retrieved, we included 27 reviews26–52 (online supplemental figure S1). Characteristics of the reviews are in online supplemental table S2, with the risk of bias assessments (by review, online supplemental table S3 and domain, online supplemental figure S2). 11 of the reviews, we assessed at low risk of bias27 29 30 33–35 40 41 43 47 49 and the remaining26 28 31 36–39 42 44–46 48 50–52 unclear risk of bias.

    Overall, evidence of causal effect was strong for obesity and PDM and moderate for advanced maternal age and pre-existing hypertension. The remaining factors were assessed as having weak evidence of causality (table 1). The PAF was 2.7%–4.9% for maternal obesity and 2.1%–2.7% for PDM.

    View this table:
    Table 1

    Bradford Hill criteria assessment of strength of evidence for causal nature of associations between prevalent maternal factors and CHDs

    The assessment of each BH criterion is discussed below for each factor, except for coherence, which requires consideration of the evidence across all factors and is, therefore, at the end of the results.

    Advanced age

    One pooled association (unadjusted)26 showed a modest elevated risk of CHDs in women ≥35 years (preconception or during pregnancy) compared with those younger (RR 1.15, 95% CI 1.06 to 1.25, I2 54%, 8 studies). Another45 did not show a significant elevation in risk of CHDs for advanced maternal age not further specified (OR 1.04, 95% CI 0.96 to 1.12; I2 74%; 19 studies; confirmed in subgroup analysis restricted based on design and adjustment). Two further reviews32 39 of case–control studies (n=7) reported single study conflicting results for advanced maternal age not further specified. Both pooled associations do not meet the strength criterion (summary effect size <2) and residual confounding cannot be ruled out.

    The criterion for consistency is not met. Moderate heterogeneity was detected in the meta-analyses assessing age ≥35 years26 and in the forest plot of the pooled association for advanced age not further specified45 less than half of included studies indicated significant associations in the expected direction.

    Temporality is met as advanced maternal age at conception precedes CHD development. The biological gradient criterion is not, as no review provided data to assess whether risk increases with age.

    Several biological mechanisms could explain associations between advanced maternal age and CHDs. The risk of aneuploidy and other congenital anomalies increases dramatically with advanced age, which can give rise to CHDs occurring as part of a genetic syndrome (eg, Down syndrome).53 Maternal ageing can induce changes to epigenome54 that may influence the regulation of cardiac development.55 The criterion for analogy is met as advanced maternal age is associated with other congenital anomalies of chromosomal and non-chromosomal origin.26

    Obesity

    Pooled risk estimates reported in six reviews27 35 43 45 51 52 demonstrate a small, elevated risk of CHDs in women with obesity relative to normal weight (17%–32%), thus strength of association criterion is not met (table 2).

    View this table:
    Table 2

    Summary associations between maternal obesity and CHDs

    The criterion for consistency is with most associations significant in the expected direction and most I2 statistics <50%.

    The criterion for temporality is met as the pooled risk estimates were strengthened in the meta-analysis restricted to studies that assessed weight prepregnancy rather than early pregnancy (OR 1.44, 95% CI 1.23 to 1.68). There is also evidence of a biological gradient, for example, one review35 found the risk of CHDs increased by 7% for every 5 kg/m2 increase in the maternal body mass index.

    The criterion plausibility is met. Abnormal glucose metabolism in early pregnancy is strongly implicated in CHD development in human and animal studies (described in more detail below). Both type 2 and gestational diabetes mellitus (GDM are increased in women with prepregnancy obesity, as is mild glucose intolerance in the absence of overt diabetes.56 Even small increases in maternal glucose levels in early pregnancy confer increased CHDs risk,57 which may explain why risk is attenuated but remains elevated with maternal obesity in meta-analyses that exclude women with pre-existing or GDM. Fetal cardiac development may be adversely affected by other metabolic and inflammatory disturbances present with maternal obesity including abnormal lipid metabolism, hyperinsulinaemia, insulin resistance, increased oxidative stress, endothelial cell dysfunction and subclinical inflammation which can impair placental function with detrimental effects on fetal vascular circulation.58 59 Additionally, a poor diet during pregnancy, particularly low intake of micronutrients such as folate, is more common

    among women with obesity and may contribute to risk of CHDs.60

    The criterion for analogy is met as maternal obesity is associated with other congenital anomalies (eg, neural tube defects, cleft lip).43 60

    Diabetes mellitus (pre-existing including types 1 and 2 or gestational: treated or untreated)

    For PDM, the criteria for strength and consistency are met. Pooled estimates in five reviews28 37 41 42 49 demonstrate that women with PDMs mellitus (type 1 or 2) have a 3–4 fold increase in risk of having a baby with a CHD compared with women without diabetes (table 3).

    View this table:
    Table 3

    Summary associations between maternal diabetes mellitus, hypertension and CHDs

    The direction of effect is very consistent, with >50% of the studies in review analyses showing significant associations in the expected direction. However, significant heterogeneity was detected. Subgroup analysis28 indicated a higher risk among women in North America than in Asia, Europe or Oceania. The high heterogeneity could also reflect the inclusion of mothers with either type 1 or 2 diabetes28 and/or differences in management.

    Criteria for strength and consistency were not met for GDM, with pooled estimates in reviews28 37 49 typically not exceeding 2. Substantial heterogeneity was identified, which may reflect differences in the rate of maternal obesity across studies reporting on GDM. While no pooled analyses examined potential modification of GDM-CHDs association by maternal weight, one review37 reported that elevated risk associated with GDM was present only in women with GDM and obesity (OR 3.47, 95% CI 1.7 to 7.0; data from one study).61

    For PDM, the temporality criterion is met, as by definition the disease diagnosis predates pregnancy. The criterion for biological gradient is not met as no review reported CHDs risk according to indicators of diabetes severity, for example, based on degree of hyperglycaemia. No reviews examined differences in risk based on treatment of diabetes.

    For GDM, temporality and biological gradient criteria are not met as GDM is commonly diagnosed mid-pregnancy, and no review examined risk by disease severity.

    Animal studies provide compelling evidence linking maternal hyperglycaemia during embryogenesis to cardiac malformations via a number of pathways including overexpression of glucose transporter proteins, impaired left-right axis formation, altered expression of genes such as Pax3, increased oxidative stress leading to apoptosis and altered cardiac cell proliferation and dysregulation of signalling pathways critical for cardiac development.62 63 Several of these pathways have also been linked to increased risk of a wide range of other congenital anomalies in diabetic pregnancies,64 thus also satisfying the criteria for analogy. Based on the available data, it seems that the major organ systems affected by PDM are the cardiovascular and the central nervous systems, which could be related to their embryonic origin in the neural crest.64 In the case of GDM, although it is diagnosed mid-pregnancy, it is possible that subclinical changes in glucose metabolism arise earlier in pregnancy65 contributing to elevated risk. Early antenatal scans suggest heart of fetus carried by women who go on to develop GDM are subtly different to those who did not, suggesting early glycaemic changes or other factors related to maternal risk profile may be at play.66 PDM and GDM may also lie on a common pathway, either directly genetic or via shared mediator such as obesity. Alternatively, the association between GDM and CHDs could reflect a degree of misclassification of undiagnosed PDM as GDM, as a large proportion of women with GDM are diagnosed with type 2 diabetes in the postnatal period.67 Thus, for PDM and GDM, plausibility criterion is met.

    Hypertension (pre-existing or gestational or either: treated or untreated and either/overall)

    For pre-existing hypertension (treated or untreated) the strength criterion is not met, with the one summary RR<2; however, the consistency criterion is, as 8 of the 12 studies in this meta-analysis50 showed a significantly elevated risk. Temporality was satisfied by definition (table 3).

    For gestational hypertension, also reported in one pooled analysis,50 the strength and consistency criterion is not satisfied. Additionally, as gestational hypertension is the onset of hypertension after 20 weeks of gestation, the criterion for temporality is not met.

    No data were identified to support a biological gradient for pre-existing or gestational hypertension.

    Three reviews30 39 40 reported data for any hypertension in pregnancy, comprising of either pre-existing or gestational, treated or untreated, and one40 reported treated and untreated separately.

    For treated hypertension, the pooled association40 showed a doubling in risk but with considerable imprecision. Further, on stratification by treatment type variation in risk based on treatment type was seen, such that there remained a significant association for women treated with beta-blockers, however, not ACE inhibitors or Calcium channel blockers. Notably, covariates adjusted for varied, and very few studies reported adjustment for maternal diabetes. Thus, the criterion for strength is not met. The criterion for evidence consistency is, however, as forest plot examination showed all but one study indicating significant risk elevation.

    For untreated hypertension assessed at any time during pregnancy, a criterion for strength is not met, with a pooled risk of 1.5 reported,40 and variation in the degree of control for confounding. The criterion for consistency is met, with most studies pooled showing significant risk elevation.

    With the uncertainty surrounding the timing of hypertension onset in the studies included in the analyses, the temporality criterion is not satisfied, for either treated or untreated hypertension. Neither is the criterion for biological gradient, with no data on the severity of these hypertensions in relation CHDs risk provided.

    For any hypertension during pregnancy (treated and untreated combined), the criterion for strength is not met as the pooled risk estimate40 indicated a 1.8-times increased risk of CHDs. The magnitude of risk elevation suggested by most of the single studies reported in the other two reviews was similar.30 39 The criterion for consistency is clearly met with most studies indicating similar risk elevations.

    The plausibility criterion is met for hypertension that predates the time of cardiac development in the fetus, whether treated or not. Maternal hypertension is associated with poor placentation, placental insufficiency and chronic hypoxia, which contribute to increased oxidative stress and angiogenic imbalances, with direct evidence of altered expression of angiogenic factors including VEGF (vascular endothelial growth factor) and hypoxia-inducing genes in human fetal hearts with CHD.68 In addition, there may be shared genetic risks predisposing to both maternal hypertension and fetal CHD.69 Further, animal studies indicate there may be direct teratogenic effect of medications such as beta-blockers.70 Criteria for analogy are met as maternal hypertension (untreated and treated) has been associated with an increased risk of other types of birth defects including hypospadias.71

    Smoking

    The criterion for strength is not met. Pooled associations29 34 36 47 suggest smoking during pregnancy is associated with increased risk in the order of 10%–20%. One review only specifically examined smoking in very early pregnancy33 and reported an imprecise association suggesting a 3-fold risk elevation (OR 2.80; 95% CI 1.7 to 4.4; 1 study, 365 participants). Criterion for consistency is not met, due to a high degree of heterogeneity and variation in direction of associations across studies in the reviews (table 4).

    View this table:
    Table 4

    Summary associations between maternal smoking and CHDs

    Criterion for temporality is not met as the vast majority of studies assessed smoking at any time in pregnancy and, therefore, could not confirm that exposure occurred in the critical period of fetal cardiac development.

    The available evidence also does not satisfy the criterion for biological gradient, as no clear differences were reported in reviews that attempted to look at dose-response effects.33 34 47 Important caveats when interpreting this finding are imprecision and reporting bias problems that plague research on the effects of smoking (and alcohol), (other than in those using rare methodologies (eg, cotinine studies)).

    Criteria for plausibility are met. Animal studies demonstrate nicotine exposure during embryogenesis increases oxidative stress in fetal hearts in a dose-dependent manner, altering gene expression related to cardiomyocyte growth resulting in reduced cell proliferation and altered epithelial to mesenchymal transition.72 It has also been postulated that toxins in cigarette smoke may induce epigenetic changes in the fetus and placenta altering micro RNA expression with effects on fetal development.73 Smoking also causes prematurity, which frequently co-occurs with congenital anomalies, presenting another plausible common pathway between smoking and cardiac defects.74

    Smoking is associated with an increased risk of other congenital anomalies, including cleft lip and/or palate75 therefore, criterion for analogy is met.

    Alcohol

    Strength criterion is not met for any alcohol consumption, prepregnancy or during pregnancy, with all pooled associations <2.44–46 48 Criterion for consistency is not met as there was high variation in direction of risk estimates and substantial heterogeneity. This likely reflects variation in adjustment for confounding, which typically included sociodemographic factors and multivitamin/folic acid use but not for concurrent chronic disease (table 5).

    View this table:
    Table 5

    Summary associations between maternal alcohol consumption and CHDs

    For heavy (≥2 drinks/24 g per day) and binge (≥4 or 5 drinks/any one occasion) drinking, one review 201546 reported marked risk elevation (2–3 fold) with either, but with considerable imprecision. Another48 reported only a modest increase in risk with binge drinking, and the forest plot revealed variation in the direction of effect estimates. Thus, the criteria for strength and consistency are not met. As with smoking, the variation in risk estimates and imprecision found likely reflects variation in methods for ascertainment of exposure and degree to which this is influenced by recall and social desirability bias.

    The temporality criterion is not met. One review only48 reported risk estimates associated with drinking during the periconception period, specifically the first trimester, and there was wide variation, suggesting possible bias in measurement related to recall and stigma. Criterion for biological gradient is not met. Dose-response analysis showed a non-linear relationship between alcohol and CHDs risk overall such that ‘when maternal alcohol consumption was more than 116 g/day, the risk of total CHDs in offspring significantly increased, by 42% (OR 1.42, 95% CI 1.07 to 1.88)’ (p 413).48 However, the variation in risk estimates reported for binge versus any drinking does not support a clear dose–response relationship.

    Criteria for plausibility and analogy are met. Animal studies demonstrate reduced expression of genes that encode signalling molecules in embryonic hearts after pregnant mice are exposed to binge dose of alcohol.76 In addition, alcohol consumption during pregnancy is known to cause fetal alcohol spectrum disorder (FASD), which includes structural brain abnormalities, and there is some evidence that CHDs occur more frequently in children with FASD than the general population.77

    For all risk factors, the criterion for coherence is satisfied. The available evidence does not conflict with knowledge about the natural history of CHD, which is widely considered to be of multifactorial origin. For several risk factors we examined there are distinct causal mechanisms (eg, chromosomal abnormalities arising with advanced maternal age, fetal alcohol toxicity). It is also possible that there are shared underlying mechanisms, for example, hyperglycaemia underpins the excess risk of CHDs in diabetic pregnancies and may amplify effects in women with obesity, which, in turn, may be influenced by shared genetic risks for metabolic diseases and CHD. Risk may be amplified by the presence of several maternal risk factors, as metabolic disease risk factors often cluster together (eg, advanced age, hypertension and diabetes), however, none of the reviews formally examined potential additive effects.

    Further, the rise in global birth prevalence of CHDs in the last 40 years1 78 coincides with increases in the later onset of childbearing and in the prevalence of obesity and diabetes in pregnancy, globally.79 Notably, the highest increase in CHDs has occurred in the Asia region,1 which also has had high rates of increase in hyperglycaemia in pregnancy.79

    With regard to smoking and alcohol, there has been an overall reduction in smoking in pregnancy in the past 30 years, however, tobacco use in pregnancy continues to vary widely between regions.80 For example, in some low-income and middle-income countries, rates have plateaued and, in others, increased.81 Studies estimating global and regional prevalence in alcohol use around pregnancy, including any or binge, similarly, point to high variation in rates between regions.82 83 Further, any observed reductions in the use of alcohol and tobacco in pregnancy do not preclude a causal effect as women may cease to use only when a pregnancy is identified, which for some, may be after the critical period for development of most CHDs, particularly in pregnancies that are unplanned. Importantly, however, evidence suggests quitting smoking in pregnancy may reduce prematurity and by implication, risk of cardiac and other birth defects.84

    Discussion

    We conclude that there is strong evidence of a causal relationship between maternal obesity and PDM and the development of CHDs. A causal relationship may be present between CHDs and pre-existing maternal hypertension (untreated or treated) and advanced maternal age, as for these factors causal evidence is moderate. For other maternal factors including GDM, gestational hypertension, smoking and alcohol consumption the evidence for causality was weak.

    Our findings are broadly consistent with a recent overview12 which did not formally assess causality, although we found stronger evidence for a causal implication of maternal obesity and PDMs. The earlier overview12 argues that further research on all potentially non-genetic modifiable factors is required to provide more powerful sequential evidence. Contrarily, we suggest that research examining maternal obesity and PDM is not necessary based on the strength of available evidence including coherence with animal studies which identify hyperglycaemia as a primary teratogen and implicate other metabolic disturbances (eg, insulin resistance) as causal mechanisms. Our study questions the value of further research on maternal alcohol use and smoking using current published methodologies due to the difficulties involved in gathering precise estimates of these exposures in early pregnancy.

    Further research on maternal hypertension is, however, warranted to distinguish the impacts of disease severity and antihypertensive medications on CHD susceptibility and thereby optimise treatment recommendations in early pregnancy. Additional synthesis of evidence concerning maternal age could provide more precise estimates of risk according to specific age categories. Future original research on environmental exposures that have received limited attention but have broad levels of population exposure, including air pollutants, environmental chemicals and solvents is important. This would allow for the development of precise recommendations about specific exposures rather than current general advice, to avoid or reduce exposure to ‘hazardous substances’ during pregnancy. Consideration of how environmental exposures and maternal factors cluster together and interact is also important to advance understanding of CHD development.10

    In this overview, we focused on the outcome any CHDs. As this outcome is heterogeneous, future research replicating our analysis for CHD groups based on suspected shared causal pathways (eg, left-sided obstructive lesions, conotruncal defects) would be beneficial.

    Our PAF calculations suggest that, globally, approximately 2% of cases of CHD are attributable to PDMs and just under 5% to maternal obesity. These estimates are more conservative but broadly consistent with existing studies, which attribute 4% of cases to PDMs and up to 8% to obesity.84 With approximately 1.78 million babies born annually with a CHD,85 these findings suggest that even modest improvements in reducing the prevalence of maternal obesity and PDMs would translate to significant reductions in the number of babies born with CHD.

    Evidence suggests that to reduce the burden of maternal obesity, the current predominant lifestyle intervention during pregnancy approach86 must be accompanied by a public health approach that addresses the broad determinants of obesity, interpregnancy weight retention and chronic disease in women of reproductive age, which are rooted in social disadvantage.87 88 This requires much stronger multisector investment and action to address current inequities in access to healthy foods and opportunities for physical activity.89 There is presently no effective population intervention to reduce obesity in any population so the existing repertoire of strategies is unlikely to be effective in reducing pre-pregnancy BMI.

    In addition to primary prevention, among those with PDMs, preconception care programmes that focus on optimal diabetes management can dramatically reduce the risk of CA.90 Yet access to preconception care is highly variable, even among women with pre-existing disease.91 At a minimum, encouraging providers of healthcare for women with chronic diseases to routinely ask about pregnancy intention would be a major step forward.92

    Strong evidence suggests a protective effect of folic acid supplementation during the periconceptional period on cardiac anomalies.93–95 Thus, providing all women with access to this is also a CHDs prevention strategy priority.96

    Strengths and limitations

    We used best practice overview methodology to identify and summarise relevant associations19 and an established approach to assign strength of causal evidence.13–18 This is the first systematic review of associations between maternal modifiable factors and CHDs to assess causal nature of associations using BH perspectives and draw implications for primary prevention strategy. Management of overlapping studies in reviews of reviews is an unresolved issue.97 We adopted the approach of including all reviews meeting eligibility criteria except exact duplicates to ensure comprehensive coverage of the evidence base and were guided by the findings of the most recent review when assessing causality.

    Assessment of risk of bias in reviews was difficult due to infrequent reporting of items required for comprehensive assessment, including confounding variables used in adjustment in included studies. We did not access ‘grey literature’ reviews which may contain smaller studies with null results not accepted for publication, and reviews not published in English (which may or may not exist) were not eligible. Most of the included reviews did not specifically search for ‘grey literature’ studies, although most did assess publication bias (eg, through use of funnel plots) and found no such bias.

    We did not consider two criteria originally recommended by BH: experimental evidence, which was deemed not applicable as it is not ethical to obtain evidence through experimental studies of maternal risk factors (eg, smoking); and specificity, which was due to the multifactorial nature of CHD development. This approach is consistent with other BH assessments on topics which rely solely on observational evidence.17 18 We considered an RR>2.0 with precision to indicate a strong association, which is consistent with the GRADE approach widely used to assess experimental evidence.14 15 Nevertheless, other assessments have considered an RR cut-off of ≥1.2,98 thus, our assessments of strength of association may be conservative.

    Conclusion

    There is more than sufficient causal evidence now to advocate for increased resources and policy action to tackle the prevalent maternal CHDs risk factors obesity and PDM. Research should be directed towards environmental and chemical exposures, to further inform strategy for prevention of the most common type of congenital abnormality.

    Data availability statement

    Data are available on reasonable request.

    Ethics statements

    Patient consent for publication

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    Footnotes

    • Contributors Dr JG contributed to the design of the review, designed the data extraction instruments, collected data, carried out the initial analysis, drafted the initial manuscript and critically reviewed the manuscript. Professor AR contributed to the conceptualisation and design of the review, supervised the data extraction and analysis, critically reviewed the analysis, contributed to the drafting of the initial manuscript and critically reviewed and revised the manuscript. Professor VM contributed to the conceptualisation of the review, contributed to the initial analysis and critically reviewed and revised the manuscript. Dr RF collected data, contributed to the initial analysis and critically reviewed and revised the manuscript. Associate Professor LCG, and Professors LG and MD critically reviewed and revised the manuscript. JG and AR were responsible for the overall content as guarantors. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

    • Funding All phases of this study were supported by the Australian Medical Research Future Fund (ARGCHD-41). LG was supported by a Channel 7 Children’s Research Foundation Fellowship (CRF-210323). The other authors received no additional funding.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.