The PRISMA flow diagram30 in Figure 1 shows that we identified 4,004 articles and screened 3,592 abstracts. Of the 661 articles that underwent full-text screening, 592 were ineligible and 22 were removed as they reported only associations covered by more comprehensive or Cochrane Reviews (see Table S4), resulting in 47 reviews being included.12, 31-76 Six eligible reviews were identified through citation tracking,77-82 resulting in a final sample of 53 reviews.

3.1 Review characteristics

The characteristics of the 53 reviews, including the number of databases and range of publication years searched, eligibility criteria and preconception exposures reported, are presented in Table S5. Included reviews were published between 2005 and 2020, with the publication dates for their included studies ranging from 1973 to 2019. Two were published in Portuguese40, 80 and therefore translated to English, with the remainder published in English. There were 205 exposure-outcome associations reported across 1,383 studies. Twelve of these associations were based on clinical and/or randomised trials, and five included evidence from a combination of trials and observational studies. The remainder relied on observational studies only. A total of 994 (71.9%) primary studies were conducted in high-income countries and 355 in low- and middle-income countries.

3.2 Methodological quality of included studies and certainty of the evidence

Two included reviews were rated as ‘high’-quality,12, 41 two as ‘moderate’,38, 61 11 as ‘low’36, 39, 42, 50, 51, 57, 60, 63, 68, 73, 77 and the remaining 38 as ‘critically low’ (Table S6). The most common ‘critical’ methodological concerns were lack of: appropriate methods for combining results (76.9% of relevant reviews—primarily due to a lack of justification for combining data in a meta-analysis and/or combining unadjusted estimates), justification for study exclusions (76.9%), comprehensive literature search (59.6%) and evidence of a priori establishment of review methods (50.0%). Two exposure-outcome associations were rated as ‘high’-certainty, 27 as ‘moderate’, 56 as ‘low’ and 120 as ‘very low’ (Table S3). Risk of bias was the most common reason for downgrading evidence certainty.

3.3 Synthesis of results

Figures 2-6 show the exposure–outcome associations, grouped by their exposure domain, along with key information such as whether the exposure continued into the broader periconceptional period and whether the included studies had observational or interventional designs. Associations that were assigned a ‘very low’ GRADE rating are not included in the figures or in the narrative synthesis below, as very little confidence can be had in these findings.83 A summary of the findings for all 205 associations, regardless of GRADE rating, can be found in Table S7. Of the 205 associations identified, 191 (93.2%) relate to maternal exposures. These include pre-pregnancy body mass index (BMI; 75 associations), interpregnancy or birth intervals (23), interpregnancy weight change (18), age (14), folate supplementation (11), diet and nutrition (10), parity and education (seven each), physical activity (five), abuse or neglect, over-the-counter drugs and environmental exposures (four each), smoking (active or passive exposure), other vitamin supplementation and immigration status (two each), and vaccination, alcohol consumption and ethnicity (one each). The remaining 14 (6.8%) associations are related to the paternal exposures of age (10) and alcohol consumption (four).

Health behaviour and wider determinants of health exposures and their associations with adverse pregnancy, birth and postpartum outcomes (high, moderate and low GRADE ratings only). Legend: Pre, Preconception; Post, Postconception; Obs, Observational; Int, Interventional; (a)OR, (adjusted) Odds ratio; AHEI, Alternative Healthy Eating Index; RR, Risk ratio. aPhysical, emotional or sexual; bOr other vitamins/minerals; cExcluding neural tube and congenital heart defects and cleft lip and palate

Reproductive and demographic preconception exposures and their associations with adverse pregnancy, birth and postpartum outcomes (high, moderate and low GRADE ratings only). Legend: Pre, Preconception; Post, Postconception; Obs, Observational; Int, Interventional; (a)OR, (adjusted) Odds ratio; aRE, Adjusted risk estimate; IPI, Interpregnancy interval; BI, Birth interval. aCombined adjusted odds ratios, hazard ratios and rate ratios; bAt five minutes postpartum

Pre-prepregnancy weight/BMI exposures and their associations with adverse pregnancy, birth and postpartum outcomes (moderate GRADE ratings only). Legend: Pre, Preconception; Post, Postconception; Obs, Observational; Int, Interventional; BMI, Body mass index; OR, Odds ratio; aRR, Adjusted risk ratio. aAuthor defined; bPregnancy-induced

Pre-prepregnancy weight/BMI exposures and their associations with adverse pregnancy, birth and postpartum outcomes (low GRADE ratings only). Legend: Pre, Preconception; Post, Postconception; Obs, Observational; Int, Interventional; BMI, Body mass index; OR, Odds ratio; (a)RR, (adjusted) Risk ratio; NICU, Neonatal Intensive Care Unit. aAuthor defined; bAt five minutes postpartum

Interpregnancy weight change exposures and their associations with adverse pregnancy, birth and postpartum outcomes (high, moderate and low GRADE ratings only). Legend: Pre, Preconception; Post, Postconception; Obs, Observational; Int, Interventional; BMI, Body mass index. (a)OR, (adjusted) Odds ratio

For associations relating to BMI, the reference group was ‘normal’ BMI (20–24.9 kg/m2) and underweight, overweight and obesity corresponded to BMI values of <20, 25.0–29.9 and ≥30 kg/m2 unless otherwise stated. Adjusted risk estimate is used where review authors combined adjusted odds ratios, hazard ratios and rate ratios without converting them to a single measure of association.

3.3.1 Health behaviours and wider determinants of health

Figure 2 shows there is high-certainty evidence that maternal folate supplementation (<0.4-4 mg) beginning preconceptionally and terminating before 12 weeks’ of gestation, relative to no intervention/supplementation or placebo, reduces the risk of both neural tube defects (risk ratio [RR] 0.31, 95% confidence interval [CI] 0.17, 0.58) and pregnancy termination for a foetal anomaly (RR 0.29, 95% CI 0.15, 0.56).41 Moderate-certainty evidence was found that maternal preconception physical activity is associated with a reduced risk of both pre-eclampsia (adjusted RR 0.65, 95% CI 0.47, 0.89; highest vs lowest level of activity)33 and gestational diabetes mellitus (odds ratio 0.70, 95% CI 0.57, 0.85; any vs no activity).59

Low-certainty evidence was found that maternal periconception folate supplementation is associated with a reduced risk of preterm birth54 and that there is limited evidence of associations between this exposure and the risk of twinning, miscarriage, low birthweight, congenital heart defects and birth defects other than neural tube and congenital heart defects and cleft lip and palate.41 Low-certainty evidence was also found that maternal vitamin supplementation (any) beginning preconceptionally and terminating in the first trimester does not affect the risk of either miscarriage or stillbirth,12 and that paternal consumption of any alcohol in the 3 months before conception is associated with an increased risk of congenital heart defects.76 Further low-certainty evidence was found for associations between maternal preconception iron intake and an increased risk of gestational diabetes mellitus,59 adherence to a Mediterranean or High Alternate Healthy Eating Index diet and a reduced risk of gestational diabetes mellitus,59 and maternal experience of abuse (physical, emotional or sexual) at any time before pregnancy and an increased risk of low birthweight.61

3.3.2 Demographic and reproductive exposures

Figure 3 shows moderate-certainty evidence that paternal age of ≥40 years is associated with a greater risk of miscarriage, and low-certainty evidence that paternal age of 35–39 years may not be associated with greater or reduced risk of this outcome.42 Low-certainty evidence was found that paternal age of <20 years is associated with an increased risk of spina bifida,51 that maternal age of ≥35 years is associated with a greater risk of urinary incontinence,36 and that maternal age of ≥45 years is associated with increased risk of: an abnormal five-minute Apgar score, foetal loss, pregnancy complications and caesarean delivery, relative to maternal age of <45 years.52 Low-certainty evidence was also found that interpregnancy intervals shorter than 6 months are associated with an increased risk of low weight, small-for-gestational-age and preterm births, and that interpregnancy intervals of ≥60 months are also associated with an increased risk of these outcomes.38 Further low-quality evidence was found that interpregnancy or birth intervals of >48 months are associated with a greater risk of pre-eclampsia39 and that multiparity is associated with an increased risk of urinary incontinence, relative to nulliparity but not primiparity.36

3.3.3 Pre-pregnancy body mass index (BMI)

Figure 4 shows moderate-certainty evidence that maternal BMI in the overweight (BMI 25–29) and obese (BMI >30) ranges is associated with a greater risk of gestational diabetes mellitus,74 pregnancy-induced antenatal hypertension65 and pre-eclampsia81 and a reduced risk of placental abruption.31 Moderate-certainty evidence was also found that maternal obesity is associated with an increased risk of foetal distress,82 shoulder dystocia (vs BMI <30),75 foetal macrosomia (vs BMI 18.5–24.9)56 and large for gestational age births (vs BMI <25).44 Further moderate-certainty evidence was found that, relative to the lowest category of BMI, increasing maternal BMI is associated with a greater risk of both miscarriage and neonatal death,77 and that maternal underweight (BMI <18.5) is associated with a reduced risk of pregnancy-induced hypertension.65

Figure 5 shows low-certainty evidence that maternal underweight is associated with a reduced risk of pre-eclampsia,81 gestational diabetes mellitus,74 large-for-gestational-age and macrosomic births56 and an increased risk of small-for-gestational age birth55 and placental abruption.31 Regarding maternal overweight, low-certainty evidence suggested associations between this exposure and an increased risk of foetal distress,82 large-for-gestational-age and macrosomic births56 and a reduced risk of small-for-gestational-age birth.56 Further low-certainty evidence was found that maternal overweight and obesity are both associated with an increased risk of miscarriage,35 post-term pregnancy and a longer hospital stay82 and that maternal obesity, specifically, is associated with an increased risk of maternal depression,60 failure to progress in labour, caesarean delivery, a low Apgar score at five minutes postpartum82 and neonatal intensive care unit admission.56

3.3.4 Interpregnancy weight change

Figure 6 shows moderate-certainty evidence that maternal interpregnancy weight gain of >2 BMI units, relative to BMI maintenance (change of ≤2 units), is associated with a greater risk of gestational hypertension,57 and that interpregnancy weight gains of both 1 to <3 and ≥3 BMI units, relative to BMI maintenance (≤1 unit change), are associated with greater risk of caesarean delivery,63, 73 large-for-gestational-age birth73 and gestational diabetes mellitus.72 Low-certainty evidence was found that: interpregnancy BMI losses and gains of >1 unit are associated with an increased and reduced risk of small-for-gestational-age birth, respectively63; that interpregnancy BMI reduction of >1 unit is associated with an increased risk of preterm birth and a reduced risk of large-for-gestational-age birth73; and that interpregnancy weight gain of >2 units is associated with an increased risk of pre-eclampsia.57