Associations Between Periconceptional Lifestyle Behaviour Change and Adverse Pregnancy Outcomes

While the effect of prenatal exposure to unhealthy lifestyle is widely evidenced, little is known about these exposures in the periconception period. We investigated associations between periconceptional lifestyle behaviour change and adverse pregnancy outcomes. Methods A retrospective secondary analysis took place within a prospective multicentre cohort study in the Netherlands, including 3,684 pregnant women. Baseline characteristics and preconceptional and rst-trimester lifestyle behaviours were assessed through a self-administered questionnaire. Adverse pregnancy outcomes (hypertensive disorders in pregnancy (HDP), small for gestational age (SGA), gestational diabetes (GDM) and spontaneous preterm birth (sPTB)) were reported by healthcare professionals. Data were collected between December 2012 - January 2014 and analysed between August - December 2019, using multivariate logistic regression.

consumption in at least the rst trimester of pregnancy remains 7% and approximately 40%, respectively (11). Moreover, in many Western countries, up to 50% of women are overweight or obese when they become pregnant (12). The maternal metabolic environment of overweight and obese women tends to affect placental development and these women are therefore more prone to develop adverse pregnancy outcomes like gestational diabetes or pre-eclampsia (13).
Health promotion activities, such as education, advice and a general health assessment, are likely to improve pregnancy outcomes, by early identi cation of risk factors encouraging behavioural change (14,15). One way to incorporate health promotion activities in maternity care is through preconception care (PCC). Several studies have aimed to implement PCCprograms and some have successfully led to an improved level of knowledge regarding PCC and subsequent improved periconceptional lifestyle behaviours (16,17). The potential effect of periconceptional lifestyle behaviour change on reducing multiple adverse pregnancy outcomes together is yet understudied, and it has been studied only in small sample sizes (16,18). Therefore, the objective of our study was to investigate the association between periconceptional lifestyle behaviour change and adverse pregnancy outcomes.

Design
From December 2012 through January 2014, a prospective multicentre cohort study was conducted in the central region of the Netherlands; the RESPECT (Risk EStimation for PrEgnancy Complications to provide Tailored care) study. The current study is a secondary analysis of a prospective multicentre cohort study. The initial aim of the RESPECT study was to perform an external validation and direct comparison of published prognostic models for early prediction of the risk of developing adverse pregnancy outcomes, including predictors applicable in the rst trimester of pregnancy (19).

Setting
Participants were recruited in 31 midwifery practices (primary care) and six hospitals (secondary/tertiary care). All pregnant women less than 14 weeks of gestation were eligible for inclusion in the study. A detailed description of the cohort has previously been published (19,20). The RESPECT study has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht (protocol no. 12-432/C) and written informed consent was obtained from all individual participants.

Sample
In total, 4,347 pregnant women participants from the RESPECT study were assessed for eligibility. For this speci c analysis, we excluded women with pregnancies complicated by chromosomal anomalies, miscarriages before 15 weeks of gestation, births prior to 18 weeks, multiple pregnancies, women who discontinued their pregnancy or were lost to follow-up. Hence, 3,684 participants were included in this speci c analysis as visible in Fig. 1.

Measures
At enrolment in the rst trimester of the pregnancy, women were asked to ll out a questionnaire speci cally designed for this study. This self-reported questionnaire contained items on socio-demographic characteristics, lifestyle behaviours, and medical, family and obstetrical history. After birth, healthcare professionals reported the presence or absence of pregnancy outcomes through standardized forms. The de nitions of lifestyle behaviours, sociodemographic characteristics and adverse pregnancy outcomes are shown in Table 1: A delivery with spontaneous onset before 37 weeks of gestation (62).

Composite outcome
Women with one of the following complications; pregnancy-induced hypertension, preeclampsia, small for gestational age < p3, gestational diabetes, spontaneous preterm birth or fetal death.
The following lifestyle behaviours were assessed both preconceptionally and in the rst trimester of pregnancy: daily fruit intake, use of tobacco and alcohol, body mass index (BMI) and the use of the following supplements; folic acid, vitamin C, vitamin D, calcium or multivitamin. A periconceptional lifestyle behaviour change was de ned as the actual cessation or initiation of the speci c behaviour. The use of any vitamin or calcium supplement were combined and analysed as one determinant called 'vitamin use'. As multivitamin includes folic acid, women using multivitamin were categorized in both 'folic acid use' and 'vitamin use'. BMI was calculated based on self-reported answers to questions concerning one's height and weight before conception. Even though BMI itself is not a lifestyle behaviour, certain lifestyle behaviours such as diet or exercise can in uence a person's BMI. The following socio-demographic characteristics were assessed: age, ethnicity, educational level, parity and mode of conception. The following pregnancy outcomes were assessed: hypertensive disorder in pregnancy (HDP; either pregnancyinduced hypertension or preeclampsia), small for gestational age (SGA) de ned as birth weight < 3rd percentile, gestational diabetes (GDM), and spontaneous preterm birth (sPTB). The choice for these speci c pregnancy-and neonatal outcomes was based on its prevalence, the relevance for both mother and child and its need for preventive intervention early in pregnancy.
Participants were classi ed into either having experienced an uncomplicated pregnancy or being diagnosed with any adverse pregnancy outcome, included in our composite outcome. In case of more than one adverse pregnancy outcome, women were assigned to multiple groups except when HDP occurred simultaneously with SGA since these complications are likely to coexist with each other. In case this situation occurred, women were assigned to the HDP group, women were assigned to the SGA group when SGA was the only adverse outcome.

Statistical analysis
The original dataset contained missing data for some participants; there were 1,111 cases (30.2%) with at least one missing value. A more detailed description and an assessment of these missing values can be found in the Appendix (Supplemental File 1). Missing values were imputed using multiple imputation (19,21). All variables and outcomes were used in the imputation model and ten imputations were performed. Results shown are the results after multiple imputation. Rubin's rules were applied to combine the results into summary estimates (22). Baseline data for all participants are presented as medians and interquartile range (IQR) for continuous variables or as numbers and percentages for categorical variables. Logistic regression analysis was performed to identify associations between lifestyle behaviours and adverse pregnancy outcomes. Crude odds ratios (OR) and accompanying 95% con dence intervals (CI) were calculated by univariate analysis. Subsequently, adjusted ORs were calculated by multivariate analysis, taking potential confounders into account (maternal age, educational level, ethnicity, parity and mode of conception). Reference categories were chosen for categorical variables based on the desired lifestyle behaviour. The statistical analysis of the data was performed in the nal months of 2019, using SPSS version 25.0. P-values < 0.05 were considered statistically signi cant.
Conception occurred spontaneously in 3,429 (93.1%) women, 2,131 (57.8%) women were highly educated and 1,643 (44.6%) women were nulliparous. The proportion of women who smoked and used alcohol preconceptionally was 20.9% (n = 771) and 60.9% (n = 2,244), respectively. The majority of these women changed their unhealthy lifestyle behaviours in the rst trimester, 492 women (63.8%) quit smoking and 2,216 women (98.7%) quit drinking alcohol. A total of 2,177 (59.1%) women started using folic acid supplements preconceptionally, while 1,077 (29.2%) women started using folic acid supplement after conception took place. 3.6%), GDM (n = 184; 5.0%), sPTB (n = 127; 3.4%). In total 712 (19.3%) of all women experienced an adverse pregnancy outcome. These adverse pregnancy outcomes appeared signi cantly more often when women were non-Caucasian, were low-or medium educated, were nulliparous, had a non-spontaneous conception, were either under-or overweight or smoked preconceptionally. . We found that women who smoked before pregnancy were more likely to experience sPTB (aOR 1.76 (95%CI 1.05-2.93)) compared to women who did not smoke preconceptionally. Women who continued to smoke during pregnancy were also more likely to give birth to an SGA neonate aOR 1.91 (95%CI 1.05-1.15), which was not the case for women who quit smoking after conception (aOR 1.14 (95%CI 0.59-2.21)). Women who consumed alcohol preconceptionally, yet discontinued in the rst trimester, had a lower odds of developing GDM compared to women who were not used to drink alcohol prior to pregnancy recognition (aOR 0.65 (95% CI 0.46-0.93)). Compared to women who used folic acid supplements from the preconception period onwards, women who did not use folic acid supplements tended to have a (non-signi cantly) higher odds of developing adverse pregnancy outcomes (aOR 1.28 (95%CI 0.97-1.69)), while women who started folic acid supplements during pregnancy did not (aOR 1.01 (95%CI 0.82-1.25)). No associations were found between daily fruit intake or vitamin use and the development of adverse pregnancy outcomes.

Discussion
This study con rms that unhealthy periconceptional lifestyle behaviours are associated with the prevalence of adverse pregnancy outcomes. Women who were obese prior to the pregnancy had the highest odds of developing adverse pregnancy outcomes, particularly HDP and GDM. These odds persisted in overweight women, although much lower. Underweight women, on the other hand, were more likely to give birth to an SGA neonate. Smoking prior to pregnancy was associated with sPTB and SGA, but, interestingly, for SGA this association did not persist when women quit smoking during the rst trimester.
In accordance with previous studies, we indeed found that smoking is associated with a higher odds of sPTB and birth of SGA neonates (23)(24)(25)(26). Although some studies showed that pregnant smokers who quit during the rst-trimester are no longer at risk for sPTB, we found otherwise but this might very well be a spurious nding (27)(28)(29). On the other hand, we found that women who quit smoking in the rst-trimester did have a similar odds of developing SGA compared to non-smokers, as previous studies have also suggested (25,26,28). Cigarette smoke contains substances that affect placental endothelial function, which can lead to the development of ischemic vascular changes impacting placental growth and functions (30). A previous systematic review showed that cessation of smoking before and shortly after becoming pregnant was not associated with SGA and this suggests that the mechanisms affecting fetal growth predominantly act in the second half of pregnancy (31). Nevertheless, smoking cessation prior to conception remains the best approach to improve health bene ts.
Alcohol is suggested to lower levels of in ammation markers and endothelial dysfunction, increase insulin sensitivity, increase HDL cholesterol concentrations, which, for example, may lower the risk of type 2 diabetes mellitus and possibly also GDM (32)(33)(34). Several studies have shown that pre-pregnancy or prenatal consumption of small alcohol amounts has a mildly protective effect on preterm birth, intrauterine growth restriction and birth weight. The possible explanation provided for this paradox is the "healthy drinker effect", in which women with poor obstetric prognosis, socio-economic status or well-being are more likely to abstain from drinking alcohol (35,36). We indeed found that women who used alcohol preconceptionally were signi cantly more often Caucasian, higher educated, nulliparous, were pregnant by spontaneous conception, had a lower pre-pregnancy BMI and used more folic acid supplements compared to women who did not use alcohol preconceptionally (data not shown).
We found that women with a BMI of 25 kg/m 2 or more, especially women with a BMI above 30 kg/m 2 , have the highest odds of developing adverse pregnancy outcomes. Previous meta-analyses suggest that higher amounts of preconception physical activity are associated with a lower risk of gestational diabetes and pre-eclampsia (37,38). In addition, a population-based study showed that a 10% lower preconception BMI was associated with clinically meaningful risk reduction in pre-eclampsia, gestational diabetes, preterm birth, macrosomia, and stillbirth (4). A previous study showed that only 57% of pregnant women were aware of the fact that obesity increases the overall risk of pregnancy-and birth complications and that weight loss prior to the pregnancy can reduce to overall risk for complications (39). Hence, here lies an opportunity for PCC to encourage obese women to enter weight loss programs to improve their own health and the health of their future child.
Finally, our results showed that encouraging women to start folic acid supplements, after pregnancy recognition, can still bene t the health of mother and child. Although non-signi cant, we found a higher odds of adverse pregnancy outcomes for women who did not use folic acid supplements compared to preconceptional commencement. Although we found no difference in adverse pregnancy outcomes between women who started folic acid supplements before or during the pregnancy, it is widely evidenced that early initiation (ideally before conception) of folic acid supplements does decrease the risk for congenital malformations such as neural tube defects (40). In our study, congenital malformations were excluded from analysis and therefore we cannot provide any results regarding these outcomes.
Our results are alarming since an unhealthy diet, lifestyle behaviours and exercising pattern are progressively becoming part of Western society, including among a high percentage of women in their reproductive age (5,6,15). Encouraging women to develop and maintain a healthy lifestyle has long been a focus of prenatal care, while our ndings support emerging evidence indicating that the preconception period might even be a better window of opportunity to address these unhealthy lifestyle behaviours. PCC is known to increase the health and well-being of prospective parents, still, the uptake of PCC-consults remains remarkably low (41). This is particularly the case for vulnerable women, who often have multiple unhealthy lifestyle behaviours and are speci cally hard to reach (42). PCC-interventions often require engagement from prospective parents who are not yet thinking about becoming a parent in the future and are not yet known by maternal health services (43). Although some studies suggest that awareness of preconception health and care is low, pregnancy planning appears relatively common, indicating a missed and unexploited opportunity for intervention (44).
A possible strength of this study is that we used a large, multicentre, population-based cohort where we accounted for missing data by using multiple imputation, which decreases the risk of bias and allows to investigate multiple exposures and outcomes. Also, we distinguished lifestyle behaviours between the preconception period and the rst trimester, a distinction rarely made in previous studies. A limitation of this study is the inclusion of a relatively high number of Caucasian and highly educated women.
In addition, the data on lifestyle behaviours is collected by the use of self-administered questionnaires. Although this method is suggested to negatively affect the validity, we merely assessed the presence (yes/no questions) instead of frequencies of lifestyle behaviours, by which we probably have diminished the chance of over-or underreporting of behaviour (45). However, due to this method of questioning the distinction between preconception and rst-trimester exposure is dependent upon women's perception of when conception occurred. Moreover, examining potential dose-response relationships was not possible and blood markers were not available to validate, for example, micronutrient or smoking status. Finally, as this study was only able to measure associations between periconceptional lifestyle behaviours and adverse pregnancy outcomes, and the sample size calculation was not performed for the current aim of this paper, results should be interpreted with caution and we recommend future research to focus on large-scale interventions to discover a possible (causal) effect.

Conclusion
Overall, our ndings indicate that women should be encouraged to change unhealthy lifestyle behaviours, preferably before conception. Therefore, future research on interventions to improve awareness on the importance of PCC and the (cost)effectiveness of these interventions on pregnancy outcomes are needed. Findings from such studies could enhance the choice to start future preventive measures and interventions regarding unhealthy periconceptional lifestyle behaviours, to optimize the health of future generations.
List Of Abbreviations aOR adjusted odds ratio; BMI = body mass index; CI = con dence interval; GDM = gestational diabetes; HDP = hypertensive disorders in pregnancy; IQR = interquartile range; PCC = preconception care; PE = pre-eclampsia; PIH = pregnancy-induced hypertension; RESPECT study = Risk EStimation for PrEgnancy Complications to provide Tailored care; SGA = small for gestational age; sPTB = spontaneous preterm birth Declarations Ethics approval and consent to participate The RESPECT study has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht (protocol no. 12-432/C) and written informed consent was obtained from all individual participants. All methods were performed in accordance with the relevant guidelines and regulations con rm the Declaration of Helsinki.