Synergistic effects of cardiovascular health and social isolation on adverse pregnancy outcomes

Background: Adverse pregnancy outcomes affect approximately 20% pregnant women, and their incidence is increasing.

To investigate the effect of cardiovascular health during pregnancy on adverse pregnancy outcomes and the effect modification by psychological distress, social isolation, and income. Study Design: We analyzed data from 14,930 pregnant women in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Cardiovascular health status during pregnancy was assessed using the eight components of Life’s Essential 8 as proposed by the American Heart Association, including diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Adverse pregnancy outcomes were defined as composite outcomes of preeclampsia, gestational diabetes mellitus, preterm birth, and small for gestational age. Using logistic regression analyses, we examined the associations between cardiovascular health and adverse pregnancy outcomes, preeclampsia, gestational diabetes mellitus, preterm birth, small for gestational age, large for gestational age, low birth weight, and neonatal intensive care unit admission. Interactions with psychological distress, social isolation, and income were examined.

The numbers of participants with high, moderate, and low cardiovascular health status were 2,891 (19.4%), 11,498 (77.0%), and 541 (3.6%), respectively. Moderate and low cardiovascular health status were positively associated with adverse pregnancy outcomes (odds ratio and 95% confidence interval: 1.17 (10.04 to 1.32) and 2.64 (2.13 to 3.27), respectively). Low cardiovascular health status was also associated with a higher prevalence of preeclampsia, gestational diabetes mellitus, preterm birth, large for gestational age, and neonatal intensive care unit admission, and lower prevalence of small for gestational age. Among pregnant women with low cardiovascular health status, those who reported social . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 5 isolation had a higher prevalence of adverse pregnancy outcomes than did those without social isolation (36.4% vs. 27.4%). However, this difference was attenuated for pregnant women with high cardiovascular health status (13.6% vs. 13.1%).

Cardiovascular health status assessed using Life’s Essential 8 may be useful for assessing the risk of adverse pregnancy outcomes. Socially isolated pregnant women are more vulnerable to the effects of low cardiovascular health status; thus, they should be prioritized for access to primary care, lifestyle education, and appropriate pharmacotherapy.

Cohort study, Gestational diabetes, Health disparities, Income, Life’s Essential 8, Preeclampsia, Prenatal care, Preterm birth, Psychological distress, Small for gestational age . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 6

1 Adverse pregnancy outcomes (APOs), which encompass unfavorable events or complications 2 occurring during pregnancy, delivery, or postpartum, affect approximately 20% pregnant 3 women and are increasing.1, 2 Following delivery, APOs can progress to cardiovascular 4 disease (CVD)3-5 and mortality.6 Placental formation and cardiometabolic factors play crucial 5 roles in APO development,7, 8 and their pathogenic similarity to CVDs has led to the 6 characterization of pregnancy as a “stress test for CVD.”9 Risk factors for APOs, such as 7 obesity,10 poor sleep quality,11 and poor dietary habits12 are also recognized as risk factors for 8 CVD.13 Therefore, it is expected that similar preventive strategies employed for CVD can be 9 applied to APOs. 10 In 2022, Life’ s Essential 8 (LE8) proposed by the American Heart Association,13 11 which is an approach grounded in cardiovascular health (CVH) for disease prevention and 12 health promotion. This concept emphasizes individual health while addressing existing CVD 13 and associated risk factors. LE8 serves as an operational metric for CVH that includes eight 14 components: diet, physical activity (PA), nicotine exposure, sleep health, body mass index 15 (BMI), blood lipids, blood glucose, and blood pressure (BP). In contrast to Life’s Simple 7 16 (LS7), a prior version of CVH metrics proposed in 2010,13 sleep health was introduced as a 17 new component in 2022, with all eight CVH components being rescaled to continuous 18 variables. To date, over 2,500 studies have referenced original articles describing LS7,13 and 19 evidence on LE8 is growing.14, 15 A meta-analysis revealed associations between CVH, and 20 CVD incidence, CVD mortality, and all-cause mortality.16 Furthermore, these associations 21 have been observed in adolescents and young adults.17 Therefore, we hypothesized that LE8 22 may be relevant in a wide range of APOs due to shared characteristics between CVD and 23 APOs. 24 The integration of LE8 into antenatal care could enhance maternal health. Many 25 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 7 previous studies solely quantified the impact of a single component of CVH, neglecting its 26 complex interconnections. LE8 provides a comprehensive overview of maternal CVH during 27 pregnancy and is useful for assessment in clinical scenarios where a single factor (e.g., 28 smoking cessation) is related to others (e.g., weight gain or poor dietary habits).18 To date, no 29 study has investigated the relationship between LE8 during pregnancy and APOs. However, 30 one study19 exploring the link between LS7, earlier CVH metrics, and APOs demonstrated 31 that improved CVH was associated with better pregnancy outcomes. Notably, this study 32 utilized only five of seven components, and it remains unclear whether a comprehensive 33 CVH assessment using LE8 is beneficial in antenatal care. Furthermore, the clinical 34 significance of psychological health and the social determinants involved in effect 35 modification cannot be overlooked. They have a solid clinical basis and underpin all the CVH 36 metrics, interacting bidirectionally.13, 20, 21 Previous research has revealed that poor CVH was 37 related to depressive symptoms22, 23 and social isolation.24 Another study found an effect 38 modification by CVH on the relationship between socioeconomic status and life 39 expectancy.20 To date, no study has investigated effect modification by psychological health 40 and social determinants on the relationship between CVH and APOs. 41 In this study, we aim to investigate the effect of CVH assessed using LE8 on APOs 42 in 14,930 pregnant Japanese women. We will also explore the effect modification by 43 psychological distress, social isolation, and income. 44 45

46 Participants 47 Between 2013 and 2017, the Tohoku Medical Megabank Project Birth and Three-Generation 48 (TMM BirThree) Cohort Study25, 26 recruited 23,406 pregnant women from more than 50 49 obstetric clinics and hospitals in Miyagi Prefecture, Japan. Participants who withdrew 50 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 8 consent (n=232), those with multiple births (n=313), those who delivered before or at 32 51 weeks of gestation (n=223), those who had their blood samples drawn after 32 weeks of 52 gestation (n=3,724), and those with missing data on delivery status (n=965) were excluded. A 53 cutoff of 32 weeks of gestation was chosen to capture cardiovascular changes on transition 54 from the second to the third trimester and to prevent pregnancy complications from affecting 55 the CVH status. Additionally, this cutoff value aligned with those in previous studies.19, 27 56 Participants that were involved in the TMM BirThree Cohort Study multiple number of times 57 were identified, and only their first valid data were used in this study (n=620). Finally, 58 participants with missing CVH metrics and covariates were excluded (n=3,391), leaving 59 14,930 participants for the main analysis. The study flowchart is detailed in Supplementary 60 Figure 1. Ethical approval was obtained from the Ethics Committee of the Tohoku Medical 61 Megabank Organization (2013-1-103-1), and all participants provided written informed 62 consent for study participation. 63 64 CVH definitions 65 Dietary quality was assessed using the 8-item Japanese Diet Index, which assesses adherence 66 to the Japanese diet and is related to CVD mortality in the Japanese population.28, 29 Food 67 intake was estimated using a food frequency questionnaire.30 PA, nicotine exposure, and sleep 68 health were assessed during pregnancy using self-reported questionnaires. Pre-pregnancy 69 BMI and BP before 20 weeks of gestation were obtained from medical records during 70 antenatal care. Blood lipid and glucose levels before or at 32 weeks of gestation were 71 determined from blood samples collected in the TMM BirThree Cohort Study.25 Each LE8 72 component was rated on a scale from 0 (least healthy) to 100 (most healthy), with detailed 73 information provided in Supplementary Table 1. The overall CVH score was the unweighted 74 average of all eight components.13 Overall and component CVH scores were used to 75 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 9 categorize participants into three levels: high (80–100), moderate (50–79), and low (0–49), as 76 outlined in the original article.13 77 78 Outcomes 79 APOs were defined as composite outcomes comprising preeclampsia (PE), gestational 80 diabetes mellitus (GDM), preterm birth (PTB), and small for gestational age (SGA), based on 81 their pathophysiological relevance to CVH and their clinical impact.5, 31 A diagnosis of PE 82 was established based on the American College of Obstetricians and Gynecologists 83 guidelines,32 utilizing medical records of antenatal care. GDM was identified from the 84 medical records at delivery. To ascertain PTB and SGA, neonatal gestational age at delivery 85 and birth weight were obtained from medical records at delivery. Additional neonatal 86 outcomes, such as low birth weight (LBW), large for gestational age (LGA), and neonatal 87 intensive care unit (NICU) admission, were identified from the medical records at delivery. 88 89 Covariates 90 Covariates included maternal age at conception (≥35 years old or not), alcohol consumption 91 during pregnancy, conception via in vitro fertilization (IVF), parity (primipara or not), 92 psychological distress during pregnancy, social isolation during pregnancy, and household 93 income (≤4 million yen or not). Age at conception and parity were obtained from medical 94 records during antenatal care, while the remaining variables were self-reported during 95 pregnancy. Psychological distress was evaluated using the Kessler Psychological Distress 96 Scale (K6),33 comprising six items rated on a 5-point Likert scale. The total score ranged 97 from 0 to 24, with a score of ≥9 indicating psychological distress. Social isolation was 98 evaluated using the Lubben Social Network Scale (LSNS-6),34 which consists of six items 99 rated on a 6-point Likert scale. The total score ranged from 0 to 30, with a score of ≤11 100 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 10 indicating social isolation. In addition, the LSNS-6 has two subscales: family and friends. 101 Each subscale score ranged from 0 to 15, and a score of ≤5 was considered social isolation 102 (Supplementary Table 2).34 103 104 Statistical analysis 105 Baseline characteristics, CVH scores, and study outcomes were compared across the overall 106 CVH levels and according to the APO status. Continuous variables were analyzed using 107 analysis of variance or student’s t-test, while categorical variables were analyzed using the 108 chi-square test. Pearson’s correlation coefficients were calculated for all combinations of 109 component CVH scores. 110 The association between overall and component CVH levels and study outcomes 111 was explored using multiple logistic regression analysis, employing high CVH levels as 112

and adjusting for covariates. Interactions between overall CVH levels and 113 psychological distress, social isolation, and income levels were examined. Given that a 114 significant interaction was observed with social isolation, further subgroup analyses were 115 conducted for the subscales and each item of the LSNS-6 (Supplementary Table 2). 116 Sensitivity analyses were performed to assess the robustness of the results. First, due 117 to some missing values not satisfying the “missing completely at random” assumption,35 we 118 conducted association analyses after imputing missing values in CVH metrics and covariates 119 using multiple imputation by chain equations with five iterations36 in a population of 18,321 120 eligible participants. Second, to rule out the potential of reverse causality between CVH and 121 APOs, association analyses were conducted solely on participants whose blood samples were 122 collected before or at 20 weeks of gestation (Supplementary Figure 2). Third, we excluded 123 participants with pre-pregnancy chronic hypertension (CH) (n=579) or pre-pregnancy 124 diabetes mellitus (DM) (n=71) from the main analysis. This exclusion aimed to prevent an 125 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 11 overestimation of the effect of overall CVH on APOs, given the high risk of PE for patients 126 with pre-pregnancy CH and the consequent diagnosis of GDM for those with pre-pregnancy 127 DM. 128 A threshold p-value of <0.05 was adopted for detecting statistical significa nce for the 129 association analyses, while a significance level of P < 0.2 was applied for the interaction 130 term. All analyses were conducted using the R software version 4.1.2. 131 132

133 Among the 14,930 study participants, 2,891 (19.4%), 11,498 (77.0%), and 541 (3.6%) had 134 high, moderate, and low overall CVH levels, respectively (Table 1). Among participants with 135 high, moderate, and low overall CVH levels, 380 (13.1%), 1,772 (15.4%), and 162 (29.9%), 136 respectively, had APOs (Supplementary Table 3). Pregnant women with APOs had lower 137 overall CVH scores as well as lower scores for nicotine exposure, sleep health, BMI, blood 138 glucose, and BP (Supplementary Table 4). As shown in Supplementary Figure 3, CVH scores 139 for individual components were observed to correlate positively with each other. However, 140 significant negative correlations existed between PA and nicotine exposure, PA and sleep 141 health, PA and BMI, and diet and blood glucose CVH scores. 142 In logistic regression analyses with adjustment (Table 2), moderate and low CVH 143 levels were associated with APOs with odds ratios (OR) of 1.17 (95% CI: 1.04–1.32) and 144 2.64 (95% CI: 2.13 to 3.27), respectively (P for trend < 0.001). Low CVH levels were also 145 associated with a higher prevalence of PE, GDM, PTB, LGA, and NICU admission and a 146 lower prevalence of SGA. Using a heatmap, Figure 1 shows the results of logistic regression 147 analyses with adjustments between eight component CVH levels, APOs, and other study 148 outcomes. Low nicotine exposure, BMI, blood glucose, and BP CVH levels were positively 149 associated with APOs. Low sleep health CVH levels, which was newly considered in LE8, 150 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 12 were positively associated with GDM, SGA, and LBW, while diet and PA CVH were largely 151 unrelated to the study outcomes. Low BMI, blood lipids, blood glucose, and BP CVH levels 152 tended to be positively associated with the study outcomes, except that low BMI and blood 153 lipids CVH levels were negatively associated with SGA and LBW. 154 Subgroup analyses of psychological distress, social isolation, and income 155 demonstrated that low overall CVH levels had a stronger association with APOs in socially 156 isolated participants (P for interaction = 0.180). OR for APOs was 2.40 (95% CI: 1.86 –3.10) 157 in those not socially isolated and 3.38 (95%CI: 2.20–5.18) in socially isolated participants 158 (Figure 2). Among pregnant women with low CVH levels, the prevalence of APOs at delivery 159 was higher among socially isolated pregnant women (36.4% vs. 27.4%); however, this 160 difference was attenuated among pregnant women with high CVH levels (13.6% vs. 13.1%). 161 Subgroup analyses of each item and subscale of social isolation were conducted, 162 demonstrating that low overall CVH levels were more associated with APOs in participants 163 in the low family subscale (P for interaction = 0.025). For participants with a family subscale 164 score of ≥6, the OR (95% CI) for APOs was 2.45 (1.95–3.09) and 5.15 (2.63–10.10) in 165 participants with a family subscale score of <6 (Figure 3). Analyses of each of the LSNS-6 166 items, on the family and the friend subscale, showed a significant interaction between overall 167 CVH levels and the “Call for help” item in the family subscale. 168 Sensitivity analyses showed results that were largely consistent with those of the 169 main analyses (Supplementary Figures 4-6). 170 171 Comment 172 Principal findings 173 Low overall CVH levels were associated with a higher prevalence of APOs, PE, GDM, PTB, 174 LGA, and NICU admission and a lower prevalence of SGA. The association of low overall 175 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 13 CVH levels with APOs was stronger for socially isolated pregnant women than for pregnant 176 women who were not socially isolated. Among the LSNS-6 items and subscales, participants 177 with low family subscale scores and those who reported having fewer close relatives to whom 178 they could call for help were more affected by low overall CVH levels. 179 180

in the context of what is known 181 Only one previous study has investigated the relationship between CVH and APOs.19 The 182 previous study19 calculated overall CVH status using only five components and demonstrated 183 its relationship with PE, unplanned cesarean section, LGA, sum of skinfolds, and insulin 184 sensitivity. Our results extend these findings and further illustrate the link between overall 185 CVH -comprising all LE8 components- and other clinical outcomes such as PTB and NICU 186 admission. In the previous study,19 high overall CVH levels were positively associated with 187 SGA, primarily through the BMI component, which was difficult to interpret and led to a 188 clinical misinterpretation that “high CVH is a risk factor for SGA”. Our study reported 189 similar results but also showed that a low overall CVH level is a risk factor for APOs and 190 NICU admission. Comprehensively, our findings lend credence to the integration of CVH in 191 antenatal care. Furthermore, the association between sleep health, a new component of LE8, 192 and study outcomes such as GDM, SGA, and LBW suggests that LE8 may be more practical 193 than LS7. 194 Our study demonstrated a more pronounced association between low overall CVH 195 levels and APOs in socially isolated pregnant women. Negative social determinants of health, 196 including social isolation, are well-established risk factors for CVD and mortality in non-197 pregnant people37, 38 and have been identified to influence CVH in pregnant women.39 198 However, the interaction between these factors and CVH remains elusive. Previously, a 199 study20 involving middle-aged and older adults, predominantly Europeans, showed that life 200 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 14 expectancy was comparable across socioeconomic strata among participants with optimal 201 CVH but not among those with poor CVH, suggesting that improved CVH could mitigate 202 health inequalities. Our findings are consistent with previous results indicating that pregnant 203 women have a similar risk of APOs regardless of their social isolation status when their CVH 204 improves, underscoring the importance of providing support to this population. Furthermore, 205 our findings suggest that socially isolated pregnant women, particularly those with limited 206 family relationships or fewer close relatives to whom they can call for help, may be more 207 vulnerable to the impact of low CVH. Beyond the general concept of "social isolation," it 208 may be necessary to consider the specific social conditions of pregnant women. 209 Notably, psychosocial distress during pregnancy did not significantly modify the 210 effect of CVH, suggesting that psychological distress and CVH were additively related to 211 APOs. Previous studies have reported a bidirectional relationship between CVH and 212 psychological status, identifying maternal psychological distress as a possible risk factor for 213 poor CVH during pregnancy.40 Also, improvements in CVH from early pregnancy to 6 214 months postpartum have been linked to reduced postpartum depressive symptoms.41 215 Psychological distress has been found to be associated with APOs.42, 43 Therefore, a 216 simultaneous assessment and consideration of both aspects in clinical practice is 217 recommended. 218 219 Clinical implications 220 Assessment of CVH as undertaken by our study has potential implications for clinical 221 practice. Importantly, there is a need to adopt a comprehensive approach to health assessment 222 rather than focusing solely on a specific aspect of health status. Utilizing an index of overall 223 CVH instead of a single CVH component enables clinicians to address complex interactions 224 among risk factors, such as smoking cessation that may lead obesity or exercise habits that 225 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 15 may impact the duration of sleep. Particularly for socially isolated pregnant women who 226 demonstrated a heightened vulnerability to low CVH in this study, prioritized access to 227 primary care, lifestyle education, and access to pharmacotherapies is essential. Regardless of 228 social isolation status, the risk of APOs was consistently low in the group with high CVH 229 levels, suggesting that increasing CVH levels in pregnant women may reduce health 230 disparities. 231 232 Research implications 233 Considering the correlation between CVH before and during pregnancy,44 incorporating LE8 234 in conception planning may aid in preventing future APOs. LE8 advocates improvements by 235 lifestyle modification or the use of pharmacotherapy, empowering women to proactively 236 enhance their CVH in preparation for pregnancy. Therefore, we hope that further study will 237 reveal the relationship between pre-conception CVH status and APOs 238 239 Strength and limitations 240 To the best of our knowledge, this study represents the first endeavor to investigate the 241 association between CVH assessed by LE8 and APOs. Notably, our study population was 242 approximately five times larger than that in a prior study19 that assessed CVH using LS7. One 243 strength of this study lies in the inclusion of pregnancy outcomes, providing a comprehensive 244 assessment of the clinical importance of CVH. Also, our sensitivity analyses reinforced the 245 robustness of the results. 246 Despite these strengths, our study had some limitations. First, the timing of CVH 247 measurements varied among participants, although all assessments, including questionnaires, 248 blood pressure measurements, and blood samples, were conducted during pregnancy. 249 Consequently, the point at which CVH is most strongly associated with APOs remains 250 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 16 unclear. Second, the course of pregnancy may influence behavior during pregnancy, 251 introducing the possibility of reverse causation. Sensitivity analyses in participants with 252 blood samples collected before or at 20 weeks showed results consistent with those of the 253 main analyses, suggesting limited reverse causality related to glucose and lipid status. 254 However, the effects of other conditions, such as PE diagnosis and fetal growth restriction, 255 remain uncertain. Finally, the validity of the LE8 in the Japanese population has not yet been 256 established. Population differences and variations in LE8 definition, such as the use of the 8-257 item Japanese Diet Index vs. the 16 items of Mediterranean Eating Pattern for Americans, 258 may impact the accurate assessment of CVH by LE8. 259 260

261 In conclusion, CVH status may be a useful index for evaluating the risk of APOs. 262 Socially isolated pregnant women are more vulnerable to the effects of low CVH status. 263 264 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 17

265 The authors would like to thank all the participants who consented to participate in this study 266 and all the staff at Tohoku Medical Megabank Organization, Tohoku University, Iwate 267 Tohoku Medical Megabank Organization, and Iwate Medical University. 268 A full list of the members of the Tohoku Medical Megabank Organization is available at 269 https://www.megabank.tohoku.ac.jp/english/a230901/. 270 271 Authors' contributions 272 Conceptualization: Hisashi Ohseto, Mami Ishikuro, Geng Chen, Ippei Takahashi 273 Methodology: Hisashi Ohseto, Mami Ishikuro 274 Visualization: Hisashi Ohseto 275 Supervision: Shinichi Kuriyama, Taku Obara 276 Writing – original draft: Hisashi Ohseto, Mami Ishikuro, Geng Chen, Ippei Takahashi 277 Writing – review & editing: All the authors 278 279 Data Sharing Statement 280 Individual data are available upon request after the approval of the Ethical Committee and the 281

and Information Distribution Review Committee of Tohoku Medical Megabank 282 Organization. 283 284 285 286 287 288 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 18

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J Obstet Gynaecol Res 410 2021;47:3849-56. 411 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 23 Table 1. Baseline characteristics of the complete cases in the TMM BirThree Cohort 412 Study by overall CVH levels 413 High overall CVH Moderate overall CVH Low overall CVH n = 2,891 n = 11,498 n = 541 P-value Advanced maternal age at conception, % 655 (22.7) 3,092 (26.9) 177 (32.7) <0.001 Low income, % 875 (30.3) 4,237 (36.8) 269 (49.7) <0.001 Alcohol consumption during pregnancy, % 590 (20.4) 2,303 (20.0) 81 (15.0) 0.012 Psychological distress, % 225 (7.8) 1,237 (10.8) 100 (18.5) <0.001 Social isolation, % 470 (16.3) 2,286 (19.9) 154 (28.5) <0.001 Conception via IVF, % 110 (3.8) 611 (5.3) 33 (6.1) 0.002 Primipara, % 964 (33.3) 4,698 (40.9) 224 (41.4) <0.001 GA at blood sampling, day 125.8 ± 30.2 138.3 ± 33.7 147.8 ± 34.6 <0.001 GA at BP measurement, day 79.2 ± 14.8 79.4 ± 15.4 81.4 ± 14.8 0.006 CVH scores Overall CVH score 85.0 ± 4.4 67.7 ± 7.3 44.4 ± 5.0 <0.001 Diet score 69.9 ± 26.3 44.2 ± 32.5 22.7 ± 27.5 <0.001 PA score 59.0 ± 45.3 16.7 ± 34.7 6.0 ± 21.9 <0.001 Nicotine exposure score 88.3 ± 21.0 69.3 ± 33.8 33.2 ± 34.2 <0.001 Sleep health score 83.5 ± 21.2 71.2 ± 26.6 48.5 ± 29.9 <0.001 BMI score 96.9 ± 11.3 85.8 ± 26.2 42.4 ± 32.6 <0.001 Blood lipids score 86.0 ± 22.5 65.9 ± 29.3 42.2 ± 26.2 <0.001 Blood glucose score 99.8 ± 2.5 99.3 ± 5.9 93.6 ± 17.4 <0.001 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 24 BP score 96.5 ± 10.5 89.3 ± 18.6 66.9 ± 26.6 <0.001 CVH, cardiovascular health; IVF, in vitro fertilization; GA, gestational age; BP, blood 414 pressure; PA, physical activity; BMI, body mass index. 415 The overall CVH score was used to categorize participants into three groups: high (80–100), 416 moderate (50–79), and low (0–49). 417 Data are shown as mean ± standard deviation for continuous variables and n (%) for 418 categorical variables. 419 P-values were calculated using analysis of variance for continuous variables and the chi-420 square test for categorical variables. 421 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 25 Table 2. Results of logistic regression analyses showing association between overall CVH levels and study outcomes 422 CVH Crude Adjusted levels OR (95% CI) P-value P for trend OR (95% CI) P-value P for trend APOs High Reference <0.001 Reference <0.001 Moderate 1.20 (1.07 to 1.36) 0.002 1.17 (1.04 to 1.32) 0.009 Low 2.82 (2.28 to 3.50) <0.001 2.64 (2.13 to 3.27) <0.001 PE High Reference <0.001 Reference <0.001 Moderate 2.06 (1.54 to 2.74) <0.001 1.94 (1.46 to 2.59) <0.001 Low 8.19 (5.69 to 11.81) <0.001 7.43 (5.13 to 10.76) <0.001 GDM High Reference <0.001 Reference <0.001 Moderate 2.25 (1.55 to 3.25) <0.001 2.18 (1.51 to 3.15) <0.001 Low 10.11 (6.47 to 15.80) <0.001 9.18 (5.83 to 14.44) <0.001 PTB High Reference <0.001 Reference 0.002 Moderate 1.27 (1.03 to 1.56) 0.028 1.24 (1.00 to 1.53) 0.047 Low 2.06 (1.41 to 2.99) <0.001 1.93 (1.32 to 2.82) <0.001 SGA High Reference 0.025 Reference 0.017 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 26 Moderate 0.84 (0.71 to 0.98) 0.028 0.83 (0.71 to 0.98) 0.024 Low 0.77 (0.52 to 1.13) 0.178 0.74 (0.50 to 1.09) 0.125 LGA High Reference <0.001 Reference <0.001 Moderate 1.29 (1.11 to 1.50) <0.001 1.26 (1.09 to 1.46) 0.002 Low 2.73 (2.12 to 3.51) <0.001 2.63 (2.04 to 3.40) <0.001 LBW High Reference 0.743 Reference 0.876 Moderate 1.02 (0.88 to 1.19) 0.791 0.99 (0.85 to 1.15) 0.899 Low 1.05 (0.75 to 1.47) 0.781 0.98 (0.70 to 1.37) 0.894 NICU admission High Reference <0.001 Reference 0.001 Moderate 1.35 (1.09 to 1.68) 0.007 1.30 (1.04 to 1.61) 0.020 Low 2.05 (1.39 to 3.02) <0.001 1.88 (1.27 to 2.78) 0.002 CVH, cardiovascular health; APOs, adverse pregnancy outcomes; OR, odds ratio; CI, confidence interval; PE, preeclampsia; GDM, gestational 423 diabetes mellitus; PTB, preterm birth; SGA, small for gestational age; LGA, large for gestational age; LBW, low birth weight; NICU, neonatal 424 intensive care unit. 425 ORs and 95% CIs were estimated using logistic regression analyses with high CVH levels as reference. 426 Maternal age at conception, alcohol consumption during pregnancy, conception via in vitro fertilization, parity, psychological distress during 427 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 27 pregnancy, social isolation during pregnancy, and household income were included in the adjusted models.428 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 28 Figure Legends 429 Figure 1. Heatmap showing associations between component CVH levels and study 430 outcomes. 431 The heatmap represents Log transformed ORs from multiple logistic regression analyses 432 between component CVH levels and study outcomes. Adjustments were made for maternal 433 age at conception, alcohol consumption during pregnancy, conception via in vitro 434 fertilization, parity, psychological distress during pregnancy, social isolation during 435 pregnancy, and household income. 436 High CVH levels were references. Red, blue, and grey indicate positive, negative, and no 437 association, respectively. Darker colors indicate stronger associations. The asterisk indicates 438 the p-value. 439 For clarity, extreme Log OR values are presented as 2 or -2 when their absolute values are 2 440 or more. 441 CVH, cardiovascular health; OR, odds ratio; PA, physical activity; BMI, body mass index; 442 BP, blood pressure; APOs, adverse pregnancy outcomes; PE, preeclampsia; GDM, gestational 443 diabetes mellitus; PTB, preterm birth; SGA, small for gestational age; LGA, large for 444 gestational age; LBW, low birth weight; NICU, neonatal intensive care unit. 445 446 Figure 2. Subgroup analyses by psychological distress, social isolation, and income 447 ORs and 95% CIs were calculated using multiple logistic regression analyses between overall 448 CVH levels and APOs, with adjustment for maternal age at conception, alcohol consumption 449 during pregnancy, conception via in vitro fertilization, parity, psychological distress during 450 pregnancy, social isolation during pregnancy, and household income. 451 The "n/N (%)" indicates the number of cases and the total number in that stratum and its 452 ratio. 453 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint 29 CVH: cardiovascular health; OR: odds ratio; CI confidence interval. 454 455 Figure 3. Subgroup analyses by subscales and each item in LSNS-6 456 The ORs and 95% CIs were calculated using multiple logistic regression analyses between 457 overall CVH levels and APOs, with adjustment for maternal age at conception, alcohol 458 consumption during pregnancy, conception via in vitro fertilization, parity, psychological 459 distress during pregnancy, social isolation during pregnancy, and household income. 460 The "n/N (%)" indicates the number of cases and the total number in that stratum and its 461 ratio. 462 The details of LSNS-6 were presented in Supplementary Table 2. 463 LSNS, Lubben Social Network Scale; CVH, cardiovascular health; OR, odds ratio; CI, 464 confidence interval. 465 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted July 5, 2024. ; https://doi.org/10.1101/2024.07.05.24309978doi: medRxiv preprint . 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