Hypertensive Disorders during Pregnancy (HDP), Maternal Characteristics, and Birth Outcomes among Japanese Women: A Hokkaido Study

Hypertension during pregnancy causes a greater risk of adverse birth outcomes worldwide; however, formal evidence of hypertensive disorders during pregnancy (HDP) in Japan is limited. We aimed to understand the association between maternal characteristics, HDP, and birth outcomes. In total, 18,833 mother-infant pairs were enrolled in the Hokkaido study on environment and children’s health, Japan, from 2002 to 2013. Medical records were used to identify hypertensive disorders and birth outcomes, namely, small for gestational age (SGA), SGA at full term (term-SGA), preterm birth (PTB), and low birth weight (LBW). The prevalence of HDP was 1.9%. Similarly, the prevalence of SGA, term-SGA, PTB, and LBW were 7.1%, 6.3%, 7.4%, and 10.3%, respectively. The mothers with HDP had increased odds of giving birth to babies with SGA (2.13; 95% Confidence Interval (CI): 1.57, 2.88), PTB (3.48; 95%CI: 2.68, 4.50), LBW (3.57; 95%CI: 2.83, 4.51) than normotensive pregnancy. Elderly pregnancy, low and high body mass index, active and passive smoking exposure, and alcohol consumption were risk factors for different birth outcomes. Therefore, it is crucial for women of reproductive age and their families to be made aware of these risk factors through physician visits, health education, and various community-based health interventions.


Introduction
Pregnancy-induced hypertension (PIH) is defined as hypertension (blood pressure ≥ 140/90 mmHg) with or without proteinuria (≥300 mg/24 h) emerging after 20 weeks of gestation. Furthermore, PIH is defined as a new onset proteinuria (≥300 mg/24 h) in hypertensive women exhibiting no proteinuria before 20 weeks of gestation [1]. In 2004, Japan revised the term "Toxemia of Pregnancy" to "Pregnancy Induced Hypertension," which was further revised in 2017, to "Hypertensive disorders of Pregnancy," shortly named HDP, which is consistent with the international classification [2]. HDP has been classified into four types as follows: preeclampsia, gestational hypertension, superimposed preeclampsia, and chronic hypertension, excluding eclampsia in the previous disease type classification [3]. HDP occurs in 5% of women and around 10% of primiparous women out of all pregnancies.

Participants
The Hokkaido Study on Environment and Children's Health is a prospective birth cohort that began in 2002. Further information about the aim of this study has been described previously [25][26][27]. From February 2003 to March 2012, the Hokkaido cohort included Japanese women who were recruited during early pregnancy (13 weeks of gestation) and who visited the maternity unit in one of the 37 hospitals and clinics in the Hokkaido Prefecture, Japan. These 37 health services cover the entire Hokkaido area. The cohort consisted of 20,926 pregnant women. As a current study focused on the birth outcomes, we included all mothers who completed the baseline questionnaire in the first trimester and with a medical record of their pregnancy. Participants who lacked this information were excluded from this study (n = 2093) ( Figure 1). In total, we included the data obtained from 18,833 participants in the statistical analyses and assessed the associations between HDP and SGA, term-SGA, PTB, and LBW.

Questionnaire and Medical Records
After enrolling in the study, the participants completed a self-administered questionnaire, which consisted of information on parental characteristics. Questions on maternal age, height, weight, education, occupation, medical history, maternal smoking, and alcohol consumption during and before the first trimester, paternal smoking history, and use of any assisted reproductive technologies were asked. The medical record consisted of information about gestational days at delivery, live-birth, single or multiple births, sex, and birth weight of the infant. The medical history of HDP was obtained from medical records. We used Japanese standard definition of HDP and subclassified the symptoms based on severity. The mild HDP (h) refers to blood pressure ≥140/90 mmHg but <160/110 mmHg after 20 weeks of gestation, and proteinuria (p) ≥300 mg/24 h without exceeding 2.0 g/24 h or 3 + dipstick. The severe HDP (H) refers to blood pressure ≥160/110 mmHg and proteinuria (P) exceeding 2.0 g/24 h or 3 + dipstick [1].

Cotinine Level Measurements
Blood samples collected from participants during the third trimester of gestation were frozen at −80 • C. Cotinine measurement was carried out using the highly sensitive enzyme-linked immunosorbent assay (ELISA) technique. The limit of detection was 0.12 ng/mL. Non-detectable cotinine concentrations were assigned a half value of the detection limit (0.06 ng/mL) before the statistical analysis. The detailed experimental procedure has been discussed in our previous study [28,29]. We used the cotinine cutoff amounts based on our previous study to differentiate between passive and active smokers [28,29]. Based on this cotinine value, non-passive smokers (≤0.21 ng/mL), passive smokers (>0.21-≤11.48 ng/mL) and active smokers (>11.48 ng/mL) were defined.

Birth Outcomes
Our study discussed four birth outcomes as follows: SGA, term-SGA, PTB, and LBW. SGA was defined as newborns smaller in size than expected for their gestational age, expressed as a weight below the 10th percentile for the gestational age according to the condition of parity and the sex of the infant [30]. Term-SGA was described as a birth weight lower than the 10th percentile of the normative reference birth weight born >37 weeks of gestation (at full-term). PTB was defined as live birth at <37 weeks of gestation [31]. LBW was defined as a birth weight <2500 g. BMI was calculated from the pre-pregnancy weight. Asians are smaller than Caucasian people, hence, we used the database for birth weight published by the Japan Pediatric Society as a reference to calculate SGA and term-SGA [32].

Statistical Analysis
A descriptive analysis was performed to present the demographic and socio-personal information of the mothers. Binary logistic regressions were performed to evaluate as-sociation between maternal characteristics and HDP, maternal characteristics and birth outcomes, and HDP and birth outcomes with adjustment for the following covariates: maternal age, parity, smoking during the first trimester, and alcohol consumption during the first trimester. The confidence interval (CI) was set at 95%, with a level of significance at 0.05. All statistical analyses were conducted using IBM SPSS Statistics for Windows software version 22.0 (IBM Corp., Armonk, NY, USA).

Characteristics of Infants and Mothers
Out of 18,833 mothers, 363 mothers developed HDP. There was a significant difference between the birth weight of infants, gestational age, and type of pregnancy among mothers with HDP compared to mothers without HDP. Similarly, there was a significant difference in age, BMI, parity, and fertility treatment for this pregnancy among mothers with HDP as compared to mothers without HDP. The characteristics of infants and mothers are presented in Table 1. There was no significant difference between mothers with and without HDP for types of delivery, education level, annual household income, drinking habit, smoking habit, occupation, exposure to chemicals, drip infusion, and plasma cotinine levels. In addition, no significant difference was observed in the characteristics in the education of partner, medical illness, occupation, exposure to chemicals, smoking, and drinking habits. Chi-squared test; SGA, small for gestational age; weight Z-score, gestational age-specific-Z-score; cut-off for plasma cotinine level, 0.21 ng/mL (value differentiating non passive smokers from passive smokers among non-active smokers), 11.48 ng/mL (value differentiating non-active smokers from active smokers) [28]. Table 2 presents the association between maternal characteristics and HDP. The crude model showed that the risk of HDP was significantly higher among older mothers, high BMI, multiple pregnancy, those who received fertility treatment, and those who underwent in vitro fertilization (IVF) for this pregnancy and the decreased risk for multiparous. The crude model showed no association between HDP and plasma cotinine level. The adjusted model showed that the risk of HDP was higher among older mothers, high BMI, twin pregnancy, those who received in vitro fertilization for this pregnancy and active smokers. There was no association between HDP and parity in the adjusted model. No significant association was observed between HDP and maternal characteristics such as education level, annual household income, medical illness, exposure to chemicals, and occupation.  Table 3 presents the association between maternal characteristics and SGA and term-SGA. The crude model showed that SGA was associated with the increased risk for mothers with a low BMI, twin pregnancy, smoking habit, smoking habit before and during pregnancy, drinking habit before pregnancy, those who received fertility treatment for this pregnancy, and active smokers as per plasma cotinine levels during the third trimester, and had the decreased risk for multiparity. After adjustment, SGA was associated with older age, low BMI, twin pregnancy, smoking habit during pregnancy, drinking habit before pregnancy, and active smokers as per plasma cotinine level during the third trimester. The crude model showed that term-SGA was associated with mothers with low BMI, smoking habits before and during pregnancy, drinking habits before pregnancy, and active smokers as per plasma cotinine levels during the third trimester. The adjustment model did not show any association of term-SGA with the smoking habit, smoking habit before pregnancy, and drinking habits compared to the crude model. Table 4 presents the association between maternal characteristics and PTB and LBW. The crude model showed that PTB was associated with older age, high BMI, twin pregnancy, smoking habit before pregnancy, those who received fertility treatment for this pregnancy, and those who underwent IVF. The adjusted model showed similar findings for the association of maternal characteristics and PTB.  LBW was significantly associated with older age, low BMI, twin pregnancy, smoking habit during pregnancy, drinking habit before pregnancy, those who underwent fertility treatment for this pregnancy, those who underwent IVF, and active smokers as per plasma cotinine levels during the third trimester. Table 5 presents the association between HDP and birth outcomes. The crude and adjusted model showed that HDP was found to be significantly associated with SGA, PTB, and LBW.

Discussion
This study has tried to understand the risk factors of HDP, and the association between maternal characteristics and HDP on birth outcomes such as SGA, term-SGA, PTBs, and LBW. HDP was found to be associated with SGA (2.13 OR), PTB (3.48 OR), and LBW (3.57 OR). Our findings are similar to previous studies, which have suggested a higher risk of perinatal outcomes among women with HDP [33,34]. There was no association between term-SGA and HDP in our study. PTBs have become a significant public health issue worldwide and constitute a significant cause of infant mortality and low infant development [35]. More than 60% of PTB occurs in Africa and South Asia; furthermore, on average, 12% of babies are born too early in lower-income countries, compared with 9% in higher-income countries [36]. Studies have indicated that increasing maternal age at delivery, and primiparity are a few of the few reasons that have been found to increase PTB rates [35,37]. Our study also showed an increased risk of PTB among women who were pregnant at an older age, had a high BMI, had a habit of smoking before pregnancy, and a mother who opted for IVF. Other studies have identified adolescent birth rate, short stature among women of childbearing age, underweight mothers, obesity, multifetal pregnancy, pregnancies spaced too closely, and antepartum hemorrhage as the possible causes of PTB in lower-income countries [38,39].
HDP and its subtypes are one of the major risk factors for the development of cerebral, renal, cardiovascular disease (CVD) in the mothers in later phase of life [5]. Similarly, studies have shown that babies born to mothers with HDP are at greater risk of noncommunicable diseases, women with preeclampsia are at high risk of developing stroke, hypertension, diabetes mellitus, end renal stage disease and CVD when they become adults [40]. The HDP prevalence was 1.9% in our study, which was less than the Japan Environment and Children's Study (3.1%), a nationwide birth cohort study [41]. The difference might be due to variation in the study group and Japanese population of pregnant women. The prevalence of HDP in our study was lower than that reported for Chinese (5.2%), African Americans (6.4%), and Brazilian (7.5%) studies [6,42,43]. The differences might occur due to variation in age distribution, socio-economic backgrounds, ethnicity, and the enhancement of the Japanese health care delivery system, which prioritizes health checkups during pregnancy.
The prevalence of LBW deliveries in high-income countries is lower (7%) as compared to low-income countries (12-25%) [44]. Additionally, in lower-income countries, about one in five infants are born SGA, and one in four neonatal deaths occur in SGA babies [45]. From 1985 to 2013, infants' mean birth weight in Japan reduced to 3000 g (from 3120 g) and LBW babies increased from 6.3% to 9.6% [32]. In Japan, the number of underweight women, mainly in their 20s and 30s, has significantly increased. A survey conducted by the Ministry of Health, Labor and Welfare showed that about 25% of Japanese women of reproductive age are underweight (BMI < 18.5 kg/m 2 ) and are at risk of delivering LBW infants and SGA infants [21,46,47]. Our study showed that pre-pregnancy BMI (<18.5 kg/m 2 ) showed a strong association with SGA, term SGA, PTB, and LBW. Low weight gain before and during pregnancy causes inadequate nutrient supply to the fetus and can induce poor head circumference growth in newborns [48]. This could result in fetal malnutrition, leading to various organ developmental failures. While Japan's population growth rate continues to decrease, the tendency to maintain low BMI among mothers could become a significant risk for neonatal mortality. Hence, effective health education about nutritious diet and healthy weight gain from an early stage in school life, receiving proper counseling from medical doctors, gynecologists, and nurses regarding the relationship between BMI and LBW can prevent LBW infant deliveries in the future.
An Italian population-based study revealed that low maternal education was a risk factor for PTB, LBW, and SGA [49]. No such association was found in our study. This might be because the education level of mothers in our study was higher than that of Italy. Several studies have suggested primiparity as a risk factor for PTB [50]; however, primiparity was found to be associated with SGA, term-SGA, and LBW in our study. Our findings are consistent with a previous Japanese study, which indicated that the risk of LBW is lower among multiparous women [21]. Our findings are consistent with other studies that showed an association between birth outcomes and maternal characteristics, such as LBW babies and PTB with maternal age [43,51] and LBW and PTB with maternal BMI [30,52]. This suggests that women who want to conceive their first child at a later age and who have a low or high BMI should be counseled by their family health practitioners and be continuously monitored to reduce the occurrence of birth complications.
Our study showed a strong association between twin and multiple pregnancies and HDP. Previous studies have shown an increased risk for gestational hypertension, preeclampsia, and eclampsia in twin pregnancies compared to singleton pregnancies in primiparous and multiparous women [53]. Similarly, twin pregnancy was associated with SGA, PTB, and LBW in this study. Studies suggest that PTB is more common among women with twin pregnancies than singleton pregnancies, and HDP is more common in multiple than singleton pregnancies [54].
This study showed a strong association of fertility treatment, mainly IVF, with PTB and LBW. Several studies have shown the risk of preterm delivery and LBW babies among women conceiving after fertility treatment [55,56]. The proportion of twin births was higher among women receiving fertility treatment in our study (14.8% vs. 1.3%). IVF pregnancies are precious to infertile couples, leading to labor induction, and elective cesarean section, causing an iatrogenic increase in preterm delivery and an increased risk of preterm delivery among infertile couples. A study has shown that IVF increased the risk of LBW by 3.78, similar to our study (OR: 3.62) [55]. However, the OR reduced to 3.27 when adjusted for age, parity, BMI, smoking, and alcohol consumption. As these factors affect pregnancy outcomes, they should be considered while studying the effect of fertilization on different birth outcomes. This finding is similar to our previous study that showed different risk factors for term-SGA, LBW, and PTBs in the Japanese setting; however, this study did not include mothers with HDP [31].
The smoking rate among females in Hokkaido is 16.1%, which is higher than the national average for women (9.5%) and highest among all prefectures in Japan [57]. The smoking rate among males in Hokkaido is 34.6%, which is higher than the national average smoking rate for males (31.1%) and is the fourth highest compared to other prefectures [58]. The increasing smoking habits among females and increased exposure to secondhand smokers during pregnancy can cause intrauterine growth retardation and decreased birth weight among infants and children. A Japanese study has shown the reduction of birth weight by 125-136 g among smoking mothers during pregnancy [59]. Our study showed that smoking habits before pregnancy were associated with SGA, term-SGA, and PTB, while smoking during pregnancy was associated with SGA, term-SGA, and LBW. Active smoking during the third trimester (plasma cotinine level >11.48 ng/mL) was significantly associated with SGA, term-SGA, and LBW. Smoking before and during pregnancy has a negative impact on newborn babies, either in terms of weight or gestational age. Smoking during the first and third trimester has a similar impact on neonates. Our previous study showed that passive pregnant smokers with cotinine levels ≥3.03 ng/mL had an almost equal risk of delivering SGA infants as active smokers with cotinine levels (>11.48 ng/mL) [29]. Few studies focusing on the effects of maternal smoking during pregnancy and HDP have shown that smoking reduces the risk of preeclampsia and HDP [60,61]. Our study showed a significant association between plasma cotinine levels during the third trimester and HDP when controlled for age, parity, BMI, smoking during pregnancy, and alcohol consumption during pregnancy. Our study showed an association between HDP and passive smokers (>0.21 to ≤11.48 ng/mL) and active smokers (>11.48 ng/mL). Hence, women of reproductive age must be aware of prenatal smoking exposure on their babies and the risk of abnormal birth outcomes. A Polish study suggested that the risk of PIH increased significantly among women who smoked in the first trimester and with a low BMI before pregnancy [62]. The increased risk of HDP should be monitored among passive and active smokers, in addition to adverse birth outcomes [63].
There was an association between SGA, term-SGA, and LBW babies among mothers who habitually drank alcohol before pregnancy. However, we did not find any association between alcohol consumption before pregnancy and during the first trimester and preterm delivery risk. This might have occurred because our alcohol consumption data were based on questionnaires, and not on direct observation or volume calculation. A Japanese study found that maternal alcohol consumption during pregnancy was significantly associated with an increased PTB risk but did not show any relationship with LBW and SGA [64,65]. A meta-analysis on the dose-response relationship has shown that heavy alcohol consumption increases the risks of SGA, PTB, and LBW [66]; however, further studies need to be conducted in an Asian context to understand the different doses of alcohol and their effect during pregnancy. It is highly recommended to avoid alcohol consumption during pregnancy to reduce the onset of HDP among women in Japan [32].
A Japanese national survey conducted over 55 years (1961-2016) has shown a steady decrease in systolic blood pressure levels among all age groups of men and women, but not in the diastolic blood pressure levels requiring different population-based strategies to manage and prevent hypertension [67].
The strength of this study is its prospective birth cohort study design comprising 18,833 mother-infant pairs. In this study, we calculated the HDP from the medical records, which is a highly reliable report. We measured cotinine levels during the eighth month of pregnancy, as maternal smoking during the third trimester was related to birth size reduction. However, this study has some limitations. The participants who had HDP were relatively small (1.9% of the total participants), which might have led to an underestimation of the results. The study participants were pregnant women who had visited hospitals or clinics within the Hokkaido prefecture only. The pre-pregnancy weight, maternal smoking and alcohol consumption habit were self-reported by the respondents, which might have caused biasness. As we did not have participants with chronic hypertension, they were not included in the analysis. In addition, the reported risk of gestational diabetes mellitus, type 2 diabetes mellitus, family history of hypertension, and preexisting urinary tract infection were not assessed in this study.

Conclusions
Our study showed that mothers with HDP had increased odds of giving birth to babies with SGA, PTB, and LBW than mothers with normotensive pregnancy. Therefore, women of reproductive age need to be made aware of different risk factors through physician visits, health education, and various community interventions related to public health. Risk assessment before pregnancy, management of modifiable risk factors, and medical history monitoring should be implemented as per national guidelines to reduce further complications among pregnant mothers with HDP. It is crucial to remember that these risk factors can cause maternal and neonatal complications in mothers with HDP. Our study recommends future studies on Japanese mothers with HDP to demonstrate an association between characteristics and birth outcomes, considering the mediating effects of different confounding variables.  Informed Consent Statement: All mothers, prior to participation, provided written informed consent.

Data Availability Statement:
The data are not publicly available due to ethical restrictions and specific legal framework in Japan. All inquiries should be addressed to Reiko Kishi, investigator of the Hokkaido Study on Environment and Children's Health, Center for Environmental and Health Sciences, Hokkaido University.