Authors: Mei-Wei Chang, Alai Tan, Joshua M. Smyth, Duane T. Wegener
Categories: Article, Folate, vitamin B12, stress, prenatal distress, prenatal depression
Source: Critical public health
Authors: Mei-Wei Chang, Alai Tan, Joshua M. Smyth, Duane T. Wegener
Hypertensive disorders in pregnancy (HDPs) are the leading causes of maternal mortality and morbidity. This study explored whether micronutrient intake and psychological distress were associated with HDPs. Micronutrients include folate and vitamin B12. Psychological distress refers to perceived stress, prenatal distress, and prenatal depression. HDPs were defined as systolic blood pressure (BP) ≥ 130 mmHg or diastolic BP ≥ 80 mmHg. Data were collected at ≤ 17 weeks gestation (T1), 25–27 weeks gestation (T2), and 35–37 weeks gestation (T3). T-tests comparing those with and without HDP were performed to explore the associations. Results showed that folate and vitamin B12 were associated with HDPs at T1 and T2 (T1: d = −0.41, d = −0.52; T2: d = −0.43, d = −0.24). Psychological distress was positively associated with HDPs, but associations varied between timepoints and by measure – prenatal distress at all times (T1: d = 0.26; T2: d = 0.54, T3: d = 0.40), perceived stress at T3 (d = 0.34), and prenatal depression at T2 and T3 (T2, d = 0.47; T3: d = 0.68). In summary, micronutrient intake and psychological distress are associated with HDPs but varied by construct and across gestational age.
Hypertensive disorders in pregnancy, a significant public health concern, include chronic hypertension (prior to pregnancy or before 20 weeks gestation), gestational hypertension, and preeclampsia. In the US, hypertensive disorders in pregnancy are the leading cause of maternal mortality and morbidity.^1^ The prevalence of hypertensive disorders in pregnancy has significantly increased from 1993 to 2017 (~2-fold), and continue to climb from 2017 to 2019 (1.2-fold).^1^ Women with a history of hypertensive disorders in pregnancy are likely to experience hypertensive disorders during subsequent pregnancies,^2^ cardiovascular disease, stroke, and diabetes later in life,^e.g.,2^ and premature mortality.^3^ Therefore, it is critical and urgent to promote maternal health during pregnancy and later in life by reducing incidence of hypertensive disorders in pregnancy.
The American College of Obstetricians and Gynecologists defines hypertensive disorders in pregnancy as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg at 2 different occasions. Yet, it recommends clinicians to apply chronic hypertension management to stage 1 hypertension^4^ defined as SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg at 2 different occasions by the 2017 American College of Cardiology/American Heart Association Hypertension Guidelines.^5^ With the 2017 guidelines, the prevalence of child-bearing aged women with hypertension has increased by at least 2-fold.^6,7^ A recent large prospective cohort study of nulliparous pregnant women showed that stage 1 hypertension prior to 14-week gestation is associated with gestational hypertension, preeclampsia, gestational diabetes,^8^ premature delivery and low birth weight.^8,9^ Giving the detrimental effect of hypertensive disorders in pregnancy on maternal and birth outcomes, it is imperative to identify modifiable risk factors to promote positive maternal and birth outcomes. Two possible modifiable risk factors are micronutrients (folate and vitamin B12) and psychological distress (such as perceived stress, prenatal distress, and prenatal depression).
Folate and vitamin B12 have drawn researchers’ attention because they are potentially modifiable risk factors of preeclampsia.^10,11^ Increasing evidence supports that lower folate, ^e.g.,12,13^ and vitamin B12 levels ^e.g.,12^ were associated with hypertensive disorders in adults. Although hypertensive disorders in adult and pregnancy share common mechanisms,^14,15^ the existing evidence only partially supports the associations in pregnant women, perhaps due to methodological flaws. Prior studies were restricted to preeclampsia,^e.g.,16,17^ and most utilized case control designs^e.g.,16,18^ which cannot justify claims about cause-effect relations. Despite the fact that micronutrients dynamically fluctuate^19^ or decrease^20,21^ throughout pregnancy,^19^ prior studies have typically collected micronutrients (folate and vitamin B12) only at a single point.
In addition to micronutrients, psychological distress is another modifiable risk factor for hypertensive disorders in pregnancy. Pregnancy is often stressful for women because of (for example) change of body and personal and family life.^22^ Perceived stress, not being able to cope and feelings of being out of control and overwhelmed,^23^ is associated with depression (approximately 21–27% of pregnant women).^24,25^ Unfortunately, these statistics most likely underestimate prevalence because depression often goes undiagnosed.^26^ Also, there is a disturbing increase in the rate of comorbid depression and gestational hypertension (more than 3-fold) and comorbid depression and preeclampsia (approximately 2-fold).^27^ In addition to perceived stress, pregnant women experience pregnancy related psychological distress (hereafter, prenatal distress). Prenatal distress is defined as experience specifically related to (for example) physical symptoms and body change as a result of pregnancy, concerns about the fetus’ health, anticipation of childbirth, caring for a newborn.^28,29^ Associations between psychological distress and hypertensive disorders have been inconsistent, again partially due to studies’ methodological mostly utilizing case control,^e.g.,30,31^ and cross-sectional designs,^e.g.,32,33^ often restricting to preeclampsia,^e.g.,30,31^ and collecting data only at a single point when psychological distress dynamically fluctuates throughout pregnancy.^34,35^ Also, relatively little research attention has been paid to prenatal distress.
Using data collected for a randomized controlled trial of a stress management and healthy lifestyle behavior (diet and physical activity) intervention, this secondary data analysis explored whether micronutrient intake and psychological distress were associated with hypertensive disorders in pregnancy among overweight or obese pregnant women. Micronutrients here refer to folate and vitamin B12 and psychological distress includes perceived stress, prenatal distress, and prenatal depression. The randomized controlled study was designed to evaluate intervention feasibility and to investigate preliminary intervention effects on gestational weight gain (primary outcome). Data were collected at 3 time ≤ 17 weeks gestation (baseline, T1), 25–27 weeks gestation (T2), and 35–37 weeks gestation (T3). We did not find differences in gestational weight gain between the intervention and usual care groups.^36^ Results of the feasibility evaluation have been published.^36^
Clinicians at 5 prenatal care clinics affiliated with The Ohio State University Wexner Medical Center referred their first trimester pregnant patients to the study office. To be qualified to participate in the study, women had to be 18–45 years, ≤ 13 week-gestation with a singleton fetus confirmed by ultrasound (at referral), had ≤ 3 miscarriages and no diagnosis of hypertension or type 1 or 2 diabetes. Also, their body mass index (BMI) had to be between 25.0–44.9 kg/m^2^ using self-reported height and pregnancy weight. After receiving the referral, the research assistants called women to screen for eligibility. Qualified women attended an information session via zoom followed by signing an electronic consent form for participation and completing baseline measures. After that, they (N = 70) voluntary attended the second zoom meeting and were enrolled and randomized to the intervention or usual care group. A detailed description of the setting and participants has been published.^36^ The study procedure was approved. This study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ohio State University Institution Review Board (IRB #: 2019H0441).
Demographics included age, race/ethnicity, marital status, education, receipt of financial assistance, and primiparous. Participants completed online surveys measuring psychological distress (described below) at 3 time ≤ 17 weeks gestation (baseline, T1), 25–27 weeks gestation (T2), and 35–37 weeks gestation (T3).
All participants received usual prenatal care from their Ob/Gyn or midwife at our collaborating sites. The usual prenatal care visit occurs monthly until 28 weeks gestation, every other week from 28 to 36 weeks gestation, and weekly from 36 weeks until delivery. At each prenatal visit, trained professionals measured pregnant women’s blood pressure. With participants’ permission, we extracted their SBP and DBP at each prenatal care visit through electronic health records. To identify women with hypertensive disorders in pregnancy, we used the 2017 American College of Cardiology/American Heart Association ^5^ SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg at 2 different prenatal care visits. Normal blood pressured was defined as SBP < 130 mmHg and DBP < 80 mmHg throughout the pregnancy.
At each time point of data collection, participants completed two 24-hour dietary recalls within 2 weeks through National Cancer Institute Self-Administered 24-hour Dietary Recall (ASA-24) assessment tool.^37^ This is a web-based tool that has been validated by the National Cancer Institute and has been widely used by researchers in United States, Canada, and Australia. The tool utilizes automated multiple-pass methods to increase accuracy of dietary recall. This tool uses the United States Department of Agriculture’s Food and Nutrient Database to generate indices for intake of macronutrients, fatty oil, and micronutrients, such as folate and vitamin B12.^37^
To measure perceived stress, we used the validated Perceived Stress Scale with 10 items. This survey measures the extent to which participants appraised their life situation as stressful.^38^ Participants used 5 response categories (never = 0 to very often = 4) to report their feelings and thoughts during the past month. To create a composite score, we summed responses of all 10 items. Higher scores indicated higher levels of perceived stress.
To measure prenatal distress, we used the validated Prenatal Distress Questionnaire with 17 items. This survey assesses symptoms of stress associated with pregnancy.^39^ Participants used 3 response categories (not at all = 0 to very much = 2). To create a composite score, we averaged responses of all 17 items. Higher scores meant higher levels of prenatal distress.
To measure prenatal depression, we used the validated Edinburgh Postnatal Depression Scale with 10 items.^40^ Participants used 3 categories (for example, not at all = 0 to yes, quite a lot or most of the time = 3) to report depressive symptoms related to pregnancy within the last 7 days. To create a composite score, we summed responses to the 10 items. Higher scores reflected more depressive symptoms.
Of 70 participants enrolled in the pilot intervention study, 6 dropped out (3 miscarriages and 3 too busy to continue participating). The micronutrient analysis included participants who completed dietary recalls at baseline (T1, n = 64), 25–27 weeks gestation (T2, n = 36), or 35–37 weeks gestation (T3, n = 33). For the psychological distress analysis, we included 64 (T1), 37 (T2), and 33 (T3) participants. Descriptive analyses were used to summarize sample characteristics, overall and stratified by hypertensive disorders in pregnancy (yes vs. no). Bivariate tests (two-sample t-tests and Fisher’s exact tests) were conducted to examine whether sample characteristics differ by hypertensive disorders in pregnancy. To explore the associations of micronutrient intake and psychological distress with hypertensive disorders in pregnancy, we conducted two-sample t-tests by comparing the differences in micronutrients (folate and vitamin B12) and psychological distress (perceived stress, prenatal distress, and prenatal depression) between those with hypertensive disorders in pregnancy (SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg) and those with normal blood pressure (SBP < 130 mmHg and DBP < 80 mmHg) throughout the pregnancy. Cohen’s d was used to present effect size of the between-group difference (hypertensive disorders in pregnancy, yes vs. no) in micronutrients and psychological distress. Cohen’s d values of 0.2, 0.5, and 0.8 are cutoffs for small, medium, and large effect sizes. We used SAS version 9.4 (SAS Institute®, Cary, NC) to conduct all the statistical analyses.
Table 1 presents sample characteristics of the study participants (N = 64). The participants had an average age of 32.3 years (SD = 4.0). A majority were non-Hispanic White (71.9%) and married (90.6%) had at least a bachelor’s degree (90.6%) and were not receiving any government financial assistance (95.3%). BMI was the only sample characteristic that was significantly different between those with hypertensive disorders and those with normal blood pressure throughout pregnancy. There were more obese participants among those with hypertensive disorders than those with normal blood pressure throughout pregnancy (64.3% vs. 36.4%, p = 0.033).
Table 2 presents associations of micronutrient intake (folate and vitamin B12) and psychological distress (perceived stress, prenatal distress, and prenatal depression) with hypertensive disorders in pregnancy at each time point. Our results showed that most women (42/64 participants or 65.6%) experienced hypertensive disorders in pregnancy. Folate was associated with hypertensive disorders in pregnancy at T1 (Cohen’s d = −0.41) and T2 (d = −0.43) but not T3 (d = −0.07). Vitamin B12 had a moderate association with hypertensive disorders in pregnancy at T1 (d = −0.52), but the association at T2 was smaller (T2: d = −0.24). No association was found at T3 (d = −0.15). In terms of psychological distress, perceived stress was not associated with hypertensive disorders in pregnancy at T1 (d = 0.13) or T2 (d = −0.05). However, there was an association at T3 (d = 0.34). Although prenatal distress had smaller associations with hypertensive disorders in pregnancy at T1 (d = 0.26) and T3 (d = 0.40), the association was moderate at T2 (d = 0.54). Although prenatal depression was not associated with hypertensive disorders in pregnancy at T1 (d = 0.01), there were small and moderate associations at T2 (d = 0.47) and T3 (d = 0.68), respectively.
These data allowed us to examine the important issue of whether micronutrient intake and psychological distress were associated with hypertensive disorders throughout pregnancy. Our preliminary results suggest that folate and vitamin B12 and psychological distress (perceived stress, prenatal distress, and prenatal depression) could potentially play roles in hypertensive disorders in pregnancy. The preliminary results can advance the scientific knowledge in understanding modifiable risk factors for hypertensive disorders in pregnancy. Consequently, if confirmed by continuing research, there is potential for non-medical treatment targeting dietary intake and/or psychological distress that could potentially reduce the incidence of hypertensive disorders in pregnancy.
Pre-pregnancy overweight or obesity are strong risk factors for hypertensive disorders in pregnancy.^41,42^ Compared with normal weight women, overweight or obese women are nearly 3 times (for overweight) to more than 4 times (for obesity) as likely to develop hypertensive disorders in pregnancy.^43^ Also, overweight or obese adults are at higher risk of folate^44^ and vitamin B12^45^ deficiency. Folate and vitamin B12 are essential for homocysteine metabolism. Deficiency in folate and vitamin B12 can lead to increased homocysteine concentration,^46^ consequently leading to hypertensive disorders in pregnancy.^e.g.,47,48^ Taken together, overweight or obesity coupled with folate and vitamin B12 deficiency put overweight or obese pregnant women into a very high risk group for adverse maternal and birth outcomes.
Our preliminary results revealed that folate and vitamin B12 have small to moderate associations with hypertensive disorders in pregnancy at ≤ 17 weeks gestation and during the second trimester. Direct comparison of our preliminary results with prior studies of pregnant women is challenging. We defined hypertensive disorders in pregnancy as SBP ≥ 130 mmHg or DBP ≥ 80 mmHg throughout the pregnancy. However, some prior studies have defined the disorders as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg and focused on hypertensive disorders diagnosis after 20 weeks gestation.^e.g.,16,49^ Also, although prior studies utilized serum/plasma samples to indicate micronutrient levels, we used self-reported dietary intake which might be subject to a variety of recall and reporting biases. Nonetheless, as most prior studies collected data at a single time point during pregnancy and have yielded mixed results,^e.g.,16,18,49^ these dietary recall data allowed us to investigate the associations between micronutrients (folate and vitamin B12) throughout pregnancy.
Pregnant women experienced both general (perceived stress) and pregnancy-related stress (prenatal distress), which is common among pregnant women.^50^ General perceived stress and prenatal distress are not static during the pregnancy,^51,52^ and – although they are associated with each other – perceived stress is distinct from prenatal distress.^53^ There is a robust literature linking stress (general and pregnancy related) and birth outcomes,^51^ but research has less frequently examined hypertensive disorders in pregnancy. This small literature is less conclusive, with 3 prior studies that investigated the association between perceived stress and pre-eclampsia reporting a positive association.^30,31,33^ Yet, results from 2 other studies examining the association between perceived stress and hypertensive disorders in pregnancy were inconclusive.^30,32^ Our preliminary results show a positive association between perceived stress and hypertensive disorders in pregnancy with the association only pronounced in the third trimester (but based on a relatively small amount of data). Similarly, prior studies of prenatal distress and preterm birth reported that prenatal distress at the third trimester was the best predictor of premature birth.^51^ Our study extends prior studies by examining the associations between perceived stress and hypertensive disorders throughout pregnancy. Our findings suggest the importance of examining the role of prenatal distress in hypertensive disorders throughout pregnancy and beyond birth outcomes.
Researchers have investigated the association between prenatal depression and hypertensive disorders in pregnancy (with a focus on preeclampsia). Whether general depression or pregnancy-related depression, most studies have reported that prenatal depression was associated with pre-eclampsia.^e.g., 27,31^ Again, prior studies included women in all trimesters; this raises the question of whether there might be critical periods associated with preeclampsia. Our preliminary results showed moderate associations between prenatal depression and hypertensive disorders in pregnancy during the second and third trimesters. In the US, 50–70% of pregnant women with prenatal depression are not diagnosed. With those being diagnosed, only 20% received any treatment. Of women with diagnosed prenatal depression, only 8.5% received an adequate treatment.^53^ These statistics along with results of our and prior studies call out the urgent need to further investigate the possible causal relations between prenatal depression and hypertensive disorders throughout pregnancy to promote positive maternal health outcomes.
The present study has limitations. Interpretation of the study findings must be cautious because of the small sample size. Also, we only included overweight or obese pregnant women who were predominately White. Consequently, the study findings might not be generalizable. Moreover, as an exploratory study, we reported unadjusted associations. This is because we did not find any sample characteristics that were significantly associated with hypertensive disorder during pregnancy other than BMI. BMI is a risk factor for hypertensive disorders in pregnancy. Depending on the context, a risk factor can be treated as an independent, moderator, or mediator.^54^ In this study, BMI can be potentially treated as a mediator. For example, individuals with low folate and vitamin B12 are more likely obese.^55^ As a result of a small sample size, we did not test mediation effect. Ideally, one should use serum or plasma folate and vitamin B12 to investigate their associations with hypertensive disorders in pregnancy. To our knowledge, data that included serum/plasma folate or vitamin B12 in pregnant women and measured blood pressure throughout pregnancy are not available. Also, evidence has shown a positive association between folate intake and serum folate in adults.^56^
Micronutrient intake and psychological distress are potentially modifiable risk factors for hypertensive disorders in pregnancy. We found that micronutrients (folate and vitamin B12) were associated with hypertensive disorders in pregnancy at the first and second trimesters. However, depending on the type of psychological distress, associations with hypertensive disorders in pregnancy differed by trimesters. Our preliminary results suggest the importance of investigating micronutrients and psychological distress associations with hypertensive disorders throughout pregnancy. Also, there is a need to include pregnancy-related psychological distress. Future larger prospective studies are needed to validate these preliminary findings.