Maternal and perinatal outcomes according to blood pressure levels for prehypertension: A review and meta-analysis

Abstract

Aim: This study aimed to examine whether blood pressure ≥130/80 mmHg is an appropriate reference value for hypertension in pregnant women by conducting a meta-analysis of studies reporting maternal/perinatal outcomes according to blood pressure levels at <20 weeks of gestation.

Methods: The meta-analysis of studies identified through PubMed/MEDLINE and Ichushi-Web searches was conducted to evaluate the incidence of preeclampsia, gestational hypertension, hypertensive disorders of pregnancy, preterm birth, and small-for-gestational-age birth.

Results: The meta-analysis of 12 prospective and retrospective cohort studies revealed that the risks of preeclampsia, gestational hypertension, and hypertensive disorders in pregnancy were higher in women with blood pressure ≥120/80 mmHg, particularly ≥130/80 mmHg, relative to <120/80 mmHg. The risk of preterm birth was higher in women with blood pressure ≥120/80 mmHg, and significantly higher in those with blood pressure ≥140/90 mmHg, relative to <120/80 mmHg. The risk of small-for-gestational-age birth did not differ significantly by blood pressure status.

Conclusions: Blood pressure ≥120/80 mmHg, particularly ≥130/80 mmHg, is associated with increased maternal and perinatal risks. We propose new blood pressure categories as normal (<120/80), high normal (120–129/<80), and elevated (130–139/80–89), although further studies will be needed to set ≥130/80 mmHg as a new reference for hypertension in pregnant women.

Introduction

A reference blood pressure of 140/90 mmHg for hypertension was established using data of middle-aged white men obtained by life insurance companies in the 1930s to 1950s. The risk of arteriosclerotic heart disease increases with blood pressure >140/90 mmHg.¹⁾ For hypertension in pregnant women, reference values have traditionally been defined based on evidence in the internal medicine field. In 1952, the American Committee on Maternal Welfare established a diagnostic criterion of blood pressure >140/90 mmHg for hypertension in pregnant women without chronic hypertension or an increase in systolic or diastolic blood pressure by more than 15 or 30 mmHg, respectively, in pregnant women with chronic hypertension.²⁾ Subsequently, the National High Blood Pressure Education Program, the International Society for the Study of Hypertension in Pregnancy (ISSHP), and the American College of Obstetricians and Gynecologists (ACOG) defined reference values for hypertension in pregnant women. In Japan, the reference value for hypertension in pregnant women was set for the first time in 1962 based on the American Committee on Maternal Welfare definition, rather than being adequately defined based on evidence from Japanese pregnant women.

In 2017, the American College of Cardiology/American Heart Association hypertension treatment guidelines defined hypertension as blood pressure >130/80 mmHg based on the association between blood pressure and cerebrovascular or heart diseases.³⁾ However, the reference blood pressure for hypertension in pregnant women as specified by the ISSHP guidelines (2018) and ACOG guidelines (2019) is 140/90 mmHg, as sufficient evidence is lacking for pregnant women.^4,5) A number of recent studies have examined the validity of blood pressure ≥130/80 mmHg as the reference value for hypertension in pregnant women.^6,7,8,9) Therefore, as an academic project of the Japan Society for the Study of Hypertension in Pregnancy (JSSHP), the Study Committee on the Diagnostic Criteria for Hypertension in Pregnant Women set out to review and analyze domestic and foreign articles reporting maternal and perinatal outcomes according to blood pressure levels in pregnant women. A large number of studies have examined the incidence of preeclampsia (PE), gestational hypertension (GH), hypertensive disorders in pregnancy (HDP), preterm birth, and small for gestational age (SGA) birth according to systolic and diastolic blood pressure levels at <20 weeks of gestation. In the present study, we conducted a meta-analysis of these articles to investigate whether blood pressure ≥130/80 mmHg is an appropriate reference value for hypertension in pregnant women at <20 weeks of gestation.

Methods

Search strategy: Pubmed/MEDLINE and Ichushi databases were used to search for articles that had evaluated maternal and perinatal outcomes according to blood pressure levels, including both articles in English and those in Japanese. The following combinations of search terms were used: “prehypertension”, “high normal hypertension”, “elevated blood pressure”, “blood pressure level”, and “130/80 mmHg” AND “preconception”, “pregnancy”, “postpartum”, “fertility/infertility”, “pregnancy rate”, “abortion”, “miscarriage”, “adverse obstetric outcome”, “pregnancy induced hypertension”, “hypertensive disorders of pregnancy”, “preeclampsia”, “gestational hypertension”, “placental abruption”, “eclampsia”, “cerebral hemorrhage”, “cerebral infarction”, “HELLP syndrome”, “kidney disease”, “cesarean section”, “preterm birth”, “small for gestational age”, “birth weight”, “non-reassuring fetal status”, “intrauterine fetal death”, “stillbirth”, “NICU”, “intraventricular hemorrhage”, and “respiratory distress syndrome”. The last update of the search was October 2020.

Study selection: Duplicate articles between Pubmed/MEDLINE and Ichushi were excluded. Two researchers independently examined titles and abstracts to extract articles that reported on maternal and perinatal outcomes according to blood pressure levels. The full text of the extracted articles was reviewed using the following selection criteria: cohort studies and double-blind controlled studies, excluding case reports, case-control studies, and systematic reviews; articles on office blood pressure levels, but not home blood pressure measurement (HBPM) or 24-hour ambulatory blood pressure monitoring (ABPM) (because reference values of HBPM and ABPM for hypertension in pregnant women have not been established); articles that examined systolic blood pressure 120, 130, and 140 mmHg and diastolic blood pressure 80 and 90 mmHg. The following articles were excluded: those with blood pressure categories that significantly deviated from the above-mentioned definition, those in which the timing of perinatal blood pressure measurements differed, those with no detailed data description, and those targeting only patients with chronic hypertension. When there was disagreement about an article between the two researchers, all members of the JSSHP study committee discussed the content. Articles judged not to be the subject of this study were excluded.

Extracted articles were divided into the following four categories according to the timing of perinatal blood pressure measurements: preconception, <20 weeks of gestation, ≥20 weeks of gestation, and postpartum. We initially planned to investigate the relationship between postpartum blood pressure and long-term maternal outcomes (e.g., onset of hypertension, cerebrovascular disease, cardiac disease, renal disease, and metabolic syndrome); however, only studies reporting long-term maternal outcomes according to blood pressure levels during pregnancy, but not postpartum blood pressure levels, were identified. Therefore, these articles were reviewed for postpartum data.

Outcomes of interest: The majority of articles included in the analysis had evaluated the incidence of PE, GH, HDP (PE and GH), preterm birth (delivery at <37 weeks of gestation), and SGA birth (birth weight below the 10^th percentile) according to blood pressure levels at <20 weeks of gestation. Since only a few articles had examined those outcomes at time-points other than >20 weeks of gestation during the perinatal period, the incidence of PE, GH, HDP, preterm birth, and SGA birth in women with systolic blood pressure <120, ≥120, ≥130, and ≥140 mmHg and diastolic blood pressure <80, ≥80, and ≥90 mmHg at <20 weeks of gestation were examined in the meta-analysis. The incidence of GH was analyzed for all blood pressure categories except for systolic and diastolic blood pressure ≥140 mmHg and ≥90 mmHg, respectively. Maternal and perinatal outcomes at preconception, ≥20 weeks of gestation, and postpartum were summarized as a narrative review (Supplemental text and Supplemental Tables 1–3).

Statistical analysis: Data from each study were pooled into the systolic and diastolic blood pressure categories of <120, ≥120, ≥130, and ≥140 mmHg and <80, ≥80, and ≥90 mmHg, respectively. The integrated odds ratio (OR) (95% confidence interval: CI) and p-value of each maternal and perinatal outcome were calculated for each blood pressure category using the random-effects model. The I² statistic (≥75%) and Cochran’s Q test (P<0.05) were used as indicators of heterogeneity and non-uniformity. If I² was ≥75% and Cochran’s Q test was P<0.05, leave-one-out analyses were performed repeatedly to identify and exclude studies that increased heterogeneity, until I² was <75% and Cochran’s Q test was P≥0.05. All analyses were performed using EZR statistical analysis software (R Commander (EZR ver.3.5.2)).

Results

Literature searches performed within PubMed/Medline and Ichushi identified 1,571 and 673 articles, respectively (Figure 1). In total, 2,152 articles were extracted after excluding duplicate articles. In the first screening, 2,080 articles unrelated to blood pressure and maternal and perinatal outcomes were excluded based on the title and abstract. Seventy-two articles were selected after excluding 2 reviews^8,9) and 1 case-control study.¹⁰⁾ In the second screening, the full text of 72 articles was reviewed, and 26 articles were selected after excluding 40 that did not describe evaluations according to blood pressure levels (e.g., systolic blood pressure 120, 130, and 140 mmHg and diastolic blood pressure 80 and 90 mmHg), 2^6,7) in which the timing of blood pressure measurements was not divided into the four categories described above, 2^11,12) in which detailed data were not provided, and 2^13,14) that only included pregnant women with chronic hypertension. Among the 26 articles, 7, 17, and 3 articles reported blood pressure at preconception, during pregnancy, and during the postpartum period, respectively. Among the articles on blood pressure during pregnancy, 14 and 7 had evaluated blood pressure at <20 weeks of gestation and ≥20 weeks of gestation, respectively. After excluding 1 article¹⁵⁾ without blood pressure categories and 1¹⁶⁾ without information on n numbers from the 14 articles on blood pressure at <20 weeks of gestation, 12 articles were selected for the meta-analysis to evaluate the incidence of PE, GH, HDP, preterm birth, and SGA birth.

Figure 1.

Flow diagram for the inclusion of articles in the meta-analysis.

The characteristics of the articles included in the meta-analysis are summarized in Table 1. All 12 articles^{17,18,19,20,21,22,23,24,25,26,27,28)} were observational studies; 4 were prospective cohort studies and 8 were retrospective cohort studies. Automatic blood pressure sphygmomanometers were used in 8 of 10 articles that discussed the use of blood pressure-measuring devices. Eleven articles examined only singleton pregnancies, while 1 article also included multiple pregnancies which accounted for 6.3% of all pregnancies examined.¹⁹⁾ No antihypertensive medication was administered for blood pressure <140/90 mmHg in all 12 articles. Outcomes of interest were evaluated in all articles, including those with blood pressure ≥140/90 mmHg in 7 of 12 articles. Regarding these 7 articles, no antihypertensive medication was administered for blood pressure ≥140/90 mmHg except in one article.¹⁷⁾ The administration of aspirin was described in 3 of 12 articles (2^18,20) with, and 1²²⁾ without aspirin administration).

Table 1. Characteristics of the literature included in the meta-analysis

Author, Year	Years of analysis	Country	Study design	Timing of BP	Sphygmo-manometer	Foetation number	Including CH (medication use)	Aspirin use	Outcomes
Reddy M, 202017)	2016–2018	Australia	Retrospective	<20 w	—	Singleton	Yes (—)	(—)	SGA, preterm delivery, PE, composite neonatal outcomes (still birth, neonatal death, NICU admission for ≥48 hours, or birthweight <3rd percentile), and adverse maternal outcomes (eclampsia, HELLP syndrome, ICU admission, or maternal death)
González-Valencia DP, 202018)	2017–2018	Colombia	Retrospective	<20 w	Aneroid	Singleton	No	Yes	maternal death, hypovolemic shock, cerebral dysfunction, cardiac dysfunction, ICU admission, PE & GH, PPH, acute kidney injury, GDM, use of blood products, hospital admission, labor induction, FGR, neonatal death, neonatal sepsis, preterm labor, low birthweight, and NICU admission
Ohkuchi A, 201919)	2009–2014	Japan	Retrospective	≤11 w	Automatic	Singleton & Multiple	Yes (—)	(—)	PE & GH, PE, GH, birth weeks, preterm delivery, birth weight, and SGA
Hauspurg A, 201920)	2010–2014	USA	Prospective	6–13 w	Aneroid	Singleton	No	Yes	PE & GH, PE, and GH based on blood pressure category and trajectory
Rosner JY, 201921)	2013–2014	USA	Retrospective	<20 w	–	Singleton	Yes (yes)	(—)	Primary outcome: GH, severe GH, PE, PE with severe features, and PE & GH (GH, severe GH, PE, PE with severe features), second outcomes: preterm premature rupture of membranes, GDM, ICU admission, chorioamnionitis, preterm birth, induction of labor, C/S, PPH, SGA, intrauterine fetal demise, NICU admission, arterial cord pH <7.2, neonatal sepsis, average gestational age at delivery, average birthweight, composite maternal outcome (GDM, pregnancy-related hypertension, preterm delivery, C/S, PPH, ICU admission, chorioamnionitis), and composite neonatal outcomes (SGA, NICU admission, IUFD, arterial cord pH 7.2, 5 min Apgar <7), intraventricular hemorrhage, sepsis, seizure)
Yang SW, 201922)	2005–2012	Korea	Retrospective	<20 w	Automatic	Singleton	No	No	PE & GH in prehypertension and uterine artery doppler velocimetry
He D, 201823)	2011	China	Retrospective	12 w	Automatic or mercury	Singleton	No	(—)	PE
Block-Abraham DM, 201624)	2007–2010	USA	Prospective	<15 w	Automatic	Singleton	Yes (—)	(—)	PE, early PE, SGA, and median birth weight percentile
Black MH, 201525)	2005–2010	USA	Prospective	<12 w	Automatic	Singleton	No	(—)	HDP, PE/eclampsia, GDM
Makino S, 201326)	2001–2003	Japan	Retrospective	14–19 w	Automatic	Singleton	Yes (—)	(—)	PE & GH and prolonged puerperal periods with hypertension and/or proteinuria
Jwa SC, 201127)	2003–2005	Japan	Prospective	<16 w	Automatic	Singleton	Yes (—)	(—)	PE & GH
Ohkuchi A, 200628)	1996–1999	Japan	Retrospective	<20 w	Automatic	Singleton	Yes (—)	(—)	PE & GH

w, weeks of gestation; CH, chronic hypertension; PE&GH, preeclampsia and gestational hypertension; BMI, body mass index; BP, blood pressure; SGA, small for gestational age; HDP, hypertensive disorders in pregnancy; PE, preeclampsia; GDM, gestational diabetes mellitus; GH, gestational hypertension; ICU, intensive care unit; C/S, cesarean section; PPH, postpartum hemorrhage; NICU, neonatal intensive care unit; IUFD, intrauterine fetal death; FGR, fetal growth restriction; HELLP, hemolysis, elevated liver enzymes, lowered platelets; (−), not described.

PE (Figure 2)

A total of 10 articles^{17,19,20,21,22,23,24,25,27,28)} had examined the incidence of PE. Among 9^{17,19,20,21,22,23,24,25,28)} articles reporting the incidence of PE in women with systolic blood pressure ≥120 mmHg and <120 mmHg, 4 articles^19,20,25,28) with high heterogeneity (I²=88%, P<0.01) were excluded after a leave-one-out analysis, and the remaining 5 articles^{17,21,22,23,24)} were reanalyzed. The OR of PE onset was 3.25 (95%CI 2.54–4.17, P<0.0001, heterogeneity: I²=64%, P=0.03) for systolic blood pressure ≥120 mmHg relative to <120 mmHg. Among 5 articles^{17,19,20,23,28)} reporting the incidence of PE in women with systolic blood pressure ≥130 mmHg and ≥120 mmHg, the OR was 1.39 (95%CI 1.25–1.55, P<0.0001, heterogeneity: I²=8%, P=0.36) for systolic blood pressure ≥130 mmHg relative to ≥120 mmHg. Among 3 articles^17,19,28) reporting the incidence of PE in women with systolic blood pressure ≥140 mmHg and ≥130 mmHg, the OR was 2.39 (95%CI 1.74–3.29, P<0.0001, heterogeneity: I²=0%, P=0.69) for systolic blood pressure ≥140 mmHg relative to ≥130 mmHg. Among 9 articles^{17,19,20,21,22,23,24,25,28)} reporting the incidence of PE in women with diastolic blood pressure ≥80 mmHg and <80 mmHg, 3 articles^17,19,28) with high heterogeneity (I²=81%, P<0.01) were excluded after a leave-one-out analysis, and the remaining 6 articles^{20,21,22,23,24,25)} were reanalyzed. The OR of PE onset was 2.66 (95%CI 2.30–3.07, P<0.0001, heterogeneity I²= 38%, P=0.15) for diastolic blood pressure ≥80 mmHg relative to <80 mmHg. Among 4 articles^17,21,24,28) reporting the incidence of PE in women with diastolic blood pressure ≥90 mmHg and ≥80 mmHg, the OR was 2.74 (95%CI 1.99–3.76, P<0.0001, heterogeneity: I²=0%, P=0.54) for diastolic blood pressure ≥90 mmHg relative to ≥80 mmHg. These results suggest that the risk of developing PE in the future increases with every 10-mmHg increase in systolic blood pressure above 120 mmHg relative to <120 mmHg, and with every 10-mmHg increase in diastolic blood pressure above 80 mmHg relative to <80 mmHg.

Figure 2.

Forest plot for preeclampsia by blood pressure level.

OR, odds ratio; CI, confidence interval.

GH (Figure 3)

Six articles^{18,19,20,21,22,28)} had evaluated the incidence of GH in women with systolic blood pressure ≥120 mmHg and <120 mmHg; 1 article²⁰⁾ with high heterogeneity (I²=88%, P<0.01) was excluded after a leave-one-out analysis, and the remaining 5 articles^{18,19,21,22,28)} were reanalyzed. The OR of GH onset was 6.14 (95%CI 3.51–10.73, P<0.0001, heterogeneity: I²=61%, P=0.04) for systolic blood pressure ≥120 mmHg relative to <120 mmHg. Among 3 articles^19,20,28) reporting the incidence of GH in women with systolic blood pressure ≥130 mmHg and ≥120 mmHg, the OR was 1.29 (95%CI 0.80–2.07, P=0.30, heterogeneity: I²=51%, P=0.13) for systolic blood pressure ≥130 mmHg relative to ≥120 mmHg. Three articles^19,20,28) had evaluated the incidence of GH in women with systolic blood pressure ≥130 mmHg and <120 mmHg; 1 article²⁰⁾ with high heterogeneity (I²=95%, P<0.01) was excluded after a leave-one-out analysis, and the remaining 2 articles^19,28) were reanalyzed. The OR of GH onset was 16.57 (95%CI 4.14–66.34, P<0.0001, heterogeneity: I²=72%, P=0.06) for systolic blood pressure ≥130 mmHg relative to <120 mmHg. Six articles^{18,19,20,21,22,28)} had evaluated the incidence of GH in women with diastolic blood pressure ≥80 mmHg and <80 mmHg; 2 articles^19,20) with high heterogeneity (I²=92%, P<0.01) were excluded after a leave-one-out analysis, and the remaining 4 articles^18,21,22,28) were reanalyzed. The OR of GH onset was 4.43 (95%CI 3.06–6.40, P<0.0001, heterogeneity: I²=7%, P=0.36) for diastolic blood pressure ≥80 mmHg relative to <80 mmHg. These results suggest that the risk of developing GH in the future may be higher when systolic blood pressure is ≥120 mmHg compared to <120 mmHg, and diastolic blood pressure is ≥80 mmHg compared to <80 mmHg.

Figure 3.

Forest plot for gestational hypertension by blood pressure level.

OR, odds ratio; CI, confidence interval.

HDP (Supplemental text and Supplemental Figure 1)

Seven articles^{18,20,21,22,25,26,27)} had evaluated the incidence of HDP (PE and GH). Similar to the results for PE, the risk of developing HDP in the future increased with every 10-mmHg increase in systolic blood pressure above 120 mmHg relative to <120 mmHg, and with every 10-mmHg increase in diastolic blood pressure above 80 mmHg relative to <80 mmHg.

Preterm birth (<37 weeks of gestation) (Figure 4)

Four articles^17,19,20,21) had evaluated the incidence of preterm birth in women with systolic blood pressure ≥120 mmHg and <120 mmHg. The OR was 1.55 (95%CI 1.17–2.05, P=0.002, heterogeneity: I²=72%, P=0.01) for systolic blood pressure ≥120 mmHg relative to <120 mmHg. Three articles^17,19,20) had evaluated the incidence of preterm birth in women with systolic blood pressure ≥130 mmHg and ≥120 mmHg. The OR was 1.16 (95%CI 0.99–1.36, P=0.01, heterogeneity: I²=0%, P=0.98) for systolic blood pressure ≥130 mmHg relative to ≥120 mmHg. Three articles^17,19,20) had evaluated the incidence of preterm birth in women with systolic blood pressure ≥130 mmHg and <120 mmHg; 1 article²⁰⁾ with high heterogeneity (I²=76%, P=0.01) was excluded after a leave-one-out analysis, and the remaining 2^17,19) were reanalyzed. The OR was 1.51 (95%CI 1.29–1.76, P<0.0001, heterogeneity: I²=0%, P=0.73) for systolic blood pressure ≥130 mmHg relative to <120 mmHg. Two articles^17,19) had evaluated the incidence of preterm birth in women with systolic blood pressure ≥140 mmHg and ≥130 mmHg. The OR was 2.05 (95%CI 1.45–2.89, P<0.0001, heterogeneity: I²=0%, P=0.52) for systolic blood pressure ≥140 mmHg relative to ≥130 mmHg. Four articles^17,19,20,21) had evaluated the incidence of preterm birth in women with diastolic blood pressure ≥80 mmHg and <80 mmHg; 1 article²⁰⁾ with high heterogeneity (I²=94%, P<0.01) was excluded after a leave-one-out analysis, and the remaining 3 articles^17,19,21) were reanalyzed. The OR was 1.49 (95%CI 1.28–1.73, P<0.0001, heterogeneity: I²=0%, P=0.94) for diastolic blood pressure ≥80 mmHg relative to <80 mmHg. Three articles^17,19,21) had evaluated the incidence of preterm birth in women with diastolic blood pressure ≥90 mmHg and ≥80 mmHg. The OR was 2.00 (95%CI 1.44–2.78, P<0.0001, heterogeneity: I²=0%, P=0.75) for diastolic blood pressure ≥90 mmHg relative to ≥80 mmHg. These results suggest that the risk of preterm birth is higher when systolic blood pressure is ≥120 mmHg compared to <120 mmHg, with significant increases above 140 mmHg. Similarly, the risk of preterm birth is higher when diastolic blood pressure is ≥80 mmHg compared to <80 mmHg, with significant increases above 90 mmHg.

Figure 4.

Forest plot for preterm delivery by blood pressure level.

OR, odds ratio; CI, confidence interval.

SGA birth (Figure 5)

Three articles^17,19,24) had evaluated the incidence of SGA birth in women with systolic blood pressure ≥120 mmHg and <120 mmHg; the OR was 0.91 (95%CI 0.75–1.10, P=0.34, heterogeneity: I²=30%, P=0.24) for systolic blood pressure ≥120 mmHg relative to <120 mmHg. Two articles^17,19) had evaluated the incidence of SGA birth in women with systolic blood pressure ≥130 mmHg and ≥120 mmHg; the OR was 1.04 (95%CI 0.85–1.28, P=0.68, heterogeneity: I²=6%, P=0.30) for systolic blood pressure ≥130 mmHg relative to ≥120 mmHg. Two articles^17,19) had evaluated the incidence of SGA birth in women with systolic blood pressure ≥140 mmHg and ≥130 mmHg; the OR was 0.90 (95%CI 0.56–1.45, P=0.67, heterogeneity: I²=0%, P=0.62) for systolic blood pressure ≥140 mmHg relative to ≥130 mmHg. Three articles^17,19,24) had evaluated the incidence of SGA birth in women with diastolic blood pressure ≥80 mmHg and <80 mmHg; the OR was 1.07 (95%CI 0.74–1.53, P=0.73, heterogeneity: I²=67%, P=0.05) for diastolic blood pressure ≥80 mmHg relative to <80 mmHg. Three articles^17,19,24) had evaluated the incidence of SGA birth in women with diastolic blood pressure ≥90 mmHg and ≥80 mmHg; the OR was 1.16 (95%CI 0.64–2.10, P=0.63, heterogeneity: I²=39%, P=0.20) for diastolic blood pressure ≥90 mmHg relative to ≥80 mmHg. These results suggest that elevated systolic or diastolic blood pressure is not associated with an increased risk of SGA birth.

Figure 5.

Forest plot for small-for-gestational-age birth by blood pressure level.

OR, odds ratio; CI, confidence interval.

Discussion

In this study, the meta-analysis of observational studies revealed that the risks of PE, GH, HDP, and preterm birth increase when blood pressure is ≥120/80 mmHg at <20 weeks of gestation. However, the evidence is still insufficient to set blood pressure ≥130/80 mmHg as the reference value for hypertension in pregnant women.

Blood pressure ≥120/80 mmHg, especially ≥130/80 mmHg, may have a negative impact on maternal and perinatal outcomes. The present study found that blood pressure ≥120/80 mmHg at <20 weeks of gestation is associated with an increased risk of PE, GH, HDP, and preterm birth. Similar results were obtained in the narrative review of the literature on the timing of perinatal blood pressure measurement with respect to time-points other than <20 weeks of gestation. At preconception, the pregnancy rate decreased and the incidence of HDP increased in women with blood pressure ≥120/80 mmHg, whereas the incidence of PE, GH, and preterm birth increased in those with systolic blood pressure ≥130 mmHg (Supplemental text and Supplemental Table 1). At ≥20 weeks of gestation, the incidence of PE and HDP increased in women with blood pressure ≥120/80 mmHg, and that of preterm birth and SGA birth slightly increased in those with blood pressure ≥130/80 mmHg (Supplemental text and Supplemental Table 2). During the postpartum period, the risk of developing hypertension in the future increased when blood pressure levels during pregnancy were ≥120/80 mmHg. Moreover, the risk of developing metabolic syndrome in the future increased when diastolic blood pressure levels during pregnancy were ≥80 mmHg (Supplemental text and Supplemental Table 3). Therefore, blood pressure ≥130/80 mmHg before and during pregnancy may be associated with worse maternal and perinatal outcomes, compared to <130/80 mmHg.

Adopting blood pressure 130/80 mmHg as a new reference for hypertension in pregnant women is associated with two issues. First, lowering the reference value may make physicians more conscious of the potential to lower the blood pressure target with antihypertensive medication, which may be set at a value that is too low. Under these conditions, adverse effects of hypotension on maternal organs (e.g., heart, brain, liver, kidneys) and fetal development (e.g., fetal placental insufficiency) may occur. Only 3 of the articles examined in the present study had evaluated maternal and perinatal outcomes in mothers who lowered their blood pressure with antihypertensive medication. Of these, two were observational studies that targeted only pregnant women with chronic hypertension; these articles^13,14) reported that the incidence of superimposed PE, rates of preterm birth, and adverse perinatal outcomes were lower when blood pressure was controlled at <120/80 mmHg, <130 mmHg, 120–139/80–89 mmHg, and 130–139 mmHg compared to ≥140/90 mmHg, in pregnant women with chronic hypertension. The remaining study was an intervention study (CHIPS study) targeting pregnant women with chronic hypertension (75%) and those with GH (25%), which reported that the incidence of severe maternal complications without deterioration of perinatal outcomes including SGA was lower in the tightly controlled group (diastolic blood pressure ≤85 mmHg) than in the less tightly controlled group (≤100 mmHg).²⁹⁾ With regard to normotensive blood pressure (<140/90 mmHg), there was no intervention study that investigated maternal and perinatal outcomes according to blood pressure levels controlled by antihypertensive medication. Therefore, available information is limited regarding the outcomes of reducing chronic hypertension or maintaining normotensive blood pressure. Moreover, there is insufficient evidence that lowering blood pressure to levels <140/90 mmHg is appropriate for pregnant women. Further observational studies on maternal and perinatal outcomes according to blood pressure levels, as well as intervention studies on pregnant women with chronic hypertension, will be needed. It will also be necessary to consider whether to conduct an intervention study in which blood pressure is lowered in pregnant women with normotensive blood pressure (<140/90 mmHg).

The second issue associated with lowering the reference value for hypertension is that the number of women diagnosed with PE may increase. Hu et al. (2019)⁷⁾ reported that, when the reference blood pressure for hypertension was lowered from 140/90 mmHg to 130/80 mmHg in China, the number of diagnosed cases with GH increased from 4.2 to 25.1%. When the number of PE and GH diagnoses increases, the use of antihypertensive medication may become more frequent, placing a greater burden on society. Therefore, without sufficient supportive evidence, blood pressure ≥130/80 mmHg is unlikely to be considered an appropriate new reference for hypertension.

In the present study, blood pressure levels of ≥120/80 and ≥130/80 mmHg were associated with the development of PE and GH. Previous reviews reported an association between blood pressure ≥130/80 mmHg and increased risks of PE and GH in pregnant women.^8,30) Normal HBPM values of <130/80 mmHg throughout gestation, and even lower at <20 weeks of gestation, were previously reported in Japanese pregnant women.^31,32) Thus, defining new blood pressure categories according to reference levels ≥120/80 mmHg and ≥130/80 mmHg may be reasonable, and possibly useful for identifying those at high risk of PE and GH. Accordingly, we propose the following classification system for the hypertension criteria of the Japanese Society of Hypertension³³⁾ in pregnant women: blood pressure <120/80 mmHg as ‘normal,’ 120–129/<80 mmHg as ‘high normal,’ and 130–139/80–89 mmHg as ‘elevated.’ There should be no change to the current reference value for hypertension (i.e., ≥140/90 mmHg). Physicians need to be aware of the possibility that maternal and perinatal outcomes may worsen at blood pressures ≥120/80 mmHg and ≥130/80 mmHg, and that levels ≥120/80 mmHg and ≥130/80 mmHg are high risk factors for the development of PE and GH. Furthermore, the measurement and close management of home blood pressure are also important for the early detection of PE and GH.

There are limitations to this study. First, we conducted a meta-analysis of prospective and retrospective cohort studies, with potential bias. Since no randomized control study was included, the quality of analysis may not have been sufficient. However, the present study is the first to review numerous observational studies on this topic, and the obtained results are significant. Second, articles without adequate descriptions of the use of antihypertensive medication and aspirin were included in the analysis. The administration of antihypertensive medication and aspirin in pregnant women with chronic hypertension was not mentioned in 6 of 7 articles and 9 of 12 articles, respectively. A decrease in blood pressure to <140/90 mmHg with antihypertensive medication was reportedly associated with poorer maternal and perinatal outcomes compared to when <140/90 mmHg was achieved without antihypertensive medication.³⁴⁾ The use of aspirin has been associated with a lower incidence of PE.³⁵⁾ These biases were not accounted for in the present study. Third, articles reporting blood pressure measurements used various devices, such as mercury and automatic sphygmomanometers. Blood pressure values vary depending on the measurement device used; for example, 50% of measurements obtained using an aneroid sphygmomanometer had a measurement error of ≥10 mmHg.³⁶⁾ In patients with PE, values measured using an automatic sphygmomanometer were lower than those obtained using a mercury sphygmomanometer.³⁷⁾ However, due to the small number of articles included in the present analysis, this bias related to blood pressure-measuring devices was not sufficiently addressed in this study.

In conclusion, the present meta-analysis revealed that blood pressure ≥120/80 mmHg, particularly ≥130/80 mmHg, at <20 weeks of gestation increased maternal and perinatal risks, such as the onset of PE, GH, HDP, and preterm birth, but not SGA birth. Physicians should recognize blood pressure levels ≥120/80 mmHg and ≥130/80 mmHg as high risk factors for adverse maternal and perinatal outcomes. We propose new blood pressure categories of <120/80 mmHg (normal), 120–129/<80 mmHg (high normal), and 130–139/80–89 mmHg (elevated) for pregnant women.

Acknowledgments

This study was funded by research expenses of the JSSHP as an academic project.

Conflict of interest

The authors declare that they have no competing interests.

Supplemental text

http://doi.org/10.14390/jsshp.HRP2021-018

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