Association between late pregnancy prehypertension and adverse outcomes among newborns of women delivered at a tertiary hospital in Eastern Uganda: a prospective cohort study

Abstract

Background

Prehypertension during pregnancy is currently not considered as a high-risk pregnancy state in existing guidelines despite recent research correlating it with higher rates of morbidity and mortality in both the mother and the fetus. Studies on prehypertension have not been conducted in Africa despite high rates of poor neonatal outcomes.

Aims

The study aimed to determine the association between late pregnancy prehypertension and adverse outcomes in newborns of women with late pregnancy prehypertension at Jinja Regional Referral Hospital.

Methods and materials

Between September 2022 and January 2023, a hospital-based prospective cohort study including 300 pregnant women was conducted. Participants were divided according to third-trimester blood pressure, as determined by the JNC-8 criteria. Following hospital admission for labor and delivery, 150 normotensive women and 150 prehypertensive women were identified and followed until delivery, and their neonates were followed until death or hospital discharge. A p value of ≤ 0.05 was the threshold for statistical significance when comparing the groups using the relative risk, X², and Mantel-Haenszel adjustment.

Results

Composite adverse neonatal outcomes were more common in prehypertensive women compared to normotensive women (48.67% versus 32.67%), particularly Small-for-Gestation Age (SGA), stillbirth, and composite adverse neonatal outcomes had significantly higher likelihood, with aRRs of 1.63 (95% CI 1.10–2.42, p = 0.037), 9.0 (95% CI 1.15–70.16, p = 0.010), and 1.55 (95% CI 1.16–2.08, p < 0.001), respectively. By a linear model, birthweight decreased by 45.1 g for every 10 mmHg rise in systolic blood pressure (p = 0.041, Pearson correlation of -0.118).

Conclusion and recommendations

Prehypertension in late pregnancy increased risks for adverse neonatal outcomes, thus a need to potentially lower pregnancy hypertension cut-off levels possibly through adopting the ACC/AHA blood pressure definitions for pregnant women.

Background

Hypertensive disorders of pregnancy (HDP), affecting about 5–10% of all pregnancies worldwide significantly lead to unacceptable mortality and morbidity for the mother, fetus, and the newborn [1,2,3], and despite multiple advances in obstetric care, HDP are second only to obstetric hemorrhage in causing maternal mortality, accounting for upto 16% of mothers dying due to pregnancy-related complications in Sub-Saharan Africa [4].

Prehypertension in pregnancy, referred to as elevated blood pressure (BP) 120–139/80–89 mmHg affects about 11% of all pregnancies but its prevalence varies across regions (Japan – 14.98%, United States – 23.75–61.27%, Sweden – 11.89%) and is currently not included in the HDP. Emerging evidence over the last decade has however shown that it significantly leads to adverse neonatal outcomes. The Joint National Committee 8 (JNC 8) clearly states that identifying prehypertension cases enables starting of preventive measures earlier as these cases are at higher risk for cardiovascular disease [5,6,7,8,9]. No published studies on the Ugandan burden of pregnancy prehypertension exists currently.

The exact mechanism for development of pregnancy prehypertension and its associated adverse outcomes is not clearly studied but some studies suggest a similar mechanism to pathophysiology of currently described HDP, that is, endothelial cell injury with vasospasm following a myriad of factors ranging from abnormal placentation, nutrient deficiencies, imbalance of angiogenic and antiangiogenic factors, genetic influence, and hypoxic states in the mother due to various medical and immunological conditions [10, 11] leading to maladaptation to pregnancy physiology and reduced placental function, hence adverse outcomes to both the mother, the fetus, and the newborn child [8].

Late pregnancy prehypertension is significantly linked with adverse neonatal outcomes including a 59% increase in Small-for-Gestational (SGA), a 70% rise in stillbirths, increased risks for NICU admission, low birth weight, neonatal morbidity and mortality, as well as adverse maternal outcomes like a 4.4 fold risk for developing preeclampsia/eclampsia syndrome in the current pregnancy [7, 8, 12].

The increase in these outcomes is currently not measured in the low-income countries where their burden is already unacceptably high, hence increased costs of healthcare provision and further delays in achieving the ambitious Sustainable Development Goal (SDG) 3 2030 targets in these countries. Studies have also previously shown that hypertensive disorders are more common in the black race due to a genetic influence but prehypertension studies in Sub-Saharan Africa are currently scarce [13, 14].

Despite mounting evidence of these catastrophic consequences of prehypertension and the recommendation to change BP cut-off for stage 1 hypertension by the American College of Cardiology/ American Heart Association (ACC/AHA) 2017 guidelines, no professional body of obstetrics and gynecology has adopted this adjustment, thus there are currently no existing guidelines to help maternal and child health providers mitigate the risks associated with late prehypertension in pregnancy [5].

In this study, we describe the association between late pregnancy prehypertension and adverse outcomes among newborns of women delivered a tertiary hospital in Eastern Uganda.

Methods

Study design and setting

This was a prospective cohort study on women admitted in latent labor at Jinja Regional Referral Hospital (JRRH) in Eastern Uganda from September 2022 and January 2023. JRRH is a government-funded public tertiary hospital in Eastern Uganda, located 84 km away from the capital, Kampala. The hospital has catchment districts including Jinja, Bugiri, Kamuli, Iganga, Luuka, Kaliro, Kayunga, Namayingo, Mayuge, and parts of Buikwe and conducts over 5,000 deliveries per year, with a perinatal mortality rate of 24 per 1,000 [15].

Participants

Our study population included women at gestational age 28 weeks and above admitted in latent labor at JRRH. Latent labor was defined as the presence of uterine contractions leading to cervical changes with a cervical dilatation of < 5 cm.

In the exposed group, we enrolled women with prehypertension i.e., those with blood pressure levels of 120–139/80-89mmHg, measured on two occasions. In the unexposed group, we enrolled women with normal blood pressure i.e., blood pressure of less than 120/80 mmHg, measured on two occasions. For every participant with prehypertension recruited, a normotensive participant would be recruited next as long as they met the inclusion criteria. Women reporting a history of hypertension before pregnancy diagnosed by a healthcare provider or taking antihypertensive medication before pregnancy were considered to have chronic hypertension and excluded. Women with other known chronic medical conditions as well as those with multiple gestation in the current pregnancy were also excluded. Women who met the inclusion criteria and consented to the study were enrolled in latent labor and followed until delivery with the labor in physiological mode. Their neonates were handed over to pediatricians followed by the study team every 6 h until death or hospital discharge by trained study staff.

Variables and data sources

The main exposure variable was prehypertension. Blood pressure readings were taken using an aneroid sphygmomanometer (Adult, model LSK-DE-10856) and adult-size stethoscope (Littman classic III), a digital weighing scale (180 Kg, model PS-103), with the patient seated upright and with the hand at the level of the chest.

An interviewer-administered questionnaire (specifically designed for this study and uploaded as a supplementary file) was used to collect information on the other co-variates. These included: Socio-demographic factors (marital status, maternal age, residence, education level, and Alcohol intake), obstetric and medical factors (gravidity, gestational age, Personal history of hypertension in the previous pregnancy, pregnancy interval, HIV serostatus). A digital weighing scale (180 Kg, model PS-103) was used to obtain the participant’s weight, while a height meter (200 cm, stadiometer wall mounted) was used to measure the height in centimeters. The body mass index was calculated using the standard formula of weight (kg) divided by the square of height in meters. We assessed for proteinuria (defined as ≥ 2 + protein) in all enrolled women at admission using a dipstick of a mid-stream urine sample.

The women were followed 2-hourly until delivery while their neonates were followed 6 hourly until death or hospital discharge by trained study staff.

The primary outcome was adverse perinatal outcomes occurring during the participant’s hospital stay and these were determined a priori. An adverse perinatal outcome was defined as a composite of one or more of the following: small-for-gestational age, prematurity, low APGAR score, and stillbirth. At delivery, neonatal parameters including sex of baby, mode of delivery, birthweight (recorded to the nearest 0.1 kg), neonatal viability, and APGAR score at 1 and 5 min were recorded. The neonate’s weight in grams was considered by gestational age-specific weight values by percentiles. SGA was defined as those having weight-for-gestational age < 10th percentile, with the average neonatal weight being 2862 g. The viable newborn was then followed daily until discharge to observe for early neonatal death, that is, death of the newborn from delivery up to discharge from the hospital. The total follow-up time was from labour admission up to when the neonate was discharged, referred or died. Neonates were handed over to the pediatricians for thorough examination and continued care.

Sample size and power

Assuming a 95% confidence interval and incidence of composite adverse neonatal outcomes to be 31.6% and 17.6% in mothers with prehypertension and normal blood pressures respectively [12], a sample size of 300 mothers(150 with pre-hypertension and 150 with normal blood pressure) was sufficient to detect the relative risk with a power of 80%. These data values of incidence were inserted in openepi for Cohort sample size generating this sample size proportions (OpenEpi: Sample Size for X-Sectional, Cohort, and Clinical Trials).

Data analysis

Data analysis was performed with Stata version 15. (Statacorp, College Station, TX, USA).

Maternal socio-demographic, medical, and obstetric characteristics were presented in frequency tables stratified by presence or absence of pre-hypertension. The cumulative incidence of composite adverse neonatal outcomes in both exposed and non-exposed groups was calculated using the overall sample size for each group as a denominator and expressed as proportions and percentages. Multiple adverse outcomes in one neonate were recorded as one outcome in the composite adverse outcome variable. For the specific adverse outcomes of small-for-gestational age, prematurity, low APGAR score, and stillbirth, the numerator comprised the neonates with the specific outcome, and the denominator was the number of exposed or unexposed women. For early neonatal death, the numerator comprised the neonates who died within the first seven days of delivery, while the denominator was the number of neonates delivered alive. This information was summarized in a bar graph.

To establish the association between late pregnancy prehypertension and adverse outcomes in newborns, the risk difference for the composite adverse and each specific adverse outcome, the crude relative risk (cRR) and adjusted relative risk (aRR) using cross-tabulation with measures of association and Mantel-Haenszel adjustment, respectively, with the respective 95% confidence intervals and p values, as well as the chi-square (X²) and its p value, were all used in assessing the association of adverse outcomes in women with late pregnancy prehypertension. For numerical outcomes, linear regression models with corresponding p values were used to estimate the risk of the specific outcomes. For statistically significant association, adjustment was done using Mantel-Haenszel ratios to control for confounding, with the variables assessed declared for each outcome.

Data was then coded and entered into a database created using Microsoft Excel, cleaned and edited. Dataset was then imported into STATA 14.2 (Statacorp, Lakeway Drive, USA Texas) for analysis. Data on independent variables, that is, Socio-demographic factors, Obstetric and medical factors, and urine sample results is presented as frequencies and percentages, and has been presented in a tabular format. Independent variables are also presented for each exposure category.

Results

Characteristics of study participants

Among 300 participants, most were aged 20–29, lived rurally, were married, unemployed, had secondary education, abstained from alcohol, had a normal BMI, were HIV-negative, lacked hypertension history (personal or family), were multigravidas with cesarean deliveries and female newborns. These characteristics were similar in prehypertension and normotension groups, with education being the key difference—normotensive women were mostly primary-educated, while prehypertensive women had mostly secondary education. Only 2 of 300 (0.7%) participants had urine protein 0–30 mg/dl, all from the prehypertensive group (Tables 1 and 2).

Incidence of adverse neonatal outcomes

Overall adverse outcomes: 48.7% in prehypertensive, 32.7% in normotensive (Fig. 1).

Specific incidences in prehypertension and normotensive group: small-for-gestational age (34.0% and 22%), prematurity (12.7% and 11.3%), low Apgar score (6.7% and 8.7%), 3.3% for stillbirth (6% and 7%), early neonatal death (2.8% and 1.3%). Prehypertensive group had higher rates for all adverse outcomes except low APGAR (Fig. 2).

Association between prehypertension and adverse outcomes among newborns of women with late pregnancy prehypertension

Prehypertensive women had 1.5 times more risk for composite adverse outcomes compared to normotensive women (aRR 1.55, 95% CI 1.16–2.08, p < 0.001). They also had a 63% higher risk of small-for-gestational age (aRR 1.63, 95% CI 1.10–2.42, p = 0.037) and 9 times more risk of stillbirth (cRR 9.00, 95% CI 1.15–70.16, p = 0.010). Mantel-Haenszel relative risk adjustments were made for maternal age, alcohol use, previous pregnancy hypertension history, and neonate’s sex. Birthweight decreased by 45.1 g for every 10-mmHg systolic blood pressure rise (p = 0.041, Pearson correlation − 0.118) and 37.3 g for every 10-mmHg diastolic blood pressure increase (p = 0.206) (Table 3).

Table 1 Sociodemographic characteristics of study participants

Table 2 Medical and obstetric characteristics of study participants

Fig. 1

Incidence of composite adverse neonatal outcomes

Fig. 2

Incidence of specific adverse outcomes

Table 3 Association between prehypertension and adverse outcomes among newborns of women with late pregnancy prehypertension

Discussion

Incidence of adverse neonatal outcomes

In this study, late-gestational prehypertensive women experienced a higher incidence of adverse neonatal outcomes compared to those with normal third-trimester blood pressure: 48.67% versus 32.67%. This 48.67% rate was notably higher than the 31.6% reported in a New York Langone Medical Center study, possibly due to differing study settings [16]. The World Health Organization has categorically stated that adverse neonatal outcomes are more prevalent in low-resource settings due to low-level quality of care with challenges ranging from the absence of critical staff to the absence of essential supplies for newborn care [16]. Moreover, our findings surpassed those of a Shanghai First Maternity Center study on women with stage I hypertension (SBP 130–139 mmHg or DBP 80–89 mmHg), which reported a composite incidence of 13.6%, likely influenced by variations in population in regards to both access and utilization of available healthcare services, which could be much reduced in low-resource settings and the sample size they used was much higher than that used in this study [17]. Adverse outcomes in prehypertensive cases may be linked to potential reductions in uteroplacental blood flow, a mechanism also associated with accepted hypertensive disorders of pregnancy [10].

Overall, prehypertensive women in our study exhibited an elevated risk of small-for-gestational age, stillbirth, prematurity, and early neonatal death compared to normotensive women. However, they displayed a lower risk for low APGAR scores in our study. Multiple studies support our findings, indicating a heightened occurrence of adverse outcomes in prehypertensive women, including a greater risk of SGA [7, 8, 18, 19], preterm birth [17, 20], stillbirth [7], and perinatal asphyxia [17]. Notably, while one study reported a higher incidence of asphyxia in prehypertensive women, our study suggests a reduced risk of low APGAR scores [17].

Association between prehypertension and adverse neonatal outcomes

In our study, prehypertensive women had a significant 55% increase in composite adverse outcomes (p < 0.001). Similar trends were observed in studies from China and the United States, where prehypertensive women had higher rates of composite adverse outcomes [16, 17]. This could be due to impaired uteroplacental blood flow resulting from increased peripheral vascular resistance during pregnancy [8].

Late pregnancy prehypertension increased the risk of having small-for-gestational age infants by 63% (p = 0.037). Comparable findings were reported in studies from Sweden (69% increase), New York (10% increase), and a meta-analysis (59% increase) [7, 8, 16]. This heightened risk may be linked to poorer diastolic function and placental perfusion, leading to reduced fetal weight gain [8]. Additionally, our study revealed a decline in birth weight with rising blood pressure, consistent with another research [19].

Our study indicated a 12% increased risk of preterm birth among prehypertensive women, (p = 0.722). The risk of preterm birth was however, not statistically significant when compared with normotensive women as they had relatively similar incidence. While prehypertension in our study showed similar risk with normotension during pregnancy, the occurrence of preterm birth in this study setting has been associated with demographic characteristics of the population we studied, including known risks like rural dwellings, low ANC visits, and being from Eastern Africa as cited in one study [18]. Our findings differ from similar studies showing increased risks of prematurity, including those conducted in New York (14.7% versus 10.3%), Shanghai, China (5.2%), and across maternal-fetal medicine facilities in the United States (4.2% versus 1.1%) [16, 17, 22]. Physiologically, elevated blood pressure during pregnancy may lead to endothelial dysfunction and uteroplacental vasculopathy, reducing placental perfusion and nutrient supply, ultimately increasing the risk of preterm birth or low birth weight [23].

Interestingly, our study suggested that late pregnancy prehypertension might slightly decrease the risk of a low 5-minute APGAR score compared to normotension. This contrasts with some other studies reporting increased rates of low arterial cord pH < 7.2 in prehypertensive mothers (37.0% versus 18.8%) [16]. Some studies have associated hypertensive disorders with adverse outcomes such as low APGAR scores [24] or perinatal asphyxia [17]. Physiologically, fetal lung immaturity may lead to poor extrauterine respiratory complications, however, chronic stress that is proposed in prehypertension may lead to augmented fetal lung maturity reducing the likelihood of respiratory distress-related complications. Some reviews have shown that neonates born preterm in multifetal pregnancies, oligohydramnios, and hypertensive disorders women tend to have a fairly good adaptation to extrauterine life [19], thus Prehypertension may provide a similar likelihood.

Significantly, our study found that late pregnancy prehypertension increased the risk of stillbirth by 9 times compared to being normotensive (cRR 9.0, p = 0.010). This aligns with a study from Sweden reporting a 70% increase in stillbirth risk compared to normotensive women [7]. Chronic placental deficiency resulting from under perfusion and the generation of reactive oxygen species due to hypoxia may contribute to stillbirth [20]. In Low-resource settings, stillbirth remains a major challenge due to lack of critical human resource, lack of essential supplies, and inadequate research into practical preventive approaches in these regions, further still, many participants in this study had known risks for stillbirth, including rural residence, low educational attainment, and multiparity [21,22,23]. These along with the pathophysiological placental insufficiency could explain the increased likelihood of stillbirth.

Additionally, our study indicated that late pregnancy prehypertension doubled the risk of early neonatal death compared to being normotensive (p = 0.410). While this is a relatively unexplored area in prehypertension research, studies have reported perinatal mortality rates of up to 25% among Ethiopian women with hypertensive disorders during pregnancy [24] and a neonatal mortality rate of 1.1% in a study of women with hypertension in pregnancy in Western Uganda [25]). Perinatal mortality is often linked to poor maternal follow-up and adherence to healthcare guidance [26]. Health systemic factors like access to good neonatal services and high costs of care usually compound the burden of early neonatal death, additionally, delayed help-seeking and inadequate knowledge on when to seek neonatal care services by parents also contribute to the rising burden [27, 28].

Study strengths and limitations

This study’s strengths: it raises the area which is not well studied, prospectively recorded blood pressure data during pregnancy, and comparative analysis.

On limitations, because the study was conducted at a single regional referral hospital in Eastern Uganda, the generalizability the findings may be limited. Latent labor may affect BP readings, but the study controlled for it by taking readings on both arms and repeating them, thus only random error was expected. To address confounding variables in neonatal outcomes, we employed exclusion criteria, stratification, Mantel-Haenszel adjustment, and regression models. However, unstudied variables were assumed to be randomly distributed. Further long-term studies are recommended.

Conclusion and recommendations

Adverse newborn outcomes, including SGA, prematurity, stillbirth, and neonatal death, were more common in prehypertensive women than normotensive women in our study. Lowering the blood pressure threshold in pregnancy, following ACC/AHA guidelines, might reduce adverse outcomes in prehypertensive women.

Enhanced pregnancy monitoring is essential for prehypertensive women to prevent SGA and stillbirth. Increased prenatal testing may be needed.