Risks of adverse perinatal and maternal outcomes among women with hypertensive disorders of pregnancy in southwestern Uganda.

INTRODUCTION: Hypertensive disorders of pregnancy (HDP) are a leading cause of global perinatal (fetal and neonatal) and maternal morbidity and mortality. We sought to describe HDP and determine the magnitude and risk factors for adverse perinatal and maternal outcomes among women with HDP in southwestern Uganda.
METHODS: We prospectively enrolled pregnant women admitted for delivery and diagnosed with HDP at a tertiary referral hospital in southwestern Uganda from January 2019 to November 2019, excluding women with pre-existing hypertension. The participants were observed and adverse perinatal and maternal outcomes were documented. We used multivariable logistic regression models to determine independent risk factors associated with adverse perinatal and maternal outcomes.
RESULTS: A total of 103 pregnant women with a new-onset HDP were enrolled. Almost all women, 93.2% (n = 96) had either pre-eclampsia with severe features or eclampsia. The majority, 58% (n = 60) of the participants had an adverse perinatal outcome (36.9% admitted to the neonatal intensive care unit (ICU), 20.3% stillbirths, and 1.1% neonatal deaths). Fewer participants, 19.4% (n = 20) had an adverse maternal outcome HELLP syndrome (7.8%), ICU admission (3%), and postpartum hemorrhage (3%). In adjusted analyses, gestational age of < 34 weeks at delivery and birth weight <2.5kg were independent risk factors for adverse perinatal outcomes while referral from another health facility and eclampsia were independent risk factors for adverse maternal outcomes.
CONCLUSION: Among women with HDP at our institution, majority had preeclampsia with severe symptoms or eclampsia and an unacceptably high rate of adverse perinatal and maternal outcomes; over a fifth of the mothers experiencing stillbirth. This calls for improved antenatal surveillance of women with HDP and in particular improved neonatal and maternal critical care expertise at delivering facilities. Earlier detection and referral, as well as improvement in initial management at lower level health units and on arrival at the referral site is imperative.

Introduction

Hypertensive disorders of pregnancy (HDP) including gestational hypertension, preeclampsia, and eclampsia complicate 2–8% of all pregnancies globally [1]. In developing countries where the incidence of HDP is estimated to be seven times higher compared to developed countries, these disorders are a leading cause of maternal and neonatal mortality and morbidity [2]. At the Mbarara Regional Referral Hospital in Uganda, a tertiary care hospital caring for a largely rural and agrarian population, HDP is the third leading cause of maternal death after puerperal sepsis and obstetric hemorrhage [3]. Reducing and averting morbidity and mortality from HDP requires early detection, treatment with antihypertensive therapy, seizure prophylaxis and prompt delivery in severe cases [4-7].

To date, most studies examining maternal and perinatal outcomes in women with HDP from sub-Saharan Africa have been limited to retrospective and cross-sectional data [7-17]. Additionally most studies from sub-Saharan Africa are from institutions based in large urban and metropolitan areas, thus data is lacking on outcomes among women with HDP seeking care in more rural and agrarian settings [9, 12, 15, 18]. Existing data suggest an increased risk of maternal and perinatal adverse outcomes in women with HDP compared to women without HDP [15, 17, 19, 20]. Several demographic (age, education, rural domicile), medical (pre-existing hypertension, multiparity, gestational age at delivery) and management (timing of drug administration) characteristics have been identified as risk factors for adverse perinatal and maternal outcomes among women with HDP [9–11, 14, 15, 21–23]. However, it is unknown if similar rates of adverse outcomes and risk factors persist in a mostly rural population.

An improved understanding of the rate of adverse outcomes and characteristics associated with these outcomes, will provide the basis for health system improvement and the development of protocols to guide the identification of at-risk mothers and babies and implement interventions to improve their birth outcomes.

We sought to describe HDP in a prospective cohort of women delivering in rural Uganda and determine the magnitude and risk factors for adverse perinatal and maternal outcomes among women with HDP at Mbarara Regional Referral Hospital.

Material and methods

Study design and setting

We conducted a prospective cohort study of women with hypertensive disorders of pregnancy admitted for delivery at Mbarara Regional Referral Hospital (MRRH), in Southwestern Uganda from January 2019 to November 2019. MRRH is a government funded public hospital that conducts approximately 9000 deliveries per year, with a caesarean delivery rate of 40%, maternal mortality rate of 261 per 100,000 live births and perinatal mortality rate of 33 per 1000 live birth according to the 2019 hospital records.

Participants

Our study population included all pregnant women, including emancipated minors under the age of 18 years, at ≥ 20 weeks of gestation with new-onset hypertension in pregnancy diagnosed at admission. We defined hypertension as two blood pressure readings with either a systolic blood pressure ≥ 140 or diastolic ≥ 90 mmHg) measured 4 hours apart. Women reporting a history of hypertension prior to pregnancy or prior to 20 weeks of gestation diagnosed by a health care provider, or taking an antihypertensive medication prior to pregnancy were considered to have chronic hypertension and excluded from participation.

A prior study auditing vital sign assessment at MRRH found only 50% of women had blood pressure checked as part of routine clinical care on admission [24]. Thus, to capture women meeting the study eligibility criteria, all pregnant women presenting at the maternity ward of MRRH for admission, had a screening blood pressure performed by research staff on admission. Women with an elevated blood pressure at admission had a subsequent check 4 hours later. Women who were normotensive at admission and developed an elevated blood pressure at a later time point during their labor course or postpartum course were not included in the study. Women who met the inclusion criteria and consented to the study were enrolled at admission and followed up to 12 weeks postpartum. This study was part of a prospective cohort study to examine the magnitude of persistent hypertension at 12 weeks postpartum after HDP. Mothers were interviewed at admission, discharge, 6 weeks postpartum and 12 weeks postpartum by trained study staff.

Variables and data sources

We classified enrolled women a priori as those with gestational hypertension, pre-eclampsia, pre-eclampsia with severe features and eclampsia at admission. Gestational hypertension was defined as new-onset hypertension without proteinuria. Pre-eclampsia was defined as new onset hypertension with proteinuria. The study team assessed for proteinuria (defined as ≥ 2+ protein) in all enrolled women at admission using a dipstick of a mid-stream urine sample. Severe features of pre-eclampsia included any of the following: blood pressure of ≥160 mmHg systolic or ≥110 mmHg diastolic, ≥ 3+ protein by dipstick, persistent epigastric pain, persistent headache, visual changes or elevated serum creatinine [4, 25]. A blood sample was drawn at recruitment for study purposes and analysed for renal (serum creatinine and urea) function. Liver function tests and complete blood count were abstracted from the chart if performed for clinical purposes. Women with grand mal seizures unrelated with other cerebral conditions who had signs and symptoms of preeclampsia were defined as having eclampsia [26].

The primary outcome measures were adverse perinatal and maternal outcomes occurring during the participant’s hospital stay or within seven days of delivery, whichever came first and these were determined a priori. An adverse perinatal outcome was defined as a composite of one or more of the following: antepartum stillbirth (fetal death prior to the onset of labor), intrapartum stillbirth (fetal death occurring after the onset of labor and prior to delivery), admission to the neonatal intensive care unit (NICU) or neonatal death by discharge or within seven days, whichever came first. Adverse maternal outcome was defined as a composite of one or more of the following: hysterectomy, laparotomy (women delivered vaginally who later require abdominal exploration, or a post cesarean section mother who required re-operation for abdominal exploration), primary postpartum hemorrhage (estimated blood loss of > 500mls following vaginal delivery or >1000mls following cesarean delivery within 24 hours after delivery as documented in the participant’s medical forms), admission to Intensive Care Unit (ICU), stroke, HELLP (Hemolysis Elevated Liver enzymes and Low Platelets) syndrome and blood transfusion. All adverse outcomes were obtained by chart abstraction from the participant medical forms.

Other covariates of interest included socio-demographic characteristics, past medical history, obstetric history and obstetric care factors. This information was obtained using an interviewer administered questionnaire during participant enrollment and a second questionnaire administered at discharge. Socio-demographic data included maternal age, marital status, level of education and referral status (i.e. women referred in to MRRH from another health center). Medical history included HIV status (HIV positive or negative result done within 3 months), history of chronic kidney disease and history of diabetes mellitus. Pre-pregnancy body mass index (BMI) was not available, however, we measured weight and height at enrollment to the study, and calculated the BMI (weight in kilograms divided by height in meters squared) from this measurement. We then classified women as underweight (<18.5kg/m2), normal weight (18.5–24.9kg/m2), overweight (25-29kg/m2) and obese ≥30kg/m2) at data analysis. Obstetric data collected included parity, mode of delivery, gestational age at delivery (determined primarily using the last normal menstrual period (LNMP) or first trimester obstetric ultrasound scan if available and LNMP was unknown), history of hypertension in previous pregnancy and eclampsia (grand mal convulsions). Obstetric care factors included the time to delivery (calculated as admission date/time to date/time of delivery), administration of antenatal corticosteroids (for women at 28 to 33 weeks of gestation according to the MRRH protocols), magnesium sulfate and antihypertensive treatment, captured from chart abstraction of the participant medical forms. Study data were collected and managed using REDCap electronic data capture tools hosted at MUST Department of OB/GYN. REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies [27, 28].

Sample size and power

The sample size was based on the primary cohort study examining persistent hypertension. For this sub-study, sample size and power were therefore not determined a priori.

Data analysis

Maternal socio-demographic, medical and obstetric characteristics were presented in frequency tables stratified by type of hypertensive disorder. Univariate analysis for risk factors for adverse maternal and perinatal outcomes was performed using crude risk ratios. Factors with a p value of ≤ 0.2 at univariate analysis were considered for inclusion in the adjusted analysis. Multiple logistic regression models were used to determine the independent risk factors with their corresponding 95% confidence intervals [29]. A p-value less than 0.05 was considered statistically significant. Data analysis was performed with Stata version 15. (Statacorp, College Station, TX, USA).

Ethical consideration

The study procedures were approved by the Mbarara University Research Ethics Committee (07/09-18), Uganda National Council for Science and Technology (HS 2570) and Partners Healthcare Institutional Review Board (2019P001446). Participants provided written informed consent.

Results

There were 9,096 deliveries at MRRH during the study period (January-November 2019). Of these, 155 women with hypertension in pregnancy upon admission to the maternity ward were screened for eligibility. Of these, 6 were excluded due to pre-existing hypertension before pregnancy, and 38 declined consent. Thus, a total 103 women with new-onset hypertension during pregnancy were enrolled. Of these 103 women, 4.9% (n = 5) had gestational hypertension, 1.9% (n = 2) had preeclampsia with mild features, 71.8% (n = 74) had pre-eclampsia with severe features and 21.4% (n = 22) had eclampsia.

Participant characteristics are shown in Table 1. The mean age was 27 years (SD±6). Most participants were multigravida 65% (n = 67), referred from other health facilities 63.1% (n = 65) and delivered preterm at gestational age <37 weeks 61.3% (n = 57). Over a quarter of participants were obese (27.6%, n = 27). Most women, 61.8% (n = 63) were delivered by cesarean section and 42.2% (n = 43) within 24 hours of admission. The majority of babies had either a low birth weight 37.1% (n = 36) or a very low birth weight 20.6% (n = 20). Almost all the participants 96.1% (n = 99) received anti-hypertensive medication and 92.6% (n = 87) received magnesium sulfate. Less than half, 44.7% (n = 42) received a complete dose of magnesium sulfate, only 31% (n = 9) of the women at gestational age < 34 weeks received antenatal corticosteroids. Data on age 1% (n = 1), body mass index 4.8% (n = 5), gestational age at delivery 9.7% (n = 10), eclampsia 3.9% (n = 4), mode of delivery 1% (n = 1), time to delivery 1% (n = 1), and magnesium sulfate administration 8.7% (n = 9) were missing.

Table 1

Participant characteristics.

Participant Characteristics n = 103		n (%)
Age n = 102	<35	85 (83.3)
	≥35	17 (16.7)
Marital Status	Not Married	7 (6.8)
	Married	96 (93.2)
Level of Education	Primary and below	50 (48.5)
	Secondary and above	53 (51.5)
Referral from another facility	Not Referred	38 (36.9)
	Referred	65 (63.1)
Gravidity	Primgravida	36 (35)
	Multigravida	67 (65)
History of HDP in a prior pregnancy	Yes	13(12.6)
	No	90 (87.4)
Body Mass Index n = 98	Underweight	1 (1)
	Normal	30 (30.6)
	Over weight	40 (40.8)
	Obese	27 (27.6)
Gestational Age at delivery n = 93	<28	6 (6.4)
	28–33	29 (31.2)
	34–36	22 (23.7)
	≥37	36 (38.7)
HIV status	Positive	7 (6.8)
	Negative	96 (93.2)
Eclampsia n = 99	No	77 (77.8)
	Yes	22 (22.2)
Mode of Delivery n = 102	Vaginal delivery	39 (38.2)
	Cesarean section	63 (61.8)
Time to delivery n = 102	Within 24 hours	43 (42.2)
	> 24 hours	59 (57.8)
Steroid administration	Received	9 (31)
	Not Received	20 (69)
Anti-Hypertensive medicine	Received	99 (96.1)
	Not Received	4 (3.9)
Magnesium Sulfate administration n = 94	Complete dose	42 (44.7)
	Loading dose only	19 (20.2)
	Incomplete dose	26 (27.7)
	Not Received	7 (7.4)

Adverse perinatal and maternal outcomes are reported in Table 2. Overall, 58% (n = 60) participants experienced one or more adverse perinatal outcome and 19.4% (n = 20) one or more adverse maternal outcome. Adverse perinatal outcomes included admission to the NICU 36.9% (n = 38), stillbirth 20.3% (n = 21) and neonatal death before discharge 1.1% (n = 1). Of the 21 stillbirths, 76.2% (n = 16) were antepartum stillbirths and 23.8% (n = 5) were intrapartum stillbirths. Adverse maternal outcome included HELLP syndrome 7.8% (n = 8), blood transfusion 2.9% (n = 3), ICU admission 2.9% (n = 3) and postpartum hemorrhage 2.9% (n = 3).

Table 2

Frequency and distribution of adverse perinatal and maternal outcomes.

Adverse perinatal outcome	n (%)
Intrapartum stillbirth	5 (4.8)
Antepartum stillbirth	16 (15.5)
Admission to Neonatal Intensive Care Unit	38 (36.9)
Death of infant before discharge	1 (1.1)
One or more adverse perinatal outcome	60 (58)
Adverse maternal outcomes	n (%)
Hysterectomy	1 (1.0)
Laparotomy	1 (1.0)
Blood transfusion	3 (2.9)
Admission to Intensive Care Unit	3 (2.9)
Postpartum hemorrhage	3 (2.9)
Stroke	1 (1.0)
HELLP syndrome	8 (7.8)
One or more adverse maternal outcome	20 (19.4)

In an adjusted analysis controlling for history of HDP in prior pregnancy, administration of magnesium sulfate and gravidity, the independent risk factors for adverse perinatal outcomes were gestational age at delivery <34 (aRR 1.6; 95% CI, 1.2–2.3; p<0.01) and birth weight <2.5kg (aRR 1.4; 95% CI, 1.1–2.1; p = 0.02) as shown in Table 3.

Table 3

Risk factors for adverse perinatal outcomes.

Characteristic		Adverse fetal outcome n = 60	Crude Risk Ratio	p value	Adjusted Risk Ratio	p value
Age category	<35	48 (80.0)	ref
	≥35	12 (20.0)	1.3 (0.9,1.8)	0.28	-	-
Marital Status	Single	5 (8.3)	ref
	Married	55 (91.7)	0.8 (0.5,1.3)	0.46	-	-
Level of Education	Primary and below	30 (50.0)	ref
	Secondary and above	30 (50.0)	0.9 (0.7,1.3)	0.73	-	-
Referred from another health center	Not Referred	21 (35.0)	ref
	Referred	39 (65.0)	1.1 (0.8,1.5)	0.64	-	-
HIV Status	Negative	56 (93.3)	ref
	Positive	4 (6.7)	1.0 (0.5,1.9)	0.95	-	-
Gravidity	Primgravida	14 (23.3)	ref
	Multigravida	46 (76.7)	1.8(1.1,2.7)	<0.01	1.3 (0.9,1.8)	0.09
History of HDP in prior pregnancy	No	49 (81.7)	ref
	Yes	11 (18.3)	1.6 (1.2,2.1)	0.04	1.2(0.7,2.0)	0.40
Mode of Delivery	Vaginal delivery	26 (43.3)	ref
	C-section	34 (56.7)	0.8 (0.6,1.1)	0.21	-
Gestational Age at Delivery	≥34	22 (40.0)	ref
	< 34	33 (60.0)	2.5 (1.8,3.5)	<0.01	1.6(1.2,2.3)	<0.01
BMI at admission	Not Obese (<30)	40 (71.4)	ref
	Obese (≥30)	16 (28.6)	1.1 (0.7,1.5)	0.79	-	-
Eclampsia	No	43 (74.1)	ref
	Yes	15 (25.9)	1.2(0.9,1.7)	0.33	-	-
Birth weight	≥ 2.5kg	13 (23.2)	ref
	<2.5kg	43 (76.8)	2.4 (1.5,3.9)	<0.01	1.4(1.1,2.1)	0.02
Time to Delivery	Within 24 hours	22 (36.7)	ref
	> 24 hours	38 (63.3)	1.2 (0.9,1.8)	0.21	-	-
Anti- Hypertensive	Given	59	ref
	Not Given	1	0.4 (0.1,2.3)	0.17	-	-
Steroid administration	Given	9	ref
	Not Given	18	0.9 (0.8,1.0)	0.32	-	-
Magnesium Sulfate administration	Given	32	ref
	Not Given	23	0.6 (0.4,0.8)	0.01	0.8 (0.6,1.0)	0.07

Adjusted for history of HDP in prior pregnancy, administration of magnesium sulfate and gravidity.

In an adjusted analysis controlling for level of education, mode of delivery and magnesium sulfate administration, the independent risk factors for adverse maternal outcomes were referral from another facility (aRR 3.9; 95% CI, 1.1–13.8; p< 0.01) and eclampsia (aRR 3.7; 95% CI, 1.6–8.4; p = 0.01) as shown in Table 4.

Table 4

Risk factors for adverse maternal outcomes.

Characteristic		Adverse maternal outcomes	Crude Risk Ratio	p value	Adjusted Risk Ratio	p value
		Yes = 20
Age category	<35	18 (90.0)	ref
	≥35	2 (10.0)	0.6 (0.1,2.2)	0.37	-	-
Marital Status	Single	1 (5.0)	ref
	Married	19 (95.0)	1.4 (0.2,8.9)	0.72	-	-
Level of Education	Primary and below	7 (35.0)	ref
	Secondary and above	13 (65.0)	1.8 (0.8,4.0)	0.18	1.7 (0.8,3.6)	0.14
Referred from another health center	Not Referred	4 (20.0)	ref
	Referred	16 (80.0)	2.3 (0.8,6.5)	0.08	3.9 (1.1,13.8)	<0.01
HIV Status	Negative	19 (95.0)	ref
	Positive	1 (5.0)	0.7 (0.1,4.6)	0.72	-	-
Gravidity	Primgravida	8 (40.0)	ref
	Multigravida	12 (60.0)	0.8 (0.4,1.8)	0.60	-	-
History of HDP in prior Pregnancy	No	17 (85.0)	ref
	Yes	3 (15.0)	1.2 (0.4, 3.6)	0.72	-	-
Mode of Delivery	Vaginal delivery	5 (25.0)	ref
	C-section	15 (75.0)	1.8 (0.7,4.7)	0.17	1.8 (0.7,4.8)	0.26
Body Mass Index	Not Obese (<30)	14 (77.8)	ref
	Obese (≥30)	4 (22.2)	0.8 (0.3,2.1)	0.58	-
Eclampsia	No	8 (44.4)	ref
	Yes	10 (55.6	4.4 (1.9,9.7)	<0.01	3.7 (1.6,8.4)	0.01
Time to Delivery	Within 24 hours	11 (57.9)	ref
	> 24 hours	8 (42.1)	0.5 (0.2,1.2)	0.11
Anti- Hypertensive	Given	20
	Not Given	0	0	0.32
Steroid administration	Given	3
	Not Given	2	0.3 (0.1,1.4)	0.12
Magnesium Sulfate administration	Given	14
	Not Given	5	0.3 (0.1,0.7)	0.01	0.4 (0.2,1.1)	0.05

Adjusted for level of education, mode of delivery and magnesium sulfate administration.

Discussion

In this prospective cohort study of women with hypertensive disorders of pregnancy we found a high rate of severe HDP, and high rates of both perinatal and maternal adverse outcomes, with almost two-third of babies having an adverse perinatal outcome and a fifth of women experiencing an adverse maternal outcome. Preterm delivery and low birth weight were independent significant risk factors for adverse perinatal outcomes as expected. Referral from another facility and eclampsia were independent and significant risk factors for adverse maternal outcomes.

The majority of women in this cohort had either pre-eclampsia with severe disease or eclampsia; together accounting for 93.2% of the cohort. The high rates of adverse perinatal and maternal outcomes reflects this severity and are comparable to findings in other SSA settings. Reported stillbirth rates among women with HDP in SSA range from 6.8%-22.6%, NICU admissions from 24.7% - 28.8% and neonatal deaths from 3% - 14.1% [7, 9, 11–13, 15, 16, 30]. In cohorts of women with HDP in SSA, HELLP syndrome is reported in 0.8%-13% of women, PPH in 5.9%-7% and ICU admission in 5.7%-29.3% [13–15, 17, 18, 26, 31]. Our findings on the rate of NICU admission and neonatal deaths fall in the lower end of the range of those reported these studies. However, we found a rate of stillbirth that falls on the high end of the reported range and includes a high proportion (over 70%) of antepartum stillbirths. HELLP syndrome was the commonest adverse maternal outcome and may be under reported as not all patients in this cohort had lab evaluation beyond those done for study purposes. This shows the need to have laboratory services at health facilities able to do full blood count and liver function tests. This will help in early identification of these women with evidence of organ dysfunction in order to institute the appropriate management.

These findings, along with the risk factors identified including gestational age at delivery, low birth weight, eclampsia and referral from another facility have several implications. This is because these factors suggest a possible delay in early detection of HDP, prompt treatment with antihypertensive therapy, timely administration of seizure prophylaxis and prompt delivery which measures have been shown to reduce and avert morbidity and mortality. Preterm delivery in many cases is due to the need for delivery to enable definitive management for HDP. Low birth weight as an independent risk factor likely represents undiagnosed intrauterine fetal growth restriction. However, the need for early delivery, and evidence for fetal growth restriction emphasize the severity of disease in this cohort and point to the need for strengthening antenatal fetal surveillance and the monitoring of mothers with hypertensive disorders of pregnancy, as well as the need for prevention strategies such as the use of aspirin prophylaxis in appropriate candidates [32]. Secondly, once delivered it is clear that babies born to women with HDP are in need of prompt and specialized care. Our findings highlight the need for functional NICUs, trained NICU nurses and neonatologists and protocols for neonatal resuscitation to improve the outcomes of the babies delivered prematurely and with low birth weight.

Furthermore, women with eclampsia and those who were referred from another facility had a significantly increased risk for adverse maternal outcomes. Mothers with eclampsia may have neurological dysfunction, metabolic coma, stroke, uncontrollable fits and eclamptic encephalopathy [26]. The severity of disease on admission with a high rate of severe features and high rate of eclampsia emphasizes gaps in early identification and treatment. Delays in diagnosis and management due to referral from one facility to another are well described in the obstetric literature [33, 34]. Transfer from one facility to another introduces several time points where gaps in care may occur: at the facility initiating the referral, en route, and upon arrival at the receiving facility. At each stage, inadequate numbers of trained staff, equipment, medications and systems to identify at-risk women compound the potential for women to develop complications.

Although we demonstrate a high rate of anti-hypertensive use in this population, we noted less than half of the women received appropriate dosing of magnesium sulfate, and even fewer antenatal steroids for fetal lung maturity with a trend towards the most severe cases, i.e. those receiving treatments had a non-significant increase in the risk of adverse outcomes. These findings highlight a need to develop training protocols and ensure drug availability that can extend prophylactic measures to more women to prevent adverse outcomes. Given the severity noted at admission to this tertiary care center it is clear that such management needs to occur earlier in the referral chain. Thus, a focus on ensuring training protocols and system reforms occur at lower level health care will be essential to improve outcomes among women with HDP.

Our study has some limitations. The study was conducted in a single regional referral hospital in southwestern Uganda and the findings may not be generalizable to all the other regional referral hospitals in Uganda, or other levels of facilities. As a referral hospital, our cohort may be skewed towards women with more advanced or severe disease. Additionally, we were only able to obtain adverse outcomes that occurred while in the hospital, therefore we would not have captured any additional adverse outcomes that occurred after discharge and in the community or another facility. Our estimates may thus underestimate the true burden in this cohort of women. In our study HELLP syndrome was reported documentation available in the participants’ medical records. Thus liver function tests and platelet counts were only available if done for clinical purposes. As these lab tests are not routinely available, this might have led to under estimation of participants with HELLP syndrome for those who did not do the tests. Lastly, we did not enroll women who were normotensive at admission and developed hypertension during the course of their labour and in the postpartum period, so we likely underestimated the burden of hypertension at this facility.

Conclusion

Most women in this cohort had an adverse perinatal outcome, with over a fifth experiencing a stillbirth. Given stagnation in reduction of global stillbirth and neonatal mortality rates, this study identifies women with preeclampsia as target group. Similarly, given high rates of specialized neonatal care needed and risk factors of prematurity and low birth weight, strategies are needed to identify women at risk and triage delivery to facilities with neonatal expertise. There is need to have well equipped and functional NICU, NICU nurses and neonatologists. Quality improvement strategies also need to be put in place to target the referral pathways and immediate critical care and stabilization of women with hypertensive disorders of pregnancy to prevent eclampsia and improve the outcomes of these mothers.

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8 Sep 2020

PONE-D-20-20782

Risks of adverse perinatal and maternal outcomes among women with hypertensive disorders of pregnancy in southwestern Uganda

PLOS ONE

Dear Dr. Lugobe,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Please address the issues raised, specifically:

Clarify which predictors are controlled for in the adjusted risk ratios reported in Tables 3 and 4

Clarify your intention in regard to the prevalence of hypertensive disorders in your facility (Question 2, Reviewer 1). This also relates to the question raised about the proportion of women without history of pre-pregnancy hypertension that were found to be hypertensive on admission and so included in the study and the inclusion of HELLP syndrome as an outcome variable.

Consider my suggestion for the discussion to more explicitly link back to the list of issues known to reduce morbidity and mortality in referred to the introduction: early detection, treatment with anti-hypertensive therapy, seizure prophylaxis and prompt delivery in severe cases.

==============================

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Reviewer #1: Yes

Academic Editor: Yes

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Reviewer #1: Yes

Academic Editor: Yes

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Reviewer #1: Yes

Academic Editor: Yes

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Reviewer #1: Yes

Academic Editor: Yes

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5. Review Comments to the Author

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Reviewer #1: The authors present a prospective cohort study of women with hypertensive disorders of pregnancy who were managed as inpatients in a rural referral hospital in Uganda. The objective of the study was to determine the prevalence of fetal/neonatal and maternal morbidity among women with hypertensive disorders at their center and then to identity predictors for these adverse outcomes. The authors identity a high rate of severe hypertensive disorders of pregnancy in their cohort as well as high rates of both adverse fetal/neonatal, as well as adverse maternal outcomes. They argue for education efforts in the region to help providers with early recognition of hypertensive disorders of pregnancy and initiation of appropriate management in women of rural Uganda.

Questions or comments for the authors.

1. Statistical analysis. Among women with hypertensive disorders of pregnancy, the two primary outcomes of interest were an adverse composite perinatal (fetal/neonatal) outcome and an adverse composite maternal outcome. Independent predictors to be included in the multivariable logistic regression model were chosen based on a univariate level of significance of less than 0.2. The right-hand columns in Tables 3 and 4 report the adjusted risk ratios for the predictors that were included in the model. For each of these adjusted risk ratios, is the reported point estimate given while controlling for all other listed variables in the table with univariate p-values of less than 0.2? Please clarify in the text (lines 183-185 and lines 188-190) which predictors are being controlled for in each of the reported adjusted risk ratios.

2. The conclusion statement in the abstract states, “in this cohort, we found a high rate of severe HDP and an unacceptably high rate of adverse perinatal and maternal outcomes…”. How was ‘severe HDP’ of pregnancy defined? The overall prevalence of hypertensive disorders of pregnancy in your cohort seems relatively low (149/9096 = 1.6%). I agree that among women diagnosed at your facility with eclampsia or preeclampsia with severe features, these two groups made up a large proportion of all women with hypertensive disorders of pregnancy. If this is your intention with the statement in the conclusion, maybe provide a clarifying statement that states, among women with hypertensive disorders of pregnancy at our institution, a large proportion of them had eclampsia or preeclampsia with severe features.

3. HELLP syndrome was included as an outcome variable within the adverse maternal outcome composite, rather than as a diagnosis of a hypertensive disorders that made women eligible to be included in the cohort. I guess treating HELLP syndrome as an outcome seems reasonable, but I wonder if consideration should be made for not including it as an outcome but just including it as an inclusion criteria for eligibility in the cohort. I’m not sure which approach would be more valid.

Academic Editor: This is a potentially useful study that requires some minor revisions.

Prospective cohort study of pregnant women in rural Uganda to describe hypertensive disorders of pregnancy, and determine magnitude and risk factors for adverse perinatal and maternal outcomes. The abstract refers to the last of these aims and this is in the method. It would be helpful to have a clear aim in the abstract.

The introduction to the paper includes the statement that “Reducing and averting morbidity and mortality from HDP requires early detection, treatment with antihypertensive therapy, seizure prophylaxis and prompt delivery in severe cases” (lines 38-40, p 3). This statement would be a useful framework to return to in the discussion, to show how care compared with what is known to be effective. This information is there but the reader has to look for it. It would be useful for the authors to explicitly do this.

There are three classifications reported in the paper:

- degree of condition (Line 90, p 6)

- adverse perinatal outcome (line 105, p 6 to line 108, p 7)

- weight(line 127, p 7)

It is not clear whether these classifications determined a priori or post hoc. Could this information be included please? It is also unclear how many women presenting at the hospital had their blood pressure checked (that is proportion of women without history of pre-pregnancy hypertension were included.)

I question whether is appropriate to describe 42.2% as “almost half” (line 166,, p 9).

Minor typographical and and copy-editing issues

(line 86, p 6) missing word - “of” at end of line “should be magnitude of persistent hypertension”

(Line 90, p 6) – why described as “sub-classified “ surely this is just “classified”.

(line 167 p 9) should be “37.1% (n=36) or 20.6%”

Tables

(lines 168-170) there should be some indication that the authors are referring to incomplete data. Suggest that the total number that had any Magnesium Sulphate should be reported.

Table 1 p9-10 – add n value for all characteristics where reported data is <103

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Reviewer #1: No

Reviewer #2: No

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19 Sep 2020

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

Response: The manuscript has been reformatted to be in accordance with the PLOS ONE style

2. Please provide additional details regarding participant consent. In your Methods section, please ensure you have also stated whether your study included minors, whether you obtained consent from parents or guardians of any minors included in the study, or whether the research ethics committee or IRB specifically waived the need for their consent.

Response: Pregnant participants below the age of 18 years are considered emancipated minors in Uganda and with IRB approval permitted to give their own written consent to the study. Therefore written consent was obtained from all the study participants including those under 18 without the requirement of consent from parents or minors. This has been clarified in the methods on Page 5, Line 72-73.

“ Our study population included all pregnant women, including emancipated minors under the age of 18, at ≥ 20 weeks of gestation with new-onset hypertension in pregnancy diagnosed at admission.”

3. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information."

Response: The questionnaire used to collect data was developed for the purposes of this study and has now been has been shared as supporting information as shown in line 290 at the end of the manuscript.

“S1 Questionnaire”

4. Please provide a sample size and power calculation in the Methods, or discuss the reasons for not performing one before study initiation."

The data used was from a cohort study to understand the burden of persistent hypertension postpartum. The study had the power and sample size calculation performed. For this paper, we described the data from all the enrolled participants as they had been consecutively enrolled and therefore we did not perform a sample size and power calculation. This is shown line 143-145 in the methods section.

“Sample size and power

The sample size was based on the primary cohort study examing persistent hypertension. For this sub-study, sample size and power were therefore not determined a priori.”

5. Please include an explanation for and description of the missing data found in Table 1

The n for all the variables with missing data has been included in Table 1. An account of the variables with missing data has been included in the results section line 177-180.

“Data on age 1% (n=1), body mass index 4.8% (n=5), gestational age at delivery 9.7% (n=10), eclampsia 3.9% (n=4), mode of delivery 1% (n=1), time to delivery 1% (n=1), and magnesium sulfate administration 8.7% (n=9) were missing.”

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Captions for supporting information files have been included line 288-291.

“Supporting information

S1 Dataset

S1 Questionnaire”

Reviewers Comments:

1. Statistical analysis. Among women with hypertensive disorders of pregnancy, the two primary outcomes of interest were an adverse composite perinatal (fetal/neonatal) outcome and an adverse composite maternal outcome. Independent predictors to be included in the multivariable logistic regression model were chosen based on a univariate level of significance of less than 0.2. The right-hand columns in Tables 3 and 4 report the adjusted risk ratios for the predictors that were included in the model. For each of these adjusted risk ratios, is the reported point estimate given while controlling for all other listed variables in the table with univariate p-values of less than 0.2? Please clarify in the text (lines 183-185 and lines 188-190) which predictors are being controlled for in each of the reported adjusted risk ratios.

Response: The predictors that are being controlled for in each of the reported adjusted risk ratios have been included in the text in line 190-193

“In an adjusted analysis controlling for history of HDP in prior pregnancy, administration of magnesium sulfate and gravidity, the independent risk factors for adverse perinatal outcomes were gestational age at delivery <34 (aRR 1.6; 95% CI, 1.2-2.3; p<0.01) and birth weight <2.5kg (aRR 1.4; 95% CI, 1.1-2.1; p=0.02) as shown in Table 3.”

and in line 195-198

“In an adjusted analysis controlling for level of education, mode of delivery and magnesium sulfate administration, the independent risk factors for adverse maternal outcomes were referral from another facility (aRR 3.9; 95% CI, 1.1-13.8; p< 0.01) and eclampsia (aRR 3.7; 95% CI, 1.6-8.4; p=0.01) as shown in Table 4.”

2. The conclusion statement in the abstract states, “in this cohort, we found a high rate of severe HDP and an unacceptably high rate of adverse perinatal and maternal outcomes…”. How was ‘severe HDP’ of pregnancy defined? The overall prevalence of hypertensive disorders of pregnancy in your cohort seems relatively low (149/9096 = 1.6%). I agree that among women diagnosed at your facility with eclampsia or preeclampsia with severe features, these two groups made up a large proportion of all women with hypertensive disorders of pregnancy. If this is your intention with the statement in the conclusion, maybe provide a clarifying statement that states, among women with hypertensive disorders of pregnancy at our institution, a large proportion of them had eclampsia or preeclampsia with severe features.

Response: We agree with the revieviwer this could be further clarified and we have modified this statement in line 25-26 to:

“Among women with HDP at our institution, majority had preeclampsia with severe symptoms or eclampsia and an unacceptably high rate of adverse perinatal and maternal outcomes, with over a fifth of the mothers experiencing a stillbirth.”

3. HELLP syndrome was included as an outcome variable within the adverse maternal outcome composite, rather than as a diagnosis of a hypertensive disorders that made women eligible to be included in the cohort. I guess treating HELLP syndrome as an outcome seems reasonable, but I wonder if consideration should be made for not including it as an outcome but just including it as an inclusion criteria for eligibility in the cohort. I’m not sure which approach would be more valid.

Response: In our study we included pregnant women with hypertension. We considered HELLP syndrome as an adverse outcome in line with how this was reported in other similar studies.

https://www.sciencedirect.com/science/article/abs/pii/S0020729214003725

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213240

Prospective cohort study of pregnant women in rural Uganda to describe hypertensive disorders of pregnancy, and determine magnitude and risk factors for adverse perinatal and maternal outcomes. The abstract refers to the last of these aims and this is in the method. It would be helpful to have a clear aim in the abstract.

Response: We have modified the abstract to include a clear aim of the study in the introduction section of the abstract line 4-6.

“We sought to describe HDP and determine the magnitude and risk factors for adverse perinatal and maternal outcomes among women with HDP in southwestern Uganda.”

The introduction to the paper includes the statement that “Reducing and averting morbidity and mortality from HDP requires early detection, treatment with antihypertensive therapy, seizure prophylaxis and prompt delivery in severe cases” (lines 38-40, p 3). This statement would be a useful framework to return to in the discussion, to show how care compared with what is known to be effective. This information is there but the reader has to look for it. It would be useful for the authors to explicitly do this.

Response: A comparison between the factors identified in our study and the care known to be effective, has been made in line 227-230.

“These findings, along with the risk factors identified including gestational age at delivery, low birth weight, eclampsia and referral from another facility have several implications. This is because these factors suggest a possible delay in early detection of HDP, prompt treatment with antihypertensive therapy, timely administration of seizure prophylaxis and prompt delivery which measures have been shown to reduce and avert morbidity and mortality.”

There are three classifications reported in the paper:

- degree of condition (Line 90, p 6)

- adverse perinatal outcome (line 105, p 6 to line 108, p 7)

- weight(line 127, p 7)

It is not clear whether these classifications determined a priori or post hoc. Could this information be included please?

Response: The degree of the HDP was determined a priori and this has been clarified in line 92-93.

“We classified enrolled women a priori as those with gestational hypertension, pre-eclampsia, pre-eclampsia with severe features and eclampsia at admission.”

The primary outcome of adverse perinatal and maternal outcomes was determined a priori and this has been clarified in line 105-107.

“The primary outcome measures were adverse perinatal and maternal outcomes occurring during the participant’s hospital stay or within seven days of delivery, whichever came first and these were determined a priori.”

Weight and height were measured on admission for delivery and BMI classification i.e. obese, underweight and normal weight were determined post hoc during data analysis. This has been clarified on line 130-131

“We then classified women as underweight (<18.5kg/m2), normal weight (18.5-24.9kg/m2), overweight (25-29kg/m2) and obese ≥30kg/m2) at data analysis.”

It is also unclear how many women presenting at the hospital had their blood pressure checked (that is proportion of women without history of pre-pregnancy hypertension were included.)

Response: Clarification has been made in line 80-82 that all women presenting for admission had their blood pressure checked. From the exclusion criteria, women who had a history of hypertension pre-pregnancy were excluded from the study.

“Thus, to capture women meeting the study eligibility criteria, all pregnant women presenting at the maternity ward of MRRH for admission, had a screening blood pressure performed by research staff on admission.”

I question whether is appropriate to describe 42.2% as “almost half” (line 166,, p 9).

Response: The phrase “almost half” has been deleted in line 173.

Minor typographical and and copy-editing issues

(line 86, p 6) missing word - “of” at end of line “should be magnitude of persistent hypertension”

Response: The word “of” has been added in line 88.

(Line 90, p 6) – why described as “sub-classified “ surely this is just “classified”.

Response: The word has been changed from sub-classified to classified in line 92.

(line 167 p 9) should be “37.1% (n=36) or 20.6%”

Response: The statement has been re-written in line 173-174

“The majority of babies had either a low birth weight 37.1% (n=36) or a very low birth weight 20.6% (n=20).”

Tables

(lines 168-170) there should be some indication that the authors are referring to incomplete data.

Response: An account of the variables with missing data has been included in the results section line 177-180.

“Data on age 1% (n=1), body mass index 4.8% (n=5), gestational age at delivery 9.7% (n=10), eclampsia 3.9% (n=4), mode of delivery 1% (n=1), time to delivery 1% (n=1), and magnesium sulfate administration 8.7% (n=9) were missing.”

Suggest that the total number that had any Magnesium Sulphate should be reported.

Response: The total number of women 92.6% (n=87) that received magnesium sulfate has included in line 174-176.

“Almost all the participants 96.1% (n=99) received anti-hypertensive medication and 92.6% (n=87) received magnesium sulfate.”

Table 1 p9-10 – add n value for all characteristics where reported data is <103

Response: The n value has been added for all values where data was <103 on page 10 and 11.

Submitted filename: Response to Reviewers.doc

Click here for additional data file.

12 Oct 2020

Risks of adverse perinatal and maternal outcomes among women with hypertensive disorders of pregnancy in southwestern Uganda

PONE-D-20-20782R1

Dear Dr. Lugobe,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Dell Horey

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for the amendments made to this paper. I believe that it is now suitable for publication although I suggest the following minor amendments.

The addition of footnotes to Tables 3 and 4:

Table 3: Adjusted for history of HDP in prior pregnancy, administration of magnesium sulfate and gravidity

Table 4: Adjusted for level of education, mode of delivery and magnesium sulfate administration

Minor edit to the additional statement (line 25-26) in abstract, which is missing a word. It could be written “Among women with HDP at our institution, the majority had preeclampsia with severe symptoms or eclampsia and an unacceptably high rate of adverse perinatal and maternal outcomes; over a fifth of the mothers experienced stillbirth.”

Reviewers' comments:

19 Oct 2020

PONE-D-20-20782R1

Risks of adverse perinatal and maternal outcomes among women with hypertensive disorders of pregnancy in southwestern Uganda

Dear Dr. Lugobe:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Dell Elizabeth Horey

Academic Editor

PLOS ONE