Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review.

A systematic chart review was performed to estimate the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes at facilities in Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza and Harare, Zimbabwe to provide comparisons with estimates from an ongoing clinical trial evaluating the safety of two biomedical HIV prevention interventions in pregnancy. A multi-site, cross-sectional chart review was conducted at Maternal Obstetric Units and hospitals where women participating in the ongoing clinical trial would be expected to deliver. All individuals delivering at the designated facilities or admitted for postpartum care within seven days of a delivery elsewhere (home, health clinic, etc.) were included in the review. Data were abstracted for pregnancy outcomes, pregnancy complications, maternal and neonatal death, and congenital anomalies. Data from 10,138 records were abstracted across all four sites (Blantyre n = 2,384; Johannesburg n = 1,888; Kampala n = 3,708; Chitungwiza and Harare n = 2,158), which included 10,426 pregnancy outcomes. The prevalence of preterm birth was 13% (range across sites: 10.4-20.7) and 4.1% of deliveries resulted in stillbirth (range: 3.1-5.5). The most commonly noted pregnancy complication was gestational hypertension, reported among 4.4% of pregnancies. Among pregnancies resulting in a live birth, 15.5% were low birthweight (range: 13.8-17.4) and 2.0% resulted in neonatal death (range:1.2-3.2). Suspected congenital anomalies were noted in 1.2% of pregnancies. This study provides systematically collected data on background rates of pregnancy outcomes, pregnancy complications and neonatal outcomes that can be used as a reference in support of ongoing HIV prevention studies. In addition, estimates from this study provide important background data for future studies of investigational products evaluated in pregnancy in these urban settings.

Introduction

Globally, reproductive-aged cisgender women continue to experience the largest number of new HIV infections [1]. Pregnancy represents a period of increased HIV susceptibility, with higher rates of HIV acquisition compared to non-pregnant women [2]. As novel HIV prevention products are developed and demonstrate reductions in HIV incidence [3-5], it is critical that these investigational products be carefully evaluated during pregnancy to ensure their safety and effectiveness for use during this complex time [6]. In support of this imperative, the Microbicide Trials Network (MTN) is conducting the MTN-042/DELIVER study—a phase IIIb, randomized, open-label safety trial of the dapivirine vaginal ring (25 mg) and oral pre-exposure prophylaxis (PrEP) (200 mg emtricitabine [FTC]/300 mg tenofovir disoproxil fumarate [TDF]) for HIV prevention in cisgender pregnant women (ClinicalTrials.gov #NCT03965923) [7]. The primary objectives of the DELIVER study are to describe maternal and neonatal safety and pregnancy outcomes among individuals randomized to receive the dapivirine vaginal ring or oral PrEP. Since all pregnant individuals enrolled will use an HIV prevention product, the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes will be compared to rates in the general population where the DELIVER study is being conducted.

While national data are generally available for key maternal and neonatal health indicators, such as maternal mortality, neonatal mortality and low birth weight, systematically collected data for other important outcomes and pregnancy-related complications, which may be impacted by investigational products, are sparse [8-10]. To address this gap, we performed a systematic chart review to estimate the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes at facilities in Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza and Harare, Zimbabwe. The primary aim of this study was to describe the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes among individuals delivering in specified catchment areas and compare those with estimates from an ongoing clinical trial evaluating the safety of the two biomedical interventions for HIV prevention in pregnancy [7]. These data will be used both to support the DELIVER study and provide important background data for future studies of investigational products evaluated in pregnancy.

Materials and methods

The following institutional review boards (IRB) or ethics committees (EC) reviewed this research: University of the Witwatersrand’s Human Research Ethics Committee (Johannesburg, South Africa site); Medical Research Council of Zimbabwe Institutional Review Board (Harare, Zimbabwe site); University of Malawi College of Medicine Research Ethics Committee and Johns Hopkins School of Public Health Institutional Review Board (Blantyre, Malawi site); Joint Clinical Research Center IRB/EC, Johns Hopkins Medicine Office of Human Subjects Research IRB, and Uganda National Council for Science and Technology (Kampala, Uganda site). Each site received approval and was granted a waiver of informed consent.

A multi-site, cross-sectional chart review was conducted at hospitals within proximity to clinical research sites in Blantyre, Malawi, Johannesburg, South Africa, Kampala, Uganda, and Chitungwiza and Harare, Zimbabwe [11]. Initially, each site identified primary and/or tertiary facilities that would serve the catchment area surrounding the research clinic in order to assure that all deliveries from their catchment area were represented. The maternity care system in each of these settings is based upon a group of primary care facilities that feed into the tertiary care facility for their health region, thus all pregnant individuals in the catchment area would be expected to deliver in one of these two locations. Pregnant individuals typically present to the primary care facility closest to their home but are transferred to the tertiary facility if they are either known to be high risk upon presentation from their antenatal care (e.g., prior cesarean delivery) or develop high risk characteristics during labor, delivery or postpartum (e.g., preeclampsia). Both low and high-risk individuals may also present directly to the tertiary facility, or in some cases, the tertiary facility also serves as the primary facility for the catchment area around the research clinic. At the time data abstraction was initiated in Zimbabwe, there was a localized industrial action (protests) by health care workers which affected operations at the referral hospital. As a result, at study initiation the number of deliveries was lower than expected as patients in the catchment area chose to deliver at alternative clinics. Data abstraction was temporarily paused in Zimbabwe and additional facilities were added to reach a sufficient number of deliveries. Details on the timing of data abstraction and facilities are provided in Table 1.

Table 1

Data abstraction locations and dates by site.

City, Country	Abstraction location	Primary or tertiary facility	Dates	Number of records
Johannesburg, South Africa	Charlotte Maxeke Johannesburg Academic Hospital1	Tertiary	01-Oct-2019–07 Oct-2019;	1455
			15-Oct-2019–02-Dec-2019
	Shandukani Maternal and Obstetrics Unit	Primary	05-Nov-2019–30-Dec-2019	433
Blantyre, Malawi	Queen Elizabeth Central Hospital	Tertiary	16-Aug-2019–10-Oct-2019	2016
	Ndirande Health Centre	Primary	16-Aug-2019–10-Oct-2019	368
Kampala, Uganda	Kawempe General Hospital	Primary and Tertiary4	18-Sep-2019–12-Nov-2019	3708
Chitungwiza and Harare, Zimbabwe	Zengeza Municipal Clinic1	Primary	29-Sep-2019–03-Oct-2019;	177
			12-Oct-2019–29-Nov-2019
	Mbuya Nehanda Maternity Hospital, Parirenyatwa Hospital Group1,2	Tertiary	28-Sep-2019–04-Oct-2019;	578
			12-Oct-2019–28-Oct-2019;
			07-Dec-2019–06-Jan-2020
	Chitungwiza Central Hospital3	Tertiary	10-Feb-2020–18-Mar-2020	819
	Edith Opperman Maternity Clinic3	Primary	10-Feb-2020–18-Mar-2020	584

1Some clinics underwent a one-week pause after completing the first week of data collection to allow for the study team to review data ensure the data were recorded as expected.

2During the time of the abstraction, industrial action (protests) occurred at Mbuya Nehanda Maternity Hospital, Parirenyatwa Group of Hospitals.

3Additional facilities added to close gap in reduced number of charts due to protests.

4 This facility serves as both a primary facility for uncomplicated deliveries and also a provides care for individuals referred from other settings (tertiary facility).

At each facility, medical records were identified through birth registries, maternal case records, delivery records, or admission logs over an eight-week period. All individuals delivering at the designated facility or admitted to the facility for postpartum care within seven days of a delivery elsewhere (home, health clinic, etc.) were included in the review. Patient charts identified for abstraction were assigned a unique record number. Study staff all had prior training in healthcare (medicine, nursing, or other medical background) and received study specific training on chart review and data abstraction for this project. Records were abstracted by study staff within seven days of the date of the pregnancy outcome using a standardized electronic data abstraction form. Study staff had no interaction with individuals who gave birth or their health care providers. Data were abstracted for pregnancy outcomes (full term birth, preterm birth, stillbirth or fetal demise), pregnancy complications (hypertensive disorders, post-partum hemorrhage, fever of unclear etiology, chorioamnionitis, and endometritis) and infant outcomes (low birth weight and suspected congenital anomalies) based on the presence of the diagnosis term in the chart or presumed presence of the condition based on additional data present in the chart. Estimated gestational age at delivery was assessed using a combination of data from the medical chart (as available), including date of last menstrual period, estimated date of delivery based on ultrasound and fundal height. Maternal and neonatal deaths were also assessed. Definitions for pregnancy related complications are provided in Table 2 and the data abstraction form is provided in S1 File.

Table 2

Definitions of pregnancy-related complications.

Term	Study Definition
Hypertension
Gestational	Pregnancy >20 weeks and new diagnosis of hypertension (>140 mmHg systolic and/or > 90 mmHg) without severe features of pre-eclampsia or proteinuria
Pre-eclampsia without severe features	Pregnancy >20 weeks and new diagnosis of hypertension (≥140 mmHg systolic and/or ≥ 90mmHg) and proteinuria but no severe features, which include: Severely elevated blood pressures, with systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg, which is confirmed after only minutes (to facilitate timely antihypertensive treatment) Development of a severe headache (which can be diffuse, frontal, temporal or occipital) that generally does not improve with over the counter pain medications (such as acetaminophen/paracetamol) Development of visual changes (including photopsia, scotomata, cortical blindness) Eclampsia, or new-onset grand mal seizures in a patient with preeclampsia, without other provoking factors (such as evidence of cerebral malaria or preexisting seizure disorder). Seizures are often preceded by headaches, visual changes or altered mental status New onset thrombocytopenia, with platelet count <100,000/μL New onset of nausea, vomiting, epigastric pain Transaminitis (AST and ALT elevated to twice the upper limit of normal) Liver capsular hemorrhage or liver rupture Worsening renal function, as evidenced by serum creatinine level greater than 1.1 mg/dL or a doubling of the serum creatinine (absent other renal disease) Oliguria (urine output <500 mL/24 h) Pulmonary edema (confirmed on clinical exam or imaging)
Pre-eclampsia with severe features	Pregnancy >20 weeks and new diagnosis of hypertension (≥140 mmHg systolic and/or ≥ 90mmHg) and proteinuria with severe features (see list above)
Eclampsia	Based on diagnosis term in chart
Other complications
Postpartum Hemorrhage	Based on diagnosis term in chart
Fever of Unclear Etiology	Based on diagnosis term in chart or report of mother with a temperature >38.5 degrees Celsius
Chorioamnionitis	Based on diagnosis term in chart or report of mother with a temperature >38 degrees Celsius and treated with antibiotics during labor
Postpartum Endometritis	Based on diagnosis term in chart or report of mother with a temperature >38 degrees Celsius after delivery and treated with antibiotics

Data were entered using web-based REDCap (Nashville, TN, USA) or REDCap mobile, which allows for direct data entry on mobile devices (smart phones, tablets) [12]. If technology issues emerged, data abstraction was shifted to paper case report forms and entered into the database once the technology issues were resolved. Routine data and logic checks were built into the database to ensure data quality. As an additional quality control check, each day approximately 10% of records at each facility were randomly selected for a second review. Abstraction results were compared, any discrepancies were discussed and after the reviewers reached agreement, the data were updated as needed. Descriptive statistics were utilized to summarize the frequency of the pregnancy outcomes, pregnancy complications and neonatal outcomes overall and by site. A high proportion of records reviewed indicated that the patient had been transferred to the current facility for care; therefore, a post-hoc exploratory analysis was performed using descriptive statistics to summarize select outcomes by transfer status. Data from prior studies suggest differences in the pregnancy outcomes by maternal HIV status [13,14]; therefore, a sensitivity analysis was performed assessing outcomes stratified by maternal HIV status and outcome frequencies were compared using Chi-squared tests at alpha = 0.05. All analyses were conducted using R, version 3.5.3 (R Core Team, Vienna, Austria).

Results and discussion

Data from 10,138 records were abstracted across all four clinical research sites (Blantyre, Malawi = 2,384; Johannesburg, South Africa = 1,888; Kampala, Uganda = 3,708; Chitungwiza and Harare, Zimbabwe = 2,158), which included 10,426 pregnancy outcomes. A detailed summary of maternal characteristics for the entire cohort and by site are presented in Table 3. Overall, mean maternal age was 26.4 years, mean gravidity was 2.5, 43.1% were transferred to the current facility for care and 13.6% were living with HIV. Attendance at four or more antenatal visits varied from 33.9% in Chitungwiza and Harare to 70.2% in Johannesburg. The vast majority of pregnancies (97.2%) were singleton, had deliveries that occurred at the health facility where data abstraction was performed (93.8%) and resulted in vaginal deliveries (73.1%) (Table 4).

Table 3

Maternal characteristics at data abstraction overall and by site.

	Malawi	Uganda	South Africa	Zimbabwe	Overall
	N = 2384	N = 3708	N = 1888	N = 2158	N = 10138
Maternal age	25.7±6.7 (14–48)	25.5±5.6 (13–46)	28.6±6.1 (12–48)	26.7±6.4 (14–45)	26.4±6.3 (12–48)
Gravidity	2.5±1.6 (1–10)	2.6±1.7 (0–11)	2.6±1.3 (1–12)	2.4±1.3 (1–8)	2.5±1.5 (0–12)
Parity	1.4±1.5 (0–9)	1.4±1.6 (0–9)	1.3±1.1 (0–6)	1.3±1.3 (0–7)	1.4±1.4 (0–9)
Attended 4+ antenatal care visits	1070 (46.7%)	578 (38.9%)	1259 (70.2%)	633 (33.9%)	3540 (47.6%)
HIV status
Negative	2008 (84.2%)	3185 (85.9%)	1409 (74.6%)	1765 (81.8%)	8367 (82.5%)
Positive	311 (13.0%)	391 (10.5%)	463 (24.5%)	216 (10.0%)	1381 (13.6%)
Documented as unknown	22 (0.9%)	12 (0.3%)	2 (0.1%)	100 (4.6%)	136 (1.3%)
Not documented	43 (1.8%)	120 (3.2%)	14 (0.7%)	77 (3.6%)	254 (2.5%)
Transferred for delivery from a different facility	1681 (70.5%)	1164 (31.4%)	741 (39.9%)	756 (35.5%)	4342 (43.1%)
Transferred to a different facility after delivery	2 (0.1%)	8 (0.2%)	13 (0.7%)	32 (1.5%)	55 (0.5%)
Number of infants from this delivery
1	2327 (97.6%)	3584 (96.7%)	1843 (97.6%)	2103 (97.5%)	9857 (97.2%)
2	56 (2.3%)	121 (3.3%)	42 (2.2%)	55 (2.5%)	274 (2.7%)
3	1 (0.0%)	3 (0.1%)	3 (0.2%)	0 (0.0%)	7 (0.1%)

Statistics are N (%) for categorical variables and mean±SD (range) for continuous variables.

Table 4

Pregnancy outcomes and characteristics at delivery.

	Malawi	Uganda	South Africa	Zimbabwe	Overall
	N = 2442	N = 3835	N = 1936	N = 2213	N = 10426
Place of delivery
Current health facility	2282 (93.4)	3607 (94.1)	1858 (96.0)	2032 (91.8)	9779 (93.8)
At a different health facility	131 (5.4)	180 (4.7)	26 (1.3)	71 (3.2)	408 (3.9)
At a home (private residence)	28 (1.1)	33 (0.9)	48 (2.5)	109 (4.9)	218 (2.1)
Not documented	1 (0.0)	15 (0.4)	4 (0.2)	1 (0.0)	21 (0.2)
Mode of delivery
Vaginal delivery	1819 (74.5)	2726 (71.1)	1258 (65.0)	1819 (82.2)	7622 (73.1)
Cesarean delivery	592 (24.2)	1082 (28.2)	674 (34.8)	362 (16.4)	2710 (26.0)
Other	28 (1.1)	9 (0.2)	0 (0.0)	32 (1.4)	69 (0.7)
Not documented	3 (0.1)	18 (0.5)	4 (0.2)	0 (0.0)	25 (0.2)
Pregnancy outcome
Full term live birth	2094 (85.7)	3192 (83.2)	1387 (71.6)	1775 (80.2)	8448 (81.0)
Premature live birth (<37 weeks)	261 (10.7)	400 (10.4)	400 (20.7)	258(11.7)	1319 (12.7)
Still born/intrauterine fetal demise (≥20 weeks)	75 (3.1)	152 (4.0)	64 (3.3)	122 (5.5)	413 (4.0)
Outcome not documented	12 (0.5)	91 (2.4)	85 (4.4)	58 (2.6)	246 (2.4)
Birthweight (grams)2	2934±533 (600–5000)	3027±633 (500–5400)	2946±659 (500–5570)	2977±592 (400–4960)	2979±608 (400–5570)
Low birthweight (<2500 g)2	353 (15.1)	574 (15.9)	324 (17.4)	288 (13.8)	1539 (15.5)
Neonatal death3	61 (2.6)	42 (1.2)	24 (1.3)	65 (3.2)	192 (2.0)

1Statistics are N (%) for categorical variables and mean ± SD (range) for continuous variables.

2Birthweight reported for livebirths only.

3Livebirths only. Missing data for N = 118 (1.2%) included in the denominator.

Data on pregnancy outcomes were available for 10,180 (97.6%) pregnancies (Table 4). Among records with complete data on pregnancy outcomes, 413 (4.1%) resulted in a stillbirth or fetal demise (range: 3.1–5.5) and 1,319 (13.0%) resulted in preterm deliveries (range: 10.7–21.6) (Fig 1). Among pregnancies resulting in a livebirth, 1,539 (15.5%) were low birthweight (range: 13.8–17.4) and 2.0% resulted in neonatal deaths (range: 1.2–3.2). Suspected congenital anomalies were noted in 125 (1.2%) charts (Table 5), with the most common being polydactyly (n = 47), followed by musculoskeletal anomalies (n = 24). Patterns of reported anomalies appeared similar across sites.

Fig 1

Frequency of pregnancy outcomes by site.

Data on pregnancy outcomes, overall and by site, for n = 10,180 pregnancy outcomes. Records where the pregnancy outcome could not be ascertained were excluded.

Table 5

Frequency of select suspected infant congenital anomalies identified at delivery.

	Malawi		Uganda		South Africa		Zimbabwe		Overall
	N = 2442		N = 3835		N = 1936		N = 2213		N = 10426
	n	(%)	n	(%)	n	(%)	n	(%)	n	(%)
Any congenital anomaly identified at delivery2	33	(1.4)	19	(0.5)	41	(2.1)	32	(1.4)	125	(1.2)
Polydactyly	16	(0.7)	3	(0.1)	11	(0.6)	17	(0.8)	47	(0.5)
Musculoskeletal including clubfoot	7	(0.3)	2	(0.1)	10	(0.5)	5	(0.2)	24	(0.2)
Cleft Lip and/or Palate	2	(0.1)	5	(0.1)	3	(0.2)	1	(0.0)	11	(0.1)
Neural tube defects and/or Hydrocephalus	3	(0.1)	5	(0.1)	2	(0.1)	0	(0.0)	10	(0.1)
Umbilical Hernia	3	(0.1)	1	(0.0)	4	(0.2)	2	(0.1)	10	(0.1)
Esophageal, gastrointestinal, or anorectal	2	(0.1)	1	(0.0)	1	(0.1)	2	(0.1)	6	(0.1)
Genitourinary	1	(0.0)	1	(0.0)	2	(0.1)	1	(0.0)	5	(0.0)
Trisomies	0	(0.0)	1	(0.0)	1	(0.1)	1	(0.0)	3	(0.0)

1Missing data for N = 120 (1.2%) included in the total.

2Suspective congenital anomalies occurring in >1 deliveries are included in the table by name. All suspected anomalies are included in the “Any congenital anomaly” category.

Maternal outcomes and complications are presented in Table 6. Maternal death was rare and only reported by the Blantyre site (7 deaths (0.29%)). The most common complication was gestational hypertension, which was reported among 4.4% of pregnancies and varied by site with the lowest prevalence in Kampala, Uganda (0.9%) and the highest prevalence in Chitungwiza and Harare, Zimbabwe (9.3%) (Fig 2). Pre-eclampsia without and with severe features was noted among 2.2% and 2.1% of pregnancies, respectively, while eclampsia was recorded in 63 (0.6%) records. Postpartum hemorrhage was the next most common complication and was reported in 3.2% of pregnancies (range: 2.5–5.0). All other complications, including fever of unclear etiology, chorioamnionitis and postpartum endometritis, occurred in less than 1% of records reviewed.

Table 6

Frequency of maternal deaths and pregnancy complications.

	Malawi		Uganda		South Africa		Zimbabwe		Overall
	N = 2384		N = 3708		N = 1888		N = 2158		N = 10138
	n	(%)	n	(%)	n	(%)	n	(%)	n	(%)
Maternal death	7	(0.29)	0	(0)	0	(0)	0	(0)	0	(0)
Hypertension1
Any hypertension	320	(13.4)	234	(6.3)	250	(13.2)	275	(12.7)	1079	(10.6)
Chronic	16	(0.7)	2	(0.1)	51	(2.7)	10	(0.5)	79	(0.8)
Gestational	128	(5.4)	33	(0.9)	88	(4.7)	200	(9.3)	449	(4.4)
Pre-eclampsia WITHOUT severe features	60	(2.5)	89	(2.4)	47	(2.5)	24	(1.1)	220	(2.2)
Pre-eclampsia WITH severe features	57	(2.4)	94	(2.5)	50	(2.6)	16	(0.7)	217	(2.1)
Eclampsia	18	(0.8)	13	(0.4)	8	(0.4)	24	(1.1)	63	(0.6)
Not specified	41	(1.7)	3	(0.1)	6	(0.3)	2	(0.1)	52	(0.5)
Other complications1
Postpartum Hemorrhage	120	(5.0)	105	(2.8)	49	(2.6)	54	(2.5)	328	(3.2)
Fever of Unclear Etiology	4	(0.2)	3	(0.1)	2	(0.1)	4	(0.2)	13	(0.1)
Chorioamnionitis	2	(0.1)	13	(0.4)	6	(0.3)	2	(0.1)	23	(0.2)
Postpartum Endometritis	27	(1.1)	3	(0.1)	3	(0.2)	7	(0.3)	40	(0.4)

1Missing data was <1% for hypertension outcomes and other complications. Records with missing data were included in the denominator.

Fig 2

Frequency of pregnancy complications by country.

Data presented, overall and by site, for n = 10,138 records reviewed. Data on pregnancy-related compilations were missing from <1% of records.

Given the high proportion of records indicating a transfer from another facility for delivery (42.1%), we conducted a post-hoc exploratory analysis to summarize the frequency of select outcomes by transfer status. Frequencies were qualitatively similar when comparing those who were transferred from another facility for delivery and those who were not, with a slightly higher proportion of records reporting cesarean delivery (32.4% versus 21.0%) or preterm birth (14.6% versus 10.9%) among those transferred to a different facility for delivery versus those that not been transferred, respectively (Table 7).

Table 7

Select characteristics by transfer status from a different facility for delivery.

	Not transferred from a different facility		Transferred from a different facility to current facility for delivery
	N = 5875		N = 4485
Place of delivery
Current health facility	5418	(92.2)	4300	(95.9)
At a different health facility	260	(4.4)	146	(3.3)
At a home (private residence)	183	(3.1)	34	(0.8)
Not documented	14	(0.2)	5	(0.1)
Mode of delivery
Vaginal delivery	4599	(78.3)	2985	(66.6)
Cesarean delivery	1233	(21.0)	1453	(32.4)
Other	24	(0.4)	44	(1.0)
Not documented	19	(0.3)	3	(0.1)
Pregnancy outcomes
Full term live birth	4874	(83.0)	3545	(79.0)
Premature live birth	643	(10.9)	657	(14.6)
Still born/intrauterine fetal demise (> = 20 weeks)	170	(2.9)	230	(5.1)
Outcome not documented	188	(3.2)	53	(1.2)
Deaths
Neonatal death	77	(1.4)	112	(2.7)
Maternal death	3	(0.05)	4	(0.09)

Statistics are N (%) for categorical variables.

Among pregnancies where maternal HIV status was documented (n = 10,017; 96.1%), the frequency of preterm birth and stillbirth were lower among individuals who were HIV-negative compared to those living with HIV (Fig 3; p<0.001 and 0.2, respectively). With regard to pregnancy complications, hypertension-related complications and chorioamnionitis were more frequently documented among individuals who were HIV-negative (p<0.001 and p = 0.03, respectively), while other complications did not differ by HIV status (Fig 3).

Fig 3

Pregnancy outcomes and complications by maternal HIV status.

Data presented by maternal HIV status for n = 10,017 individuals where HIV status was documented in the chart.

In this cross-sectional chart review of pregnancy outcomes, neonatal outcomes and pregnancy complications recorded at facilities in four urban centers in eastern and southern Africa, we noted similar frequencies for most outcomes across the different geographic areas. Levels of missing data were extremely low for all study outcomes assessed, providing critical information on pregnancy and neonatal outcomes as well as pregnancy complications for which data from low and middle-income countries (LMICs) are sparse [8]. Estimates from this study provide important background data for ongoing studies assessing the safety of novel HIV prevention products as well as future studies of investigational products evaluated in pregnancy in these urban settings.

We observed that site estimates of certain outcomes differed somewhat from national data sources. While national data estimate preterm birth rates of 10.5% for Malawi, 12.4% for South Africa, 6.6% for Uganda and 12.0% for Zimbabwe [15], the prevalence of preterm birth reported in this chart abstraction was slightly higher for Johannesburg, South Africa and Kampala, Uganda. The prevalence of stillbirth estimated using national data was slighter lower than estimates reported in the chart review (national stillbirth estimates for Malawi = 2.2%, South Africa = 1.7%, Uganda = 2.1% and Zimbabwe = 2.1%) [16]. These differences could be a result of underlying differences in the catchment area, differences due to the type of facilities included in the chart review, differences in outcome definition or a combination of these factors. Variation between national estimates and those reported in this analysis highlight the need for local estimates of pregnancy outcomes in order to ensure appropriate comparisons between the frequency of outcomes observed in interventional studies.

While data on pregnancy outcomes and maternal and neonatal mortality are routinely reported as priority health indicators, data for pregnancy complications, which may be more difficult to accurately ascertain, are lacking. A recent systematic review conducted by our group assessed studies conducted in Malawi, South Africa, Uganda and Zimbabwe over the past 20 years that estimated the frequency of pregnancy complications. Few published studies were identified that estimated the prevalence of gestational hypertension (n = 14), pre-eclampsia/eclampsia (n = 9), postpartum endometritis (n = 5) and chorioamnionitis (n = 3) and most studies included a small number of participants or populations that may not be generalizable to the general population of pregnant women (Lokken et al. under review at PLOS ONE) [8].

Given reports of higher rates of preterm birth among women living with HIV relative to national preterm birth rates [14,17], we performed a sensitivity analysis comparing the prevalence of study outcomes by maternal HIV status. Consistent with prior studies, we observed a higher frequency of preterm birth among women living HIV compared to those that were not living with HIV. Data were not collected on antiretroviral therapy (ART) use in pregnancy for this review; therefore, we are not able to determine if the frequency of preterm birth differed by ART regimen or compared to HIV-uninfected women. In contrast, we observed lower frequencies of pregnancy-related hypertensive disorders among pregnant women living with HIV compared to HIV-uninfected women and no substantive differences for all other complications. Data are limited on the frequency of pregnancy complication by HIV status [8]. A recent systematic review of studies assessing the impact of ART and the risk of hypertensive disorders in pregnancy reported mixed results with substantive differences in study design and population that likely contributed to variation in the results [18]. High quality, rigorously collected data on pregnancy complications in in low and middle-income countries (LMICs) are urgently needed to better inform care for all women.

In addition to the paucity of published data on pregnancy complications in LMICs, challenges in underreporting of pregnancy complications and variation in outcome definitions may limit comparability across studies even when complications are assessed [19,20]. To improve the quality and comparability of safety data collected as part of maternal immunization studies conducted in LMICs, the Global Alignment of Immunization Safety Assessment in pregnancy project (GAIA) was established in 2015 to develop standardized definitions for pregnancy outcomes, pregnancy complications and neonatal outcomes that can be applied across a range of health care settings [19,21]. In an effort to facilitate comparability, this review utilized GAIA project definitions when possible; however, due to limitations in the data routinely collected in medical charts we were not able to apply those definitions for all pregnancy complications.

This analysis includes several strengths. Rigorous methods for data abstraction were implemented, including the use of standardized outcome definitions and daily quality control checks to ensure consistency and agreement across abstractors. The level of missing data was low, with less than 2.5% missing data for key outcomes. In addition, data abstractors were able to complete reviews and abstraction for all deliveries that occurred at the facilities during the periods of chart abstraction. Such high levels of completeness and comprehensive data abstraction minimizes bias that could be introduced by incomplete abstraction. However, this analysis should be interpreted in the context of several limitations. Most notably, this review relied on the presence of the diagnosis term in the chart or sufficient clinical information documented in the chart in support of the diagnosis. While we observed high levels of completeness, it is still possible that this review underestimated the frequency of pregnancy complications due to insufficient or variable levels of documentation in the medical chart [22,23]. Suspected congenital anomalies reported in this review only included those that would be identified upon visual examination at the time of birth; anomalies identified later in development or requiring additional diagnostic assessment were not included due to the nature of the study design. Additional data on the reason for transfer to another facility were not available; therefore, the present summaries should be interpreted with caution. Lastly, while our sample size was quite large, it may have been insufficient to capture rare outcomes, such as maternal death, in all settings.

Conclusions

There is an urgent need and ethical imperative to include pregnant individuals in clinical trials in order to generate safety data in support of biomedical interventions for use during pregnancy, including those for HIV prevention [6]. The data presented in this chart review provide critical information for use by researchers, public health professionals, community members and national regulatory bodies to inform comparisons of outcomes from safety studies of investigational products with those in observed in the general population of pregnant cisgender women in Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza and Harare, Zimbabwe.

MTN-042B data abstraction form.

(PDF)

Click here for additional data file.

17 Nov 2020

PONE-D-20-32360

Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review

PLOS ONE

Dear Dr. Balkus,

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. Please submit your revised manuscript by Jan 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

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1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a multi-site, cross-sectional chart review to estimate the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes at four urban centers across four African countries (Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza and Harare). These data could provide important background information of pregnancy outcomes in Southeastern African countries, which may have public health value.

In the METHODS, “Initially, each site selected one or two facilities for data abstraction, representing a balance of primary and tertiary care facilities to ensure that the data abstracted would be representative of outcomes experienced by the general population in the catchment area.”

Q. All selected facilities in this study seemed to be tertiary hospitals and located in urban area rather than primary care hospitals in the rural areas.

To make up for this potential shortcoming, I would suggest using the “Transferred for delivery from a different facility (43.1%)" as a proxy, because they are most likely to be transferred from rural hospitals and could represent women in rural areas to some extent. I hope that the authors can further compare the difference between the two groups of "transferred" and "non-transferred" women. The results of the analysis may increase the richness of this paper.

Do all HIV (+) women take ARV prescriptions? Although there is no ARV regimen information for every woman, in principle, the same country will use the same regimen. Please sort out the ARV regimen of all countries for reference. And try to analyze the correlation between these regimens and complication rates.

Reviewer #2: The purpose of this systematic chart review is to make available pregnancy outcome data from multiple African sites to help in assessment of adverse events when new devices and drugs are evaluated during pregnancy and immediate postpartum. Overall, this is a simple analysis. Few comments below:

1. The investigators mention that that they did a review of the literature as part of the study. Would be a good complementary material to summarize those findings in a table showing frequency of the adverse outcome in African countries - preferably stratified by HIV infection status and antiretroviral use - showing time of study conduct and African region.

2. The investigators in more than one place mention that they are collecting this data to compare with outcomes from an on-going clinical trial ..... this appears misleading since no description of that study or conduct of that study is part of the writeup. Would be fine to state as part of the overall intent only.

3. The aims that appear at the beginning of Methods section should be moved to end of Introduction section.

4. In Methods provide definition of pregnancy outcomes used. Were these based on newborn weight and gestational age measurement checks ---- or based on a recorded diagnosis only (in this case it is a major limitation). If gestational age and birth weight measurements were abstracted (available) some validity checks - even on a sample - would be helpful.

5. Missing data seem extremely low: Is this a bias with the abstraction process -- i.e., forms with extensive missing data are not included altogether because there is nothing there to abstract? How many at each site met this potential abstraction problem?

6. Tables and other analyses are fine.

**********

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Reviewer #1: Yes: Solomon Chih-Cheng Chen

Reviewer #2: No

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17 Dec 2020

Reviewer #1:

This is a multi-site, cross-sectional chart review to estimate the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes at four urban centers across four African countries (Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza and Harare). These data could provide important background information of pregnancy outcomes in Southeastern African countries, which may have public health value.

1. In the METHODS, “Initially, each site selected one or two facilities for data abstraction, representing a balance of primary and tertiary care facilities to ensure that the data abstracted would be representative of outcomes experienced by the general population in the catchment area.” All selected facilities in this study seemed to be tertiary hospitals and located in urban area rather than primary care hospitals in the rural areas. To make up for this potential shortcoming, I would suggest using the “Transferred for delivery from a different facility (43.1%)" as a proxy, because they are most likely to be transferred from rural hospitals and could represent women in rural areas to some extent. I hope that the authors can further compare the difference between the two groups of "transferred" and "non-transferred" women. The results of the analysis may increase the richness of this paper.

We appreciate the opportunity to clarify the selection of facilities for data abstraction. Since the primary goal of this work was to describe the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes among individuals delivering in specified catchment areas and compare those with estimates from an ongoing clinical trial evaluating the safety of the two biomedical interventions for HIV prevention in pregnancy, we selected delivery facilities from within those catchment areas. We do indeed have a balance of primary and tertiary care facilities from the catchment area, which may or may not include peri-urban and rural areas. Since we did not collect residential information or the location where the individual was transferred from, we are not able to provide further insight into differences in outcomes by geographic location.

2. Do all HIV (+) women take ARV prescriptions? Although there is no ARV regimen information for every woman, in principle, the same country will use the same regimen. Please sort out the ARV regimen of all countries for reference. And try to analyze the correlation between these regimens and complication rates.

The impact of antiretroviral therapy (ART) on pregnancy outcomes is an important research question; however, given the goal of this chart review, we did not collect data on ART use at the time of delivery. Malawi, South Africa, Uganda and Zimbabwe each have national guidance for ART use which is based on WHO recommendations and regimens may vary by country and whether an individual is on a first-or second-line regimen. Since we can’t say for certain which regimens, if any, women were using at the time of delivery, we are not able to conduct any additional analysis among women who are living with HIV. This was noted as a limitation in our discussion.

Reviewer #2:

The purpose of this systematic chart review is to make available pregnancy outcome data from multiple African sites to help in assessment of adverse events when new devices and drugs are evaluated during pregnancy and immediate postpartum. Overall, this is a simple analysis. Few comments below:

3. The investigators mention that that they did a review of the literature as part of the study. Would be a good complementary material to summarize those findings in a table showing frequency of the adverse outcome in African countries - preferably stratified by HIV infection status and antiretroviral use - showing time of study conduct and African region.

The findings from the systematic review have been submitted to PLoS One for publication and include a detailed review of 10 different outcomes (Dr. Erica Lokken is the first author and the manuscript is currently under review). The review is incredibly detailed an includes analysis by region as well as by HIV status. Given the detail provided in the review, we hope to be able to cite the findings in this manuscript rather than duplicate what is presented in the review.

4. The investigators in more than one place mention that they are collecting this data to compare with outcomes from an on-going clinical trial ..... this appears misleading since no description of that study or conduct of that study is part of the writeup. Would be fine to state as part of the overall intent only.

We would like to highlight that a description of the DELIVER study is provided in the first paragraph of the introduction along with a reference linking to the study protocol and the clinicaltrials.gov registration number. Because the DELIVER study is ongoing and the focus of this manuscript was on reporting our findings from the chart review, which may have comparative benefit above and beyond the DELIVER study, we felt is was appropriate to only include a brief over view of the DELIVER study. The final sentence in the review comment leads us to believe that the review agrees with this approach.

5. The aims that appear at the beginning of Methods section should be moved to end of Introduction section.

Thank you for this suggestion, we have moved the sentence that describes the aim of the study to the end of the introduction.

6. In Methods provide definition of pregnancy outcomes used. Were these based on newborn weight and gestational age measurement checks ---- or based on a recorded diagnosis only (in this case it is a major limitation). If gestational age and birth weight measurements were abstracted (available) some validity checks - even on a sample - would be helpful.

The gestational age at delivery was assessed using a combindation of data available in the medical chart including, date of last menstrual period (LMP), estimated date of delivery based on ultrasound and fundal height. We have added this information to the methods.

7. Missing data seem extremely low: Is this a bias with the abstraction process -- i.e., forms with extensive missing data are not included altogether because there is nothing there to abstract? How many at each site met this potential abstraction problem?

We appreciate the opportunity to clarify the volume of missing data. No charts were excluded based on level of missing data. For pregnancy outcomes, pregnancy complications and neonatal outcomes, data abstractors were asked to determine the outcome/complication based on the presence of the diagnosis term in the chart or the presumption of the diagnosis based on other available data in the chart that supported the diagnosis based on our a priori definitions (see Table 2). This approach allowed for a higher-than-expected complete data, with < 2% data missing only neonatal death congenital anomalies, and hypertension (missing data is noted in the text and footnotes of the tables). HIV infection status was missing from ~4% of records and those without complete data were excluded from the sensitivity analysis stratified by HIV status. In the discussion, we noted that while this approach allowed us to determine an outcome for the vast majority if records, it is possible that we underestimated the frequency of pregnancy complications due to insufficient or variable levels of documentation in the medical chart.

8. Tables and other analyses are fine.

Thank you for this note.

Submitted filename: Review comments_2020-12-15.docx

Click here for additional data file.

8 Jan 2021

PONE-D-20-32360R1

Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review

PLOS ONE

Dear Dr. Balkus,

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.

Please submit your revised manuscript by Feb 22 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I am not satisfied with the author's Response because they did not respond to my suggestions appropriately.

For example, these 43% cases "Transferred from different facility" are already available information, but the authors refuse to analyze it further.

Your Response: ”We do indeed have a balance of primary and tertiary care facilities from the catchment area, which may or may not include peri-urban and rural areas.”

Please specify how the authors did indeed obtain "a balance of primary and tertiary care facilities"? Please list in detail which medical institutions are PRIMARY and how many people are there? Which medical facilities are TERTIARY and how many people are there?

Reviewer #2: The authors should cite the pending systematic review. The analyses will help interpretation of data from the on-going trial as well as data addressing use and safety of experimental devices during pregnancy in African women.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: PLOS ONE.docx

Click here for additional data file.

21 Jan 2021

Dear Dr. Chen,

Thank you for the additional reviewer comments for our manuscript titled “Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review.” Please see our revisions in the track changes version of the manuscript, as well as our responses to the additioanl reviewers’ comments in the following pages. The reviewers’ comments are written in plain text and our responses are provided in italics. We recognize that reviewer #1 had two additional comments based on our prior responses. We hope that these most recent modifications will be acceptable to the reviewer and the editors at PLOS ONE. Thank you again for considering our submission and we look forward to hearing from you.

Sincerely,

Jennifer Balkus, PhD, MPH

Assistant Professor

Department of Epidemiology

University of Washington School of Public Health

Reviewer #1:

1. I am not satisfied with the author's Response because they did not respond to my suggestions appropriately. For example, these 43% cases "Transferred from different facility" are already available information, but the authors refuse to analyze it further.

We appreciate the reviewer’s comment and the opportunity to provide further information on this topic. While we abstracted data on whether an individual was transferred from a different facility, we did not collect any additional information on the reasons why a transfer occurred. The settings where data abstraction was conducted, transfers can occur for a variety of reasons, some of which are not directly linked to the need for higher level care. The maternity care system in each of these settings is based upon a group of primary care facilities that feed into the tertiary care facility for their health region, thus all women in the catchment area would be expected to deliver in one of these two locations. Pregnant individuals typically present to the primary care facility closest to their home but are transferred to the tertiary facility if they are either known to be high risk upon presentation from their antenatal care (e.g., prior cesarean delivery) or develop high risk characteristics during labor, delivery or postpartum (e.g., preeclampsia). However, both low and high-risk individuals may also present directly to the tertiary facility, or in some cases, the tertiary facility also serves as the primary facility for the catchment area around the research clinic (such is the case for Uganda). This is consistent with the fact that while ~43% of records indicated a transfer for care, ~94% of deliveries occurred at the facility where data abstraction was performed.

Given that data were not available regarding the reason an individual was transferred, we were concerned about the interpretation of such data in the absence of additional context, thus our reluctance to perform additional analysis stratified by this variable. To address the reviewer’s comment above we have performed an additional analysis describing pregnancy outcomes and maternal and neonatal deaths among those that were transferred from a different facility and those that were not. Data are provided in the table below. (Please see attached letter for formatted table as it does not display properly here).

Select characteristics by the mother’s transfer for delivery from a different facility

Not transferred from a different facility Transferred from a different facility to current facility Overall

N=5875 N=4485 N=10426

Place of delivery

Current health facility 5418 (92.2) 4300 (95.9) 9779 (93.8)

At a different health facility 260 (4.4) 146 (3.3) 408 (3.9)

At a home (private residence) 183 (3.1) 34 (0.8) 218 (2.1)

Not documented 14 (0.2) 5 (0.1) 21 (0.2)

Mode of delivery

Vaginal delivery 4599 (78.3) 2985 (66.6) 7622 (73.1)

Cesarean delivery 1233 (21.0) 1453 (32.4) 2710 (26.0)

Other 24 (0.4) 44 (1.0) 69 (0.7)

Not documented 19 (0.3) 3 (0.1) 25 (0.2)

Pregnancy outcomes

Full term live birth 4874 (83.0) 3545 (79.0) 8448 (81.0)

Premature live birth 643 (10.9) 657 (14.6) 1319 (12.7)

Still born/intrauterine fetal demise (>= 20 weeks) 170 (2.9) 230 (5.1) 413 (4.0)

Outcome not documented 188 (3.2) 53 (1.2) 246 (2.4)

Deaths

Neonatal death 77 (1.4) 112 (2.7) 192 (2.0)

Maternal death 3 (0.05) 4 (0.09) 7 (0.07)

The estimates listed by transfer status are similar to the overall estimates and the range of estimates by site (see Table 4 for estimates by country). Since the reason for transfer was not recorded, we continue to have some concerns about the interpretation of these data. However, we have included the above table in the revised manuscript with additional text throughout the manuscript as appropriate.

2. Your Response: ”We do indeed have a balance of primary and tertiary care facilities from the catchment area, which may or may not include peri-urban and rural areas.” Please specify how the authors did indeed obtain "a balance of primary and tertiary care facilities"? Please list in detail which medical institutions are PRIMARY and how many people are there? Which medical facilities are TERTIARY and how many people are there?

To address this comment we have added a column to Table 1 to indicate which facilities are considered primary and which are considered tertiary. Our local collaborators identified the primary and tertiary facility in their region that potential participants would most likely attend for delivery. For example, our Johannesburg site included the Shandukani Maternal and Obstetrics Unit, which is a primary unit located in the same building as the research clinic, and the Charlotte Maxeke Johannesburg Academic Hospital, which is the tertiary facility that serves residents of the area. One exception to this was the Harare site that was forced to switch facilities due to industrial actions (protests) in the area that resulted in patients, including those seeking obstetric services, needing to seek care at other clinics and hospitals (as described in the methods section of the manuscript). As described in the updated manuscript, the facility used in Uganda provides both primary and tertiary care for the site’s catchment area so a single facility was utilized there.

Regarding the second question about the number of individuals at each facility, all individuals delivering at the designated facility or admitted to the facility for postpartum care within seven days of a delivery elsewhere (home, health clinic, etc.) were included in the review. The number of records evaluated during the periods of review at each facility is displayed in Table 1.

Reviewer #2:

I have reviewed the responses and the revised manuscript. I approve the responses with one condition: The authors should cite the systematic review that is pending review.

1. Since we submitted our previous letter (15 December 2020), we received an invitation from PLOS One to revise and resubmit the systematic review. We have modified the current text to indicate the first author of the systematic review and that is is under review at PLOS One, in case the current manuscript is published before the systematic review.

Submitted filename: Review comments_2021-01-20_final.docx

Click here for additional data file.

16 Feb 2021

PONE-D-20-32360R2

Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review

PLOS ONE

Dear Dr. Balkus,

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.

Please submit your revised manuscript by Apr 02 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I highly appreciate authors' efforts to do further analysis and interpretation for the “transferred cases”. In addition to the cesarean delivery (32.4% versus 21.0%) and preterm birth (14.6% versus 10.9%), the almost twice death rates (2.7% versus 1.4% in neonatal death, and 0.09% versus 0.05% in maternal deaths) may be significant too. The above results really highlight the importance of “transfer” issue and cannot be ignored.

Reviewer #3: Many thanks for the opportunity to review this interesting original article. This article was a systematic chart review of pregnancy outcomes, pregnancy complications and neonatal outcomes in Malawi, South Africa, Uganda and Zimbabwe. This was an important paper because it could clarify the pregnancy and neonatal outcomes of these specified urban settings in Africa. Also, it may be clarified the effect of HIV prevention in these area by comparing ongoing study (DELIVER study).

Reviewer #4: Balkus et al analyzed the pregnancy outcomes, neonatal outcomes and pregnancy complications in eastern and southern Africa. To cover various maternal backgrounds and perinatal-care factors, the authors included both primary and tertiary facilities in each country. The authors summarized the frequency of pregnancy characteristics and outcomes. In addition, the authors compared the pregnancy outcomes between the HIV-positive and HIV-negative groups. This large population-based study enhances our understanding of maternal and neonatal outcomes in the area concerned. As the authors claimed, these results can be further used for evaluating the safety of biomedical interventions for HIV prevention during pregnancy. I believe that the data collection and analysis were performed properly. The conclusions that the authors draw from the data are fine. Furthermore, the manuscript has been revised well through the revisions. Therefore, I think this manuscript is now acceptable for publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Solomon Chih-cheng Chen

Reviewer #3: No

Reviewer #4: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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23 Feb 2021

Dear Dr. Chen,

Thank you for the additional reviewer comments from this latest round of review for our manuscript titled “Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review.” On 16 February 2021, we received your email that included reviewer comments from a third round of review of our paper. We were pleased to note that all reviewers stated that their comments from the previous revision that was submitted on 20 January 2021 were addressed. However, in your email you ask us to address an outstanding comment from reviewer #1. In the text below, we clarify that there are actually no outstanding comments from reviewer #1 as they were all addressed in our responses that were submitted on 20 January 2021. In our second round of review, reviewer #1 had continued concerns about the fact that we did not include any additional exploratory analysis by hospital transfer status. Their comment from the second review related to this concern is provided below in italics:

Reviewer #1 comment from second review:

1. I am not satisfied with the author's Response because they did not respond to my suggestions appropriately. For example, these 43% cases "Transferred from different facility" are already available information, but the authors refuse to analyze it further.

In response to this comment, we provided an extensive explanation for our initial approach in the response letter from 20 January 2021 and included a new analysis and new table in the paper (Table 3). In the email received on 16 February 2021, reviewer #1 noted "I highly appreciate authors' efforts to do further analysis and interpretation for the “transferred cases”. In addition to the cesarean delivery (32.4% versus 21.0%) and preterm birth (14.6% versus 10.9%), the almost twice death rates (2.7% versus 1.4% in neonatal death, and 0.09% versus 0.05% in maternal deaths) may be significant too. The above results really highlight the importance of “transfer” issue and cannot be ignored." This comment indicates that reviewer #1 supports the addition of the new Table 3, as it provides important summaries regarding pregnancy outcomes by transfer status which reviewer #1 lists in their comment above as affirmation for Table 3. Per the comments included in the 16 February 2021 email, reviewer #1 did not have any additional comments, did not request or suggest any additional analyses and did indicate in that all comments had been addressed.

We note that the other reviewers also indicated that all comments had been addressed and reviewer #4 states “Furthermore, the manuscript has been revised well through the revisions. Therefore, I think this manuscript is now acceptable for publication.” Given the positive comments from all reviewers and the fact that all reviewers, including reviewer #1, indicated that all comments have been addressed in our last revision, we have not made any modifications to the manuscript. We hope that this letter clarifies how we have already addressed prior reviewer comments and the editorial team will now find the manuscript suitable for publication.

On behalf of my co-authors, thank you again for considering our submission and we look forward to hearing from you.

Sincerely,

Jennifer Balkus, PhD, MPH

Submitted filename: Review comments_2021-02-23.pdf

Click here for additional data file.

26 Feb 2021

Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review

PONE-D-20-32360R3

Dear Dr. Balkus,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Tai-Heng Chen, M.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I really appreciate your efforts to respond to my comments. The current form is satisfactory to me. I hope this article can help the world learn more about maternal and child health in Africa. Thank you a lot.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Solomon Chih-Cheng Chen

3 Mar 2021

PONE-D-20-32360R3

Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review

Dear Dr. Balkus:

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. Tai-Heng Chen

Academic Editor

PLOS ONE