PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0260006 PONE-D-21-20950 Research Article Medicine and health sciencesMedical conditionsInfectious diseasesViral diseasesCOVID 19 Biology and life sciencesDevelopmental biologyNeonates Medicine and health sciencesEpidemiologyPandemics Medicine and health sciencesWomen's healthMaternal healthNeonatal care Medicine and health sciencesPediatricsNeonatologyNeonatal care Medicine and health sciencesHealth careNeonatal care Biology and life sciencesPopulation biologyPopulation metricsDeath rates Medicine and health sciencesWomen's healthMaternal healthBirthLabor and delivery Medicine and health sciencesWomen's healthObstetrics and gynecologyBirthLabor and delivery Medicine and health sciencesHealth careHealth care facilities People and placesGeographical locationsAfricaUganda Impact of the early COVID-19 pandemic on outcomes in a rural Ugandan neonatal unit: A retrospective cohort study Ugandan NICU outcomes during COVID https://orcid.org/0000-0002-3269-1892 Hedstrom Anna Conceptualization Formal analysis Investigation Methodology Project administration Supervision Validation Visualization Writing – original draft Writing – review & editing 1 * Mubiri Paul Conceptualization Formal analysis Validation Visualization Writing – original draft Writing – review & editing 2 Nyonyintono James Conceptualization Project administration Writing – review & editing 3 Nakakande Josephine Project administration Supervision Writing – review & editing 3 Magnusson Brooke Methodology Project administration Writing – review & editing 4 Vaughan Madeline Conceptualization Methodology Supervision Writing – review & editing 4 Waiswa Peter Methodology Supervision Writing – review & editing 2 Batra Maneesh Conceptualization Methodology Supervision Writing – review & editing 1 Departments of Pediatrics and Global Health, Neonatology, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States of America Makerere University School of Public Health, Mulago, Kampala, Uganda Kiwoko Hospital, Luweero Nakaseke, Kiwoko, Uganda Adara Development, Rozelle, NSW, Australia Chen Robert Jeenchen Editor Ohio State University Wexner Medical Center Department of Surgery, UNITED STATES

The authors have declared that no competing interests exist.

 * E-mail: hedstrom@uw.edu 16 12 2021 2021 16 12 e0260006 27 6 2021 30 10 2021 2021 Hedstrom et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

During the early COVID-19 pandemic travel in Uganda was tightly restricted which affected demand for and access to care for pregnant women and small and sick newborns. In this study we describe changes to neonatal outcomes in one rural central Ugandan newborn unit before and during the early phase of the COVID-19 pandemic.

 Methods

We report outcomes from admissions captured in an electronic dataset of a well-established newborn unit before (September 2019 to March 2020) and during the early COVID-19 period (April–September 2020) as well as two seasonally matched periods one year prior. We report excess mortality as the percent change in mortality over what was expected based on seasonal trends.

 Findings

The study included 2,494 patients, 567 of whom were admitted during the early COVID-19 period. During the pandemic admissions decreased by 14%. Patients born outside the facility were older on admission than previously (median 1 day of age vs. admission on the day of birth). There was an increase in admissions with birth asphyxia (22% vs. 15% of patients). Mortality was higher during COVID-19 than previously [16% vs. 11%, p = 0.017]. Patients born outside the facility had a relative increase of 55% above seasonal expected mortality (21% vs. 14%, p = 0.028). During this period patients had decreased antenatal care, restricted transport and difficulty with expenses and support. The hospital had difficulty with maternity staffing and supplies. There was significant community and staff fear of COVID-19.

 Interpretation

Increased newborn mortality during the early COVID-19 pandemic at this facility was likely attributed to disruptions affecting maternal and newborn demand for, access to and quality of perinatal healthcare. Lockdown conditions and restrictions to public transit were significant barriers to maternal and newborn wellbeing, and require further focus by national and regional health officials.

 Data collection and data analysis (PM) was supported by Adara Development (https://www.adaragroup.org/). Adara development did not influence the study design, data analysis/interpretation, information reported nor decision to publish. Data Availability All relevant data are within the manuscript and its Supporting Information files. Outbreaks COVID-19 Background

The COVID-19 pandemic has stressed health systems around the world. In addition to the massive number of deaths due to infection with the SARS-CoV-2 virus, the pandemic and associated control measures have had a negative impact on primary and essential health care services due to disruptions in health workforce and supply chains, overwhelmed health facilities and decreased care seeking for non-COVID-19 causes [1]. This has resulted in substantial negative effects on human health around the world, particularly among the most vulnerable populations. Much of the progress towards reducing maternal and newborn deaths as well as stillbirth over the last several decades has necessitated health systems strengthening, increasing care seeking and optimizing supply chains for commodities relevant to mothers and babies [2, 3]. Progress towards achieving the Sustainable Development Goals and Every Newborn Action Plan targets for reducing maternal deaths, newborn deaths and stillbirths is expected to slow substantially due to COVID-19 impacts, and may even regress without significant adjustments [3–7]. Therefore, understanding and documenting the indirect effects of the COVID-19 pandemic on newborn health and access to care are crucial to design strategies to address vulnerabilities in the healthcare system.

While direct effects of SARS-CoV-2 infection among mothers or newborns has not been reported as a significant contributor to the overall mortality due to COVID-19, evidence for impact on maternal and newborn services such as access to facility-based deliveries, antenatal care and emergency obstetric care is emerging [8–10]. An early survey by the WHO reported 80% of countries had disruptions to essential health services and these were exacerbated in lower income countries [1]. Little has been published, however, on availability of peripartum care or neonatal outcomes from low resource facilities during the COVID-19 pandemic [11–14].

Over the past decades, Uganda has made significant strides in reducing under-five mortality and maternal deaths; however as of 2019, neonatal mortality had plateaued at 20 deaths per 1000 live births [15]. Twenty five percent of births in Uganda are not delivered by skilled birth attendant, post-natal services remain low and geographical inequalities in access to maternal services exist [16]. It is in this background in which the first case of COVID-19 in Uganda was reported on 21 March 2020 [17]. As a result, the government of Uganda instituted measures to control the spread of the disease including restrictions to movement and a national lockdown that began 30 March and began to ease on 26 May. These restrictions exacerbated existing maternal and newborn service challenges, most notable in decreased ability for pregnant women or parents with a newborn to travel urgently to health facilities. As of May 2021, Uganda had recorded over 43,000 cases of COVID-19 with 357 deaths [18]. Pandemic control measures affecting access to newborn care remain highly dynamic and no country-level data of neonatal survival during this period are available.

We have been prospectively collecting data at one rural Ugandan neonatal unit since 2005 where provision of care for small and sick newborns, including CPAP therapy has been well established. During the early COVID-19 pandemic, this facility was able to obtain personal protective equipment for staff and maintain neonatal care but peripartum mothers had difficulty traveling to the facility due to lockdown. The aim of this study is to describe this facility’s experience with providing peripartum care during the pandemic by utilizing this longitudinal dataset to explore changes to facility-based neonatal outcomes before and during the early phase of the COVID-19 pandemic.

 Methods Study design

Retrospective cohort study of a clinical database.

 Study population

Included in this study are patients admitted to the Kiwoko Hospital (KH) neonatal unit during the period of study. There were no exclusion criteria.

 Setting

Kiwoko Hospital is a rural, private, not-for-profit secondary level care hospital that acts as a referral center for three districts (total population 1,000,000) in central Uganda. During fiscal year 2019–2020, the perinatal mortality rate in the hospital’s district (Nakaseke) was in the range of 29–42 per 1,000 live births and 19–28 in the two other districts the hospital serves (Nakasongola and Luwero) [19, 20]. The neonatal mortality rate for Uganda was 27 per 1,000 live births [21].

The KH neonatal care unit was established in 2001 and is a regional leader in care of small and sick newborns [22]. The unit admits more than 1,000 patients annually, generally neonates with a gestational age greater than 24 weeks and up to 44 weeks. About half of admitted patients are born at KH and the remainder are “outborn,” or admitted after birth at home or another facility. Outborn patients are treated in the same unit and receive the same care as those born at KH. There are 5–7 nurses on duty each shift, as well as one assigned medical officer and one pediatric physician who round on the patients and are on call each day. Staff generally live on site. Electricity is continuously available with the help of a standby generator. The unit provides thermoregulatory support primarily from radiant warmers and incubators, infection control and treatment, nasogastric and cup feeding, intravenous hydration, phototherapy, blood transfusion, basic laboratory services, oxygen therapy, and pulse oximetry. Improvised bCPAP has been the standard of care for respiratory failure in the unit since 2012 and is assembled using donated RAM nasal cannulas [23]. The unit does not provide surfactant, mechanical ventilation, total parenteral nutrition nor therapeutic hypothermia for birth asphyxia. The national referral hospital is located two hours travel by car and referrals from the Kiwoko NICU are transported free of charge. Admissions via ambulance to KH are assisted by government primary health care subsidies. General care in the neonatal unit is subsidized and families pay for any additional lab tests or imaging. Mothers are offered free accommodation and basic meals during their baby’s stay.

 COVID-19 experience

The first COVID-19 tests at Kiwoko hospital were conducted on 5 May 2020 and the first case of COVID-19 was confirmed on 2 August. Following a total of 752 tests of staff, patients and community members, 14 total cases were confirmed before October and transferred to isolation centers. No neonates were denied care and access to and provision of care continued unchanged in the neonatal unit. Mothers were screened for symptoms on entrance to the unit. Experience at KH was determined through interviews with neonatal and maternity unit doctors as well as supervising midwives and nurses (summarized in S1 Table).

Nationally during the 2020 period of the COVID-19 pandemic in Uganda, restrictions included: banning mass gatherings (18 March), closing schools (20 March), suspending public transportation and requiring police presence for private transport (25 March), and a nationwide lockdown with curfew (30 March). All non-essential services and activities were closed in this period [24]. Until 19 April, approval from a Resident District Commissioner was required to move during a medical emergency, and each district had only one Commissioner [25, 26]. Transport restrictions began to ease on 26 May: public transport resumed at half capacity (and increased cost) on 4 June, and the most common form of transport (via motorcycle) resumed on 27 July. Overnight curfews remained in place through the end of 2020.

 Dataset

The neonatal unit has maintained an electronic database of all neonatal admissions since late 2012. On admission, nurses record patient and maternal information on a designated bedside form. After discharge, a data entry team extracts additional information from the medical file including treatments and final diagnosis as assigned by the physician at discharge, death, or transfer. Data are manually entered into Epi Info version 7 [27]. The data was exported to STATA v.15 for analysis [28].

 Outcome

We utilized this database to explore outcomes from all infants admitted to the neonatal unit during the pre-COVID-19 period (October 2019 through March 2020) and the first six months of the pandemic in Uganda, which we will refer to as the early COVID-19 period, or the COVID-19 period (April through September 2020). These periods were selected to capture the first lockdown period in Uganda (April/May) as well as the subsequent phased relaxation of COVID-19 restrictions (June/July) and then two additional months (August/September) to allow for six month seasonal comparisons with previous years. We also show seasonal variation and pre-existing trends in mortality by reporting outcomes from reference periods one year prior to study periods: Oct 2018 –March 2019 and April–Sep 2019. Death before discharge was the primary outcome- defined as a death as an infant that was admitted to the neonatal unit and died before discharge home.

 Other variables

The analysis was further stratified by inborn/outborn status. Patients were classified as ‘inborn’ if they were born at KH while others were classified as ‘outborn’ (born at another facility, at home or on the way to the hospital). Birthweight-specific and diagnosis-specific mortalities were also computed. When birthweight was unknown, admission weight was used if the patient was admitted within 3 days of birth. Gestational age is not reliably available from this dataset and is therefore not reported for this study. Primary diagnoses were assigned by doctor at patient discharge, transfer, or death. Additional data on availability of health workforce in the neonatal unit was retrospectively reported by the nurse in-charge.

 Statistical analysis

The mortality rate pre and during the early COVID-19 period was computed as a proportion of infants who died to the total number of infants admitted to the unit in the same period. To determine the potential impact of the COVID-19 pandemic on neonatal mortality in the unit, we computed the relative change in mortality rate between two time periods of the same months for the 2 sequential years. Proportion tests were used to compare the rates between two time periods of the same months.

 Ethical considerations

Human Subjects Approval was obtained from Makerere University School of Public Health Institutional Review Board (protocol number 917) and approved by the Uganda National Council for Science and Technology (registration number SS813ES). The data were fully anonymized before accessed by the research team and the ethics committee waived the requirement for informed consent. The University of Washington institutional review board designated this as an exempt study.

 Results

The study included 2,494 patients admitted during the period of study and admissions during each period are shown in Table 1. A total of 567 patients were admitted during the early COVID-19 period (April-Sept 2020) representing a 14% decrease in admissions compared to the same period in the preceding year (April-Sept 2019). Out of 2,494 patients included in the analysis, 49% (1,234) were outborn (born elsewhere and admitted to the KH unit). Proportion of outborn patients decreased during the early COVID-19 period, as shown in Fig 1. Five patients did not have inborn/outborn status recorded, and these were excluded from the stratified analyses by birth location. The average daily census increased during the early COVID-19 period to 42.3 (sd 6.3) from a range of 38.6–41.6 in the periods before COVID-19.

10.1371/journal.pone.0260006.g001 Admissions by birth location.

Proportion of admissions of outborn patients decreased to 46.1% during the early COVID period (April–September 2020) from 51.6% pre-COVID (October 2019 to March 2020). All transport was banned or tightly limited during April and May and public transport was costly and restricted during June and July. “Outborn” refers to patients born outside KH. “Inborn” includes those born at KH.

 10.1371/journal.pone.0260006.t001 Admissions per period, unit census and staffing levels.
Reference periods pre-COVID-19 period Early COVID-19 period
Date range Oct 2018 –Mar 2019 April–Sep 2019 Oct 2019 –Mar 2020 April–Sep 2020
Number of patients admitted (n) 649 659 619 567
    Outborn n (%) 326 (50.1%) 323 (49.1%) 321 (51.6%) 264 (46.1%)
Average Daily Census (sd) 38.6 (4.9) 41.3 (6.6) 41.6 (5.3) 42.3 (6.3)
Nurses per shift 5 5 5 5

Maternal and neonatal demographics are shown in Table 2. Nineteen percent (474/2,494) of patients had missing birth weight and admission weight was used as proxy for 400 of this group.

10.1371/journal.pone.0260006.t002 Maternal and neonatal demographics and clinical characteristics during pre-COVID (October 19 –March 20) and early COVID periods (April–September 2020) by birth location.
All Patients Inborn Patients Outborn Patients
pre-COVID (n = 619) % COVID (n = 567) % pre-COVID (n = 296) % COVID (n = 303) % pre-COVID (n = 321) % COVID (n = 264) %
Maternal Demographics
Median maternal age (years, IQR) 25 (20–29) 24 (20–29) 25 (21.5–29) 24 (21–30) 24 (20.29) 23 (20–28)
Antenatal care visits (mean, SD) 2.6 (1.3) 2.6 (1.3) 2.6 (1.3) 2.6 (1.3) 2.5 (1.2) 2.5 (1.3)
Mode of transport to facility: (pregnant mother) (newborn)
    Motorcycle 51.8 44.8 55.7 50.5 48.0 38.3
    Taxi/Special hire 29.6 27.9 30.7 28.4 29.3 27.3
    Ambulance 15.8 24.7 9.5 17.5 21.8 32.9
    Bicycle or foot 0.8 1.8 1.0 2.3 0.6 1.1
    Unknown 1.9 0.9 3.7 1.3 0.3 0.4
Lives outside district 67.2 67.2 64.5 65.3 69.8 69.3
Type of birth attendant
    Doctor 27.1 27.0 44.3 42.6 11.2 9.1
    Midwife/Nurse 65.3 66.7 55.7 57.4 74.4 77.3
    Traditional birth attendant 1.8 1.9 - - 3.4 4.2
    Family member 4.0 2.8 - - 7.5 6.1
    Unknown/other 1.8 1.6 - - 3.4 3.4
Birth location (n = 585)
    Another facility - - - - 86.3 88.6
    Home - - - - 11.5 9.5
    On the way to hospital - - - - 2.2 1.9
Cesarean section 25.8 27.0 42.9 41.9 10.0 9.8
Singleton birth 82.2 82.4 81.4 79.9 82.9 85.2
Infant characteristics
Female 45.4 43.9 46.6 43.6 44.6 44.3
Age at admission (days) - - - - 0 (0–2) 1 (0–2)
    Median (IQR)
    Mean (SD) - - - - 2.5 (5.6) 3.2 (8.8)
Low birthweight (<2.5kg) 51.5 51.8 53.7 58.1 49.5 44.7
Very low birthweight (<1.5kg) 14.4 15.7 11.5 17.2 17.1 14.0
Primary diagnosis
    Prematurity/LBW 47.7 46.9 50.3 52.8 45.2 40.1
    Birth asphyxia 15.0 22.4 12.2 17.5 17.4 28.0
    Infection 21.8 18.9 17.6 17.2 25.9 20.8
    Other 15.5 11.8 19.9 12.6 11.5 11.0
Clinical Course
Therapies received:
    Phototherapy 34.3 44.3 30.1 42.6 38.1 46.2
    Blood transfusion 4.8 2.5 3.7 1.6 5.9 3.4
    Bubble CPAP 14.0 15.7 13.8 16.5 14.3 14.8

▯Yellow highlighted cells show trends of particular clinical significance.

As seen in Table 2, during the early COVID-19 period admitted patients were born to younger mothers (median of 24 vs. 25 years). Both expectant mothers and newborns were more likely to be transported via ambulance or on foot during COVID-19.

Outborn patients during the early COVID-19 period were admitted on average one day later than pre-COVID-19 (median admission at 1 day of age vs. on the day of birth). Outborns admitted were less likely to have been born at home (9.5% vs 11.5%), and their births were less likely to be attended by a doctor (9% vs. 11%) (Table 2).

There was an increased proportion of admission with birth asphyxia, most notably among outborn patients (28% from 17% pre-COVID-19). Concurrently, outborn admissions were less likely to have a diagnosis of prematurity (40% down from 45%) or infection (21% from 26%). Inborn admissions had an increased proportion due to low birthweight (58% from 54%) and very low birthweight (17% from 11%) while these decreased among outborn patients (Table 2).

All patients were more likely to be treated with phototherapy (44% up from 34%) and less likely to receive a blood transfusion (3% down from 5%). Bubble CPAP therapy, however, was used more frequently in only inborn patients (17% vs. 14%) during the pandemic and likely corresponds to the increase in prematurity among this group (Table 2).

Mortality significantly differed between the COVID-19 period and pre-COVID-19 periods [15.7% (89/567) vs. 11.1% (69/619), p = 0.017]. Fig 2 illustrates mortality pre-COVID-19 and during the early COVID-19 period compared with the reference periods one year prior to allow for seasonally appropriate trends. When we compared mortality pre-COVID and the reference period of the same months, mortality increased proportionally by 5.7% while during COVID, mortality increased proportionally by 41.4% compared to the reference period. Therefore an excess mortality of 35.7% (41.4–5.7%) occurred during the early COVID-19 period.

10.1371/journal.pone.0260006.g002 Newborn mortality by birth location including expected mortality trend (dotted lines) without the COVID-19 pandemic based on seasonally matched periods prior to COVID-19.

Excess mortality is the amount of mortality seen above what would be expected for trend, calculated as the relative difference between periods divided by mortality in the reference period. 1,234 patients were outborn (born outside Kiwoko hospital) and 1,260 born at Kiwoko (inborn) during the periods of study.

Among the inborn patients, mortality pre-COVID was 7.8 per 100 hospital admissions while during COVID, mortality was 10.9 per 100 hospital admissions. Mortality increased by 20.0% pre-COVID when compared to the reference period, however during COVID, mortality increased by 25.3%. Therefore an excess mortality of 5.3% (25.3% - 20.0%) among inborn patients occurred during the early COVID-19 period.

Among outborn patients, the excess mortality was 55.2% (55.9- -0.7%). Further, mortality among the outborn infants significantly differs during early COVID compared to the immediate pre-COVID period (21.2% vs. 14.3%, p = 0.028).

Table 3 shows increased mortality during the COVID-19 period among almost all categories of diagnosis and birthweight. Mortality among inborn patients with prematurity increased from 8.7% pre to 13.7%. Mortality among the smallest inborn patients (<1.5kg birthweight) was increased from 26.5% to 38.5% while other categories of birthweight among inborns remained unchanged. Outborn patients, however, had significantly increased mortality in all major categories of birthweight- patients <1.5k up through 4kg.

10.1371/journal.pone.0260006.t003 Mortality by birth location, birthweight and diagnosis during early COVID and pre-COVID periods.
Inborn Patients Outborn Patients
pre-COVID period (Oct 19—Mar 20) n = 296 Early COVID period (April–Sep 20) n = 303 pre-COVID period (Oct 19—Mar 20) n = 321 Early COVID period (April–Sep 20) n = 264
Birth Location
(23/296) 7.8% (33/303) 10.9% (46/321) 14.3% (56/264)* 21.2%
Diagnosis
    Prematurity/ low birthweight (13/149) 8.7% (22/160) 13.7% (18/145) 12.4% (15/106) 14.1%
    Birth asphyxia (5/36) 13.9% (8/53) 15.1% (19/58) 33.9% (25/69) 35.1%
    Infection (0/52) 0% (1/52) 1.9% (8/83) 9.6% (8/55) 14.5%
Birthweight
    <1.5 kg (9/34) 26.5% (20/52) 38.5% (12/55) 21.8% (13/37) 35.1%
    1.5 to 2.49 kg (6/125) 4.8% (5/124) 4.0% (6/104) 5.8% (10/81) 12.3%
    2.5 to 4kg (8/126) 6.3% (8/119) 6.7% (21/131) 16.0% (28/122) 23.0%
    >4 kg (0/11) - (0/8) - (1/5) 20.0% (2/12) 16.7%

*p< 0.05. ▯Yellow highlighted cells show trends of particularly clinical significance.

Table 4 summarizes the impact of reported maternal child health impacts globally and how they affected KH. Descriptions and data from KH on these topics are found in S1 Table.

10.1371/journal.pone.0260006.t004 Summary of impacts on maternal child and health reported globally during the early COVID-19 pandemic and the experience at Kiwoko hospital.
Kiwoko Impacted Kiwoko not impacted
Maternity
Restricted transport for mothers[1, 29, 30] Increased adolescent pregnancy[31, 39]
Decreased antenatal care[1, 31–34] Increased stillbirth[2, 32, 39]
Decreased facility birth[1, 6, 8, 12, 30, 33–35] Decreased cesarean sections[39]
Increased births at home or with traditional birth attendant[36] Restricted personal protective equipment (PPE)[1, 8, 30]
Decreased availability of labor medications [32, 37]
Decreased staffing levels[1, 3, 8, 38]
Neonatal Unit
Restricted transport for babies[1, 29, 30] Decreased staffing levels[1, 3, 8, 38]
Decreased neonatal intensive care admissions[14, 32, 40] Restricted supplies/ personal protective equipment (PPE)[1, 8, 30]
Decreased outborn admissions[8, 41] Decreased kangaroo mother care (KMC)[8, 44]
Increased preterm birth[14, 32]
Increased birth asphyxia[14]
Decreased blood supply[1]
Increased facility neonatal mortality[12, 40, 42]
Decreased facility-based infant follow-up[8, 43]
Parents
Decreased maternal support by family at hospital[8]
Difficulty with medical expenses/ food security[1, 24, 31, 40]
Staff and Community
Staff COVID-19 fear[3, 8]
Community fear of COVID-19 at facilities[8, 33, 34]
Discussion

Mortality and admissions with birth asphyxia increased while outborn admissions decreased in this rural Ugandan neonatal unit during the first six months of the COVID-19 pandemic. The pandemic was associated with a relative increase in mortality by 36% and 55% excess mortality above seasonal trends among outborn patients. This increased mortality is likely attributed to disruptions due to the pandemic affecting maternal and newborn demand for, access to and quality of peripartum healthcare [45].

We also found that the early COVID-19 period was associated with fewer admissions but increased daily census suggesting longer lengths of stay. Inborn patients were more likely to be preterm or very low birthweight and be treated with bubble CPAP. Outborn admissions decreased, were older on admission and were less likely to be delivered by a doctor. All patients were more likely to have birth asphyxia and be treated with phototherapy. These finding suggest increased patient acuity and aligns with resultant increased mortality during this period.

In Uganda, lockdown in April and May and restricted, expensive public motorcycle transit through July created significant barriers to transport that exacerbated existing delays to maternal and neonatal care, including delayed decision to seek care and prolonged time to reach to care [41, 45]. Increased mortality among newborns in this setting due to the indirect effects of the pandemic could quickly dwarf the direct mortality rate from COVID-19 infections, and likely did so in 2020. Although primary data is sparse, other sites have also reported increased facility-based neonatal deaths during COVID-19 lockdown periods, especially among outborn patients [12, 14, 42]. Heterogeneity in mortality among sites suggests the indirect impacts of COVID-19 are context-specific [41]. The experience at KH is described in Table 4 and S1 Table. KH was resourced to provide sufficient personal protective equipment to staff and parents in the neonatal unit, was able to adequately space mothers staying in on-campus quarters, and isolated patients demonstrating COVID-19 symptoms. This ability to respond to the pandemic beyond baseline newborn resources and outcomes at KH that exceed many other facilities in Uganda, may explain why outcomes could have been worse elsewhere.

Proportion of admissions due to prematurity was increased among inborn babies but not among outborns. With single facility data we cannot infer population-level changes in prematurity rates during the pandemic as other regions have, but decreased admissions of outborn premature infants suggests they may have died before reaching KH or were less likely to be transferred from other facilities [2, 11]. Mothers who did deliver at KH may have been triaged from the community for their risk of preterm delivery while others delivered elsewhere. Despite their birth location, the smallest patients (<1.5kg) had increased mortality which reveals the fragile survival of these patients at baseline.

Limitations to this study include the fluidity and dynamic nature of impacts of the early pandemic on demand for, access to and provision of quality maternal and newborn care services. For example, transportation impacts were greatest early in the COVID-19 study period due to lockdown restrictions, but further impacts on quality of care in the hospital may have been later in the period when COVID-19 was diagnosed locally and affected maternity staffing, community morale and supply chain of obstetric medications. This analysis does not capture subsequent months during the COVID-19 pandemic, including Uganda’s peak in infections in December 2020 and most recent wave in June 2021 [46]. Finally, we could not account for all impacts on maternal and newborn health, as impacts to antenatal care may impact the health of the baby independent of the neonatal care, either during the newborn period or later in life.

Strengths of the study include the stable care model of the KH neonatal unit and the established dataset with ability to make comparisons with reference years to account for seasonal trends.

COVID-19-related disruptions to the provision of child health service and outcomes, including the impact on immunizations and primary health care, have been well documented [39, 43]. This study is among few reporting impact to essential maternal/newborn care including access to safe delivery and transfer to neonatal inpatient care [8, 11–14, 32, 40, 47]. We report the pandemic’s disruptions to outcomes for small and sick newborns, who are among the most vulnerable humans and accounted for one fifth of childhood deaths pre-pandemic [15]. The World Health Organization has highlighted the importance of evaluation of health care vulnerabilities and modifications that will allow the continuation of essential health services during the pandemic [48]. Reducing impacts on vulnerable newborns in the continued pandemic will take coordinated and deliberate actions by policymakers, countries, and regional public health officials to ensure that access and quality to maternal and newborn health services are prioritized and optimized.

 Supporting information Impacts on maternal child and health reported globally during the early COVID-19 pandemic and their experience at Kiwoko hospital.

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Small and sick newborn care during the COVID-19 pandemic: global survey and thematic analysis of healthcare providers’ voices and experiences. BMJ Glob Health. 2021;6(3). Epub 2021/03/16. doi: 10.1136/bmjgh-2020-004347 33716220. Pearson L. Direct and Indirect impact of COVID-19 pandemic on children globally, and UNCEF mitigation strategies. Pediatric Academic Societies; Virtual2021. COVID-19 Impact Audit. Vermont Oxford Network Section on Neonatal Perinatal Medicine, 2021. Chmielewska B, Barratt I, Townsend R, Kalafat E, van der Meulen J, Gurol-Urganci I, et al. Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis. The Lancet Global Health. 2021. doi: 10.1016/s2214-109x(21)00079-6 33811827 Kc A, Gurung R, Kinney MV, Sunny AK, Moinuddin M, Basnet O, et al. Effect of the COVID-19 pandemic response on intrapartum care, stillbirth, and neonatal mortality outcomes in Nepal: a prospective observational study. The Lancet Global Health. 2020. doi: 10.1016/s2214-109x(20)30345-4 32791117 Jensen C. Child health services during a COVID-19 outbreak in KwaZulu-Natal Province, South Africa. SAMJ Research. 2021;111. Abdul-Mumin A, Cotache-Condor C, Bimpong KA, Grimm A, Kpiniong MJ, Yakubu RC, et al. Decrease in Admissions and Change in the Diagnostic Landscape in a Newborn Care Unit in Northern Ghana During the COVID-19 Pandemic. Front Pediatr. 2021;9:642508. Epub 2021/04/13. doi: 10.3389/fped.2021.642508 33842411; PubMed Central PMCID: PMC8027062. UNICEF, World Health Organization, World Bank, United Nations. Levels and trends in child mortality report 2020. Estimates developed by the United Nations Inter-Agency Group for Child Mortality. New York: UNICEF, 2020. Uganda Demographic and Health Survey 2016. Kampala, Uganda: Uganda Bureau of Statistics, 2018. Ugandan Ministry of Health. Timeline Kampala, Uganda: Republic of Uganda; 2020 [22.April.2021]. Available from: https://covid19.gou.go.ug/timeline.html. Ministry of Health Government of Uganda. Coronavirus (Pandemic) Covid-19 Kampala, Uganda 2021. Available from: https://www.health.go.ug/covid/. Annual Health Sector Performance Report 2019–2020 FY. Kampala: 2020. Kabugo D, Nakamura H, Magnusson B, Vaughan M, Niyonshaba B, Nakiganda C, et al. Mixed-method study to assess the feasibility, acceptability and early effectiveness of the Hospital to Home programme for follow-up of high-risk newborns in a rural district of Central Uganda: a study protocol. BMJ open. 2021;11(3):e043773. Epub 2021/03/04. doi: 10.1136/bmjopen-2020-043773 33653756; PubMed Central PMCID: PMC7929893. The Republic of Uganda Ministry of Health. The Republic of Uganda Ministry of Health Annual Health Sector Performance Report Financial Year 2019–2020. Kampala The Republic of Uganda Ministry of Health, 2020. Kirunda KA. Kiwoko hospital excursion inspires visiting midwives from Eastern Uganda [Internet]. Kampala: Makerere University Centre of Excellence for Maternal Newborn and Child Health,. 2018. [cited 2021]. Available from: https://www.mnh.musph.ac.ug/MNH%20NEWS/kiwoko-hospital-excursion-inspires-visiting-midwives-from-eastern-uganda/. McAdams RM, Hedstrom AB, DiBlasi RM, Mant JE, Nyonyintono J, Otai CD, et al. Implementation of Bubble CPAP in a Rural Ugandan Neonatal ICU. Respir Care. 2015;60(3):437–45. Epub 2014/11/13. doi: 10.4187/respcare.03438 25389349. Development Initiatives. Socioeconomic impact of Covid-19 in Uganda. How has the government allocated public expenditure for FY 2020/21? 2020. Musisi N, Russell A, Lusimbo R. Civil society response to President Museveni’s directive that pregnant women will no longer be banned from using transport to seek health services during COVID-19 lockdown. Health Gap Global Access Project. 2020 April 20, 2020. Atim Alupo B. Gender and COVID-19 Control Measures in Uganda. Australian Institute of International Affairs. 2020 06 May 2020. Epi Info version 7.1.4 [Internet]. Center for Disease Control,. 2014. Available from: https://www.cdc.gov/epiinfo/index.html. STATA. version 15 ed2017. Katana E, Amodan BO, Bulage L, Ario AR, Fodjo JNS, Colebunders R, et al. Violence and discrimination among Ugandan residents during the COVID-19 lockdown. BMC public health. 2021;21(1):467. Epub 2021/03/10. doi: 10.1186/s12889-021-10532-2 33685420; PubMed Central PMCID: PMC7938270. Felix K. Makerere University Centre of Excellence for Maternal Newborn and Child Health, editor2020. Available from: https://www.mnh.musph.ac.ug/blog/coping-with-provision-of-maternal-newborn-health-care-during-covid-19-lockdown-in-rural-uganda/. Hivos People Unlimited, Akina Mama wa Afrika. The state of social protection in Uganda in reseponse to Covid-19. 2020. Burt JF, Ouma J, Amone A, Aol L, Sekikubo M, Nakimuli A, et al. Indirect Effects of COVID-19 on Maternal, Neonatal, Child, Sexual and Reproductive Health Services in Kampala, Uganda. 2021. doi: 10.1136/bmjgh-2021-006102 34452941 Antenatal visits, deliveries drop in health facilities in Teso. The Independent. 2020 14 May 2020. Moyer CA, Sakyi KS, Sacks E, Compton SD, Lori JR, Williams JEO. COVID-19 is increasing Ghanaian pregnant women’s anxiety and reducing healthcare seeking. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2021;152(3):444–5. Epub 2020/11/23. doi: 10.1002/ijgo.13487 33222215. Ashish K, Peterson SS, Gurung R, Skalkidou A, Gautam J, Malla H, et al. The perfect storm: Disruptions to institutional delivery care arising from the COVID-19 pandemic in Nepal. Journal of Global Health. 2021. doi: 10.7189/jogh.11.05010 34055329 Jones SA, Gopalakrishnan S, Ameh CA, White S, van den Broek NR. ’Women and babies are dying but not of Ebola’: the effect of the Ebola virus epidemic on the availability, uptake and outcomes of maternal and newborn health services in Sierra Leone. BMJ Glob Health. 2016;1(3):e000065. Epub 2017/06/08. doi: 10.1136/bmjgh-2016-000065 28588954; PubMed Central PMCID: PMC5321347. Roberton T, Carter ED, Chou VB, Stegmuller AR, Jackson BD, Tam Y, et al. Early estimates of the indirect effects of the COVID-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study. Lancet Glob Health. 2020;8(7):e901–e8. Epub 2020/05/15. doi: 10.1016/S2214-109X(20)30229-1 32405459; PubMed Central PMCID: PMC7217645. Atwine D. Rampant Absenteeism and Unsatisfactory Attendance to Duty by Health Workers. Kampala, Uganda: The Republic of Uganda, 2020 ADM. 45/273/01. Shikuku D, Nyaoke I, Gichuru S, Maina O, Eyinda M, Godia P, et al. Early indirect impact of COVID-19 pandemic on utilization and outcomes of reproductive, maternal, newborn, child and adolescent health services in Kenya. pre-print. 2020. doi: 10.1101/2020.09.09.20191247 Klingenberg C, Tembulkar SK, Lavizzari A, Roehr CC, Ehret DEY, Vain NE, et al. COVID-19 preparedness-a survey among neonatal care providers in low- and middle-income countries. Journal of perinatology: official journal of the California Perinatal Association. 2021;41(5):988–97. Epub 2021/04/15. doi: 10.1038/s41372-021-01019-4 33850282; PubMed Central PMCID: PMC8042838. Chimhuya S, Neal SR, Chimhini G, Gannon H, Cortina-Borja M, Crehan C, et al. Indirect impacts of the COVID-19 pandemic at two tertiary neonatal units in Zimbabwe and Malawi: an interrupted time series analysis. pre-print. 2021. doi: 10.1101/2021.01.06.21249322 Jensen C, McKerrow NH. Child health services during a COVID-19 outbreak in KwaZulu-Natal Province, South Africa. S Afr Med J. 2020;111(2):114–9. doi: 10.7196/SAMJ.2021.v111i2.15243 33944720 Shet A, Dhaliwal B, Banerjee P, DeLuca A, Carr K, Britto C, et al. Childhood immunisations in India during the COVID-19 pandemic. BMJ Paediatrics Open. 2021;5(1). doi: 10.1136/bmjpo-2021-001061 33928197 Minckas N, Medvedev MM, Adejuyigbe EA, Brotherton H, Chellani H, Estifanos AS, et al. Preterm care during the COVID-19 pandemic: A comparative risk analysis of neonatal deaths averted by kangaroo mother care versus mortality due to SARS-CoV-2 infection. EClinicalMedicine. 2021:100733. Epub 2021/03/23. doi: 10.1016/j.eclinm.2021.100733 33748724; PubMed Central PMCID: PMC7955179. Thaddeus. Too far to walk: maternal mortality in context. 1994. Salyer SJ, Maeda J, Sembuche S, Kebede Y, Tshangela A, Moussif M, et al. The first and second waves of the COVID-19 pandemic in Africa: a cross-sectional study. The Lancet. 2021;397(10281):1265–75. doi: 10.1016/S0140-6736(21)00632-2 33773118 Semaan A, Audet C, Huysmans E, Afolabi B, Assarag B, Banke-Thomas A, et al. Voices from the frontline: findings from a thematic analysis of a rapid online global survey of maternal and newborn health professionals facing the COVID-19 pandemic. BMJ Glob Health. 2020;5(6). Epub 2020/06/27. doi: 10.1136/bmjgh-2020-002967 32586891; PubMed Central PMCID: PMC7335688. Continuity of essential health services: Facility assessment tool. A module from the suite of health service capacity assessments in the context of the COVID-19 pandemic. World Health Organization, 2020. 10.1371/journal.pone.0260006.r001 Decision Letter 0 Chen Robert Jeenchen Academic Editor 2021 Robert Jeenchen Chen This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

14 Jul 2021

PONE-D-21-20950

Outcomes in a Rural Ugandan Neonatal Unit Before and During the Early COVID-19 Pandemic: a Retrospective Cohort Study

PLOS ONE

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**********

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Reviewer #1: Title: Outcomes in a Rural Ugandan Neonatal Unit Before and During the Early COVID-19 Pandemic: a Retrospective Cohort Study (manuscript number: PONE-D-21-20950)

Review by Ermias Sisay Chanie /MSc in pediatrics and Child health Nursing)

Debre Tabor University, Debre Tabor, Ethiopia

Thanks for give an opportunity to plos one chief editors to reviewing this article. This research is important on reducing neonatal mortality and morbidity in worldwide in general and in study ara in particular, in the meantime it is one of the international concerns. African countries including Ugandan works to reduce the mortality of neonate through monitoring and evaluation the ‘’outcomes neonate in Neonatal Unit”.

Minor

1. General English: The review recommends the article be copyedited to improve language and grammar used

2. Check the table number frequency, percentage and p- value for each column

Major concern

Title

1. In my point of view the title better to modified based on your conclusion, since it focuses on the impact of COVID-19 in “maternal and newborn demand for, access to and quality of peripartum healthcare’’ etc.

2. Rural vs Neonatal Unit? I am not clear with it. I am not expected neonatal unit in rural area.

Introduction

1. In my view, better to focus on your objective, which mean the effect of COVID-19 on maternal health, or neonatal health or healthcare system in general

2. Try to show any attempting solution to reduce the burden of COVID-19 related to your objective in the study rea

3. The identified gaps before conducting the study? And the implication of the study to fill the appreciated gaps

Methods

1. Discuss about your study populations vs source population of the study participant clearly

2. your Inclusion criteria vs Exclusion criteria of the study participant clearly

3. Better to included data set in statical analysis and try to explore about descriptive statics that was used etc.…?

4. Adding about goodness of fit and model fitness?

Reviewer #2: Abstract is too long and should not exceed 300 words for The PLOS ONE. Please describe clearly the main objective of this study and summarize the most important results and their significance.

Introduction:

The overall aim of this study and whether that aim was achieved are missing.

Methods:

The role of the funding source should not be in the method section

The statistical analysis to compare the groups are missing or incorrect (proportion tests?)

Results:

Fig 1. It should clarify the term “outborn” and “inborn” in the legend

Table 2. the “+-“ should replace the points in all numbers. Same for the text across the manuscript

p-values should be added to the table. The statistical analysis should be described in the table.

Figure 2 legend should describe the sample size and the statistical analysis used. It should not repeat the results of the figure. It also should specify the term inborn and outborn.

**********

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Reviewer #1: No

Reviewer #2: No

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 10.1371/journal.pone.0260006.r002 Author response to Decision Letter 0 Submission Version 1

6 Oct 2021

Response to Reviewers

Reviewer #1:

Minor

1. General English: The review recommends the article be copyedited to improve language and grammar used

We appreciate this recommendation. Our goal is to be grammatically accurate. The English language/grammar use has been edited where appropriate. If the editors have further suggestions for optimizing grammar we are open to them.

2. Check the table number frequency, percentage and p- value for each column

These have been checked, please see discussion of p values in response to reviewer 2 below.

Major concern

Title

1. In my point of view the title better to modified based on your conclusion, since it focuses on the impact of COVID-19 in “maternal and newborn demand for, access to and quality of peripartum healthcare’’ etc.

The title has been modified to “Impact of the early COVID-19 Pandemic on Outcomes in a Rural Ugandan Neonatal Unit: a Retrospective Study”. Although we agree with the reviewer that the impact on “maternal and newborn demand for, access to and quality of peripartum healthcare” is important we did not have any direct measures of this so do not feel comfortable including it in the title.

2. Rural vs Neonatal Unit? I am not clear with it. I am not expected neonatal unit in rural area.

As the reviewer notes, it is unusual, however Kiwoko hospital is a secondary neonatal unit in a rural area. Due to its clinical reputation, it has become a referral unit for three districts in central Uganda.

Introduction

1. In my view, better to focus on your objective, which mean the effect of COVID-19 on maternal health, or neonatal health or healthcare system in general

The introduction text has been updated to focus on the effect on maternal/neonatal health and the healthcare system in general:

“An early survey by the WHO reported 80% of countries had disruptions to essential health services and these were exacerbated in lower income countries. Little has been published, however, on low resource facility based neonatal outcomes from low resource facilities during the COVID-19 pandemic, nor describing experiences of peripartum care availability.“

2. Try to show any attempting solution to reduce the burden of COVID-19 related to your objective in the study rea

We added to the introduction: “During the early COVID-19 pandemic, this facility was able to obtain personal protective equipment for staff and maintain neonatal care but peripartum mothers had difficulty traveling to the facility due to lockdown.”

3. The identified gaps before conducting the study? And the implication of the study to fill the appreciated gaps

We added “Pandemic control measures affecting access to newborn care remain highly dynamic and no country-level data of neonatal survival during this period are available.”

Methods

1. Discuss about your study populations vs source population of the study participant clearly

We added “Study Population- Included in this study are patients admitted to the Kiwoko Hospital (KH) neonatal unit during the period of study. There were no exclusion criteria.” The “setting” section goes on to describe the type patients admitted to this unit and the typical provision of care in the unit.

2. your Inclusion criteria vs Exclusion criteria of the study participant clearly

See added text in response to #1 above re: inclusion/exclusion criteria.

3. Better to included data set in statical analysis and try to explore about descriptive statics that was used etc.…?

The dataset is now uploaded in accordance with journal requirements. We agree with the reviewer and focused on descriptive statistics in this report. If further suggestions can be considered, please clarify these.

4. Adding about goodness of fit and model fitness?

We did not use a model in this analysis.

Reviewer #2:

Abstract is too long and should not exceed 300 words for The PLOS ONE. Please describe clearly the main objective of this study and summarize the most important results and their significance.

Thank you for this guidance. The abstract is now < 300 words. It has been revised to better describe the objective and most important results and their significance.

Introduction:

The overall aim of this study and whether that aim was achieved are missing.

The introduction has been revised to better describe the aim:

“The aim of this study is to describe this facility’s experience with providing peripartum care during the pandemic by utilizing this longitudinal dataset to explore changes to facility-based neonatal outcomes before and during the early phase of the COVID-19 pandemic.”

Methods:

The role of the funding source should not be in the method section

It has been removed.

The statistical analysis to compare the groups are missing or incorrect (proportion tests?)

As suggested by the reviewer, we used a proportion test to compare the groups. This is described in the methods:

“Statistical analysis

The mortality rate pre and during the early COVID-19 period was computed as a proportion of infants who died to the total number of infants admitted to the unit in the same period. To determine the potential impact of the COVID-19 pandemic on neonatal mortality in the unit, we computed the relative change in mortality rate between two time periods of the same months for the 2 sequential years. Proportion tests were used to compare the rates between two time periods of the same months. “

Results:

Fig 1. It should clarify the term “outborn” and “inborn” in the legend

The figure legend has been updated with:

“Outborn” refers to patients born outside KH. “Inborn” includes those born at KH.”

Table 2. the “+-“ should replace the points in all numbers. Same for the text across the manuscript

p-values should be added to the table. The statistical analysis should be described in the table.

- The decimal points have been revised throughout the tables and manuscript

- We appreciate the comment and have discussed among our authors but respectfully disagree with the style of including p values in table 2 which describes demographic characteristics in the two time periods. P values may be misleading in comparing groups from two different periods given the seasonal nature of neonatal mortality and would be at risk of type 2 errors.

If the editorial team feels a formal comparison of the demographics is important to our manuscript, we would ask to change this table to a comparison of seasonally matched periods (ie comparing April to September 2020 with April to September 2019). However, we feel the most important data to show is immediately prior to the COVID-19 pandemic. Formal appropriate comparisons of mortality adjusting for seasonal trends are later in the manuscript.

Figure 2 legend should describe the sample size and the statistical analysis used. It should not repeat the results of the figure. It also should specify the term inborn and outborn.

- FIgure 2 legend now:

- no longer repeats the results of the figure

- includes “1,234 patients were outborn (born outside Kiwoko hospital) and 1,260 born at Kiwoko (inborn) during the periods of study.“

- includes “Excess mortality is the amount of mortality seen above what would be expected for trend, calculated as the relative difference between periods divided by mortality in the reference period.”

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.

This has been done.

Submitted filename: 21.docx

 10.1371/journal.pone.0260006.r003 Decision Letter 1 Chen Robert Jeenchen Academic Editor 2021 Robert Jeenchen Chen This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

2 Nov 2021

Impact of the Early COVID-19 Pandemic on Outcomes in a Rural Ugandan Neonatal Unit: a Retrospective Cohort Study

PONE-D-21-20950R1

Dear Dr. Hedstrom,

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.

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Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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 10.1371/journal.pone.0260006.r004 Acceptance letter Chen Robert Jeenchen Academic Editor 2021 Robert Jeenchen Chen This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

4 Nov 2021

PONE-D-21-20950R1

Impact of the early COVID-19 Pandemic on Outcomes in a Rural Ugandan Neonatal Unit: a Retrospective Cohort Study

Dear Dr. Hedstrom:

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.

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on behalf of

Dr. Robert Jeenchen Chen

Academic Editor

PLOS ONE