Maternal and Perinatal Outcomes Associated with Maternal HIV Infection at Nelson Mandela Academic Hospital, Eastern Cape Province, South Africa

1. Introduction

Human Immunodeficiency Virus (HIV) remains a major global public health challenge, with sub-Saharan Africa bearing a disproportionate burden of the epidemic. South Africa has one of the largest HIV epidemics worldwide, with an estimated 7.8 million people living with HIV in 2022 [1]. Despite substantial progress in HIV prevention and treatment, the disease continues to disproportionately affect women of reproductive age, posing significant risks to both maternal and child health. Within South Africa, the Eastern Cape Province has one of the highest antenatal HIV prevalence rates, second only to KwaZulu-Natal [2]. Nelson Mandela Academic Hospital, a tertiary referral hospital in the province, serves predominantly rural and socioeconomically disadvantaged populations, where access to quality healthcare services may be limited. This context highlights the importance of understanding the implications of maternal HIV infection during pregnancy in resource-constrained settings, particularly given that the Eastern Cape has an HIV prevalence of 32.0% among pregnant women and that maternal HIV infection is independently associated with adverse pregnancy outcomes [3]. The scale-up of antiretroviral therapy (ART) and the implementation of prevention of mother-to-child transmission (PMTCT) programmes have significantly improved maternal and child health outcomes. Without intervention, mother-to-child transmission (MTCT) rates range from 15% to 45%; however, in South Africa, widespread ART coverage has reduced transmission rates to below 3.5% [4]. These gains have been reinforced by World Health Organization (WHO) recommendations advocating universal ART initiation for all pregnant women living with HIV [5]. While these interventions have markedly reduced vertical transmission and improved maternal survival, maternal HIV infection remains associated with an increased risk of adverse maternal and perinatal outcomes. Evidence indicates that women living with HIV are at higher risk of complications such as preterm birth, low birth weight (LBW), and stillbirths [6,7,8]. A systematic review of Sub-Saharan African studies found that women living with HIV had significantly higher odds of LBW (AOR 9.68, 95% CI 6.72-12.64) and preterm delivery (AOR 1.72, 95% CI 1.49-1.95) compared to HIV-negative women [6]. In South Africa’s Eastern Cape province, a study of 1,709 pregnant women living with HIV reported adverse outcome rates of 33.5% for preterm birth, 18.0% for LBW, and 1.4% for stillbirth [7]. Similarly, population-based surveillance in Eswatini found significantly elevated stillbirth rates among women living with HIV (2.6% vs 1.9%, p<0.001)[8]. These complications are major contributors to maternal and neonatal morbidity and mortality, particularly in low- and middle-income countries. Neonates born to HIV-positive mothers are also more likely to experience adverse outcomes, including prematurity, impaired fetal growth, and increased risk of neonatal death [9,10]. Although ART has improved outcomes, concerns remain regarding its potential association with certain pregnancy complications, particularly when initiated prior to conception or during early pregnancy [11,12]. The relationship between maternal HIV infection, ART exposure, and pregnancy outcomes is complex and multifactorial. HIV infection may compromise immune function, increase susceptibility to opportunistic infections, and contribute to chronic inflammation, all of which may negatively affect placental function and fetal development. In addition, socioeconomic factors, nutritional status, and access to antenatal care play important roles in determining pregnancy outcomes. While some studies suggest that effective ART mitigates HIV-related risks, others report persistent or increased risks of adverse outcomes, resulting in inconsistent findings across different populations and healthcare settings [13,14,15]. These inconsistencies underscore the need for context-specific research that reflects local health system dynamics and population characteristics. In the Eastern Cape Province, healthcare delivery is challenged by structural inequalities, including limited infrastructure, workforce shortages, and barriers to timely antenatal care. Delayed antenatal booking and suboptimal utilization of maternal health services remain common, particularly among vulnerable populations [16,17]. These factors may reduce the effectiveness of PMTCT programmes and contribute to poorer maternal and neonatal outcomes. Despite the high HIV burden in this region, there is limited evidence on maternal and perinatal outcomes in the context of widespread ART use [18]. Therefore, this study aimed to evaluate the impact of maternal HIV infection on maternal and perinatal outcomes in the era of widespread ART use at a tertiary hospital in the Eastern Cape Province, South Africa. By generating locally relevant evidence, this study seeks to inform strategies to strengthen PMTCT programmes, improve the integration of HIV and antenatal care services, and ultimately enhance maternal and neonatal health outcomes in high-burden settings.

2. Methods

2.1. Study Design and Setting

This study employed a retrospective case–control design to evaluate maternal and perinatal outcomes among women with and without Human Immunodeficiency Virus (HIV) infection. A case–control approach was considered appropriate for this study as it allows for efficient comparison of outcomes between exposed (HIV-positive) and unexposed (HIV-negative) groups using existing clinical data, particularly in a high-burden setting where prospective follow-up may be resource-intensive.

The study was conducted at Nelson Mandela Academic Hospital, a tertiary referral hospital located in the O.R Tambo District Municipality of the Eastern Cape Province, South Africa. The hospital serves as a major referral centre for the surrounding district and regional hospitals and provides specialized obstetric, neonatal, and HIV care services. It manages a high volume of deliveries annually, including a substantial proportion of high-risk pregnancies, making it an appropriate setting for investigating maternal and perinatal outcomes associated with HIV infection. The hospital’s catchment area is predominantly rural, with communities characterized by high poverty and unemployment and limited access to healthcare services. These socioeconomic and structural factors may influence maternal health-seeking behaviour, timing of antenatal care initiation, and overall pregnancy outcomes. Antenatal care services in the region are primarily delivered through a network of primary healthcare clinics, with referrals made to the tertiary facility for complicated or high-risk cases. During the study period (1 January to 31 December 2019), national guidelines for the management of HIV in pregnancy were aligned with the World Health Organization (WHO) recommendations, which advocate for universal lifelong antiretroviral therapy (ART) for all pregnant and breastfeeding women living with HIV, regardless of CD4 count or clinical stage. Standard antenatal care protocols included routine HIV testing, viral load monitoring, and provision of prevention of mother-to-child transmission (PMTCT) interventions. These guidelines ensured a relatively uniform standard of HIV care across the study population, allowing for assessment of outcomes in the context of widespread ART availability. The choice of the 2019 study period was intentional, as it reflects a mature phase of ART program implementation in South Africa, characterized by high ART coverage and well-established PMTCT services. This allows for the evaluation of maternal and perinatal outcomes in the contemporary era of widespread ART use, rather than during earlier phases of program rollout. The extent and pattern of missing data were assessed. Variables with missing data were analysed using complete-case analysis, and sensitivity analyses were conducted to evaluate potential bias.

2.2. Study Population and Data Source

The study population comprised all women who delivered at Nelson Mandela Academic Hospital between 1 January and 31 December 2019. From this population, a total of 600 patient records were included in the analysis, consisting of 300 HIV-positive women (cases) and 300 HIV-negative women (controls). The sample size was determined to provide sufficient statistical power to detect differences in maternal and neonatal outcomes between the two groups, while maintaining feasibility within the available data. Eligible participants were parturient women with a confirmed HIV status documented in antenatal or delivery records, as well as complete information on key maternal and neonatal outcomes. HIV status was routinely determined through standard antenatal HIV testing protocols in accordance with national guidelines, which include provider-initiated counseling and testing. Women with undocumented HIV status, uncertain test results, or missing delivery outcome data were excluded to ensure data reliability and internal validity. A case–control sampling approach was applied, whereby HIV-positive women were identified as cases and HIV-negative women as controls. Controls were selected from the same delivery population during the study period to ensure comparability and reduce selection bias. Where possible, controls were selected using systematic sampling methods from delivery registers to minimize sampling bias and ensure representation of the underlying population. Data were obtained from routinely collected clinical records, including maternity case files, antenatal clinic cards, and labour ward registers. These data sources are part of standardized clinical documentation used in routine obstetric care and include detailed information on maternal demographics, antenatal care, clinical conditions, and delivery outcomes. To enhance data quality, records were cross-checked across multiple sources where available (e.g., antenatal cards and delivery registers) to verify consistency and completeness of key variables. Data extraction was conducted using a structured and pre-tested data abstraction tool specifically developed for this study. The tool was designed to ensure uniform data collection and included predefined variable definitions to minimize misclassification. Data collectors were trained on the use of the tool and the interpretation of clinical records to ensure consistency. In addition, periodic checks were performed during data collection to identify and resolve discrepancies. Given the retrospective nature of the study, certain limitations related to missing or incomplete data were anticipated. To address this, only records with complete information on primary exposure (HIV status) and key outcome variables were included in the final analysis. The potential impact of missing data was considered during analysis and interpretation of results.

2.3. Data Collection

Data were extracted using a structured, pre-tested data abstraction tool specifically developed for this study to ensure standardized and consistent data capture. The tool was designed based on study objectives and existing literature, and included clearly defined variable categories to minimize misclassification and enhance reproducibility. Data collected encompassed four main domains: maternal demographic characteristics, obstetric history, clinical parameters, and neonatal outcomes. Maternal variables included age, parity, and antenatal booking status (categorized as early booking ≤20 weeks’ gestation or late booking >20 weeks). Clinical variables included antenatal complications (e.g., anaemia and hypertensive disorders of pregnancy), timing of antiretroviral therapy (ART) initiation (pre-pregnancy or during pregnancy), CD4 cell count, and maternal viral load, where available. Obstetric variables included gestational age at delivery (determined based on last menstrual period and/or ultrasound where recorded) and mode of delivery (vaginal or caesarean section). Neonatal variables included birth weight, Apgar scores at 1 and 5 min, and admission to the neonatal intensive care unit (NICU). Low birth weight was defined as <2500 g, and preterm birth as delivery before 37 completed weeks of gestation. To ensure data accuracy and completeness, information was cross-verified across multiple sources, including maternity case records, antenatal clinic cards, and labour ward registers. Data collectors received training on using the abstraction tool and on standard definitions of variables. Routine data quality checks were conducted throughout data collection to identify inconsistencies and resolve discrepancies.

2.4. Statistical Analysis

Data were entered into Microsoft Excel and analysed using IBM SPSS Statistics version 27 (IBM Corp., Armonk, NY, USA). Prior to analysis, data were cleaned and checked for completeness, consistency, and outliers. Descriptive statistics were used to summarize participant characteristics. Categorical variables were presented as frequencies and percentages, while continuous variables were assessed for normality and summarized as means ± standard deviation (SD) or medians with interquartile ranges (IQRs), as appropriate. Comparisons between HIV-positive and HIV-negative groups were performed using the Chi-square test or Fisher’s exact test for categorical variables, and the independent samples t-test or Mann–Whitney U test for continuous variables, depending on data distribution. Multivariate logistic regression analysis was conducted to identify independent predictors of adverse maternal and neonatal outcomes. Variables with p < 0.20 in univariate analysis, as well as clinically relevant covariates, were included in the multivariable models to control for potential confounding. Model fit was assessed using appropriate goodness-of-fit tests (e.g., Hosmer–Lemeshow test), and multicollinearity was evaluated using variance inflation factors (VIFs). Results were reported as adjusted odds ratios (AORs) with 95% confidence intervals (CIs). Neonatal survival analysis was performed using Cox proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% CIs. The proportional hazards assumption was assessed using graphical methods and statistical tests. Time-to-event was defined as the duration from birth to neonatal death or to censoring at discharge or at the end of follow-up. Missing data were assessed and handled using complete case analysis, given the retrospective design. Sensitivity analyses were considered where appropriate to evaluate the potential impact of missing data on study findings. All statistical tests were two-sided, and p-values < 0.05 were considered statistically significant. Variables included in multivariable models were selected based on clinical relevance and statistical significance (p < 0.20) in univariate analysis.

3.1. Maternal Demographic Characteristics

A total of 600 maternity records were analyzed, comprising 300 HIV-positive women and 300 HIV-negative controls. HIV-positive women were significantly older than HIV-negative women (mean age 34 ± 6 vs. 30 ± 4 years; p < 0.001). Significant differences in age distribution were observed between the groups. A higher proportion of HIV-positive women were aged >35 years (41.0% vs. 19.3%), while younger age groups, particularly those <20 years, were more represented among HIV-negative women (19.3% vs. 1.3%) (p < 0.001). Parity also differed significantly by HIV status (p < 0.001). Nulliparity was more common among HIV-negative women (38.6% vs. 20.6%), whereas higher parity (≥3) was more frequent among HIV-positive women (25.0% vs. 16.3%). Overall, HIV-positive women tended to be older and of higher parity compared to HIV-negative women (Table 1).

3.2. Maternal Clinical Characteristics

HIV-positive women had a significantly higher prevalence of hypertensive disorders of pregnancy (66.0% vs. 49.7%; χ² = 14.86, p = 0.005). Anaemia was also more common among HIV-positive women (38.0% vs. 23.0%). In contrast, a history of previous caesarean section (1–3) was more frequent among HIV-negative women (31.7% vs. 20.0%), as was diabetes mellitus (16.0% vs. 10.0%). Other maternal infections were uncommon in both groups, with minimal differences observed. Antenatal care (ANC) utilization differed between groups, with poorer attendance among HIV-positive women. Notably, 34.7% of HIV-positive women-initiated ANC after 20 weeks’ gestation, indicating delayed engagement with maternal health services. Overall, HIV-positive status was associated with a higher burden of key maternal complications and suboptimal antenatal care utilization (Table 2).

3.3. Neonatal Outcomes

Neonates born to HIV-positive mothers had poorer outcomes compared to those born to HIV-negative mothers. Mean birth weight was lower among HIV-exposed infants (2.74 ± 0.61 kg vs. 2.92 ± 0.55 kg), and mean gestational age at delivery was shorter (36.1 vs. 37.5 weeks). Adverse neonatal outcomes were significantly more frequent among HIV-exposed infants, including preterm birth (26.3% vs. 20.3%; χ² = 4.02, p = 0.045), low Apgar scores at 5 min (14.5% vs. 9.2%; χ² = 4.62, p = 0.032), and stillbirths (χ² = 3.91, p = 0.048). Neonatal anaemia was also significantly more prevalent among infants born to HIV-positive mothers (χ² = 16.47, p < 0.001). There was no statistically significant difference in neonatal mortality between the groups (p = 0.66). Overall, maternal HIV infection was associated with an increased risk of adverse neonatal outcomes, particularly preterm birth, low Apgar scores, and stillbirth (Table 3).

3.4. Effect of ART Timing on Birth Outcomes

Among HIV-positive mothers, initiation of antiretroviral therapy (ART) during pregnancy was associated with a slightly higher mean birth weight compared to pre-pregnancy ART initiation (2512 ± 340 g vs. 2415 ± 385 g). However, this difference did not reach statistical significance (F = 2.87, p = 0.060) (Table 4).

3.5. Predictors of Adverse Maternal Outcomes

Multivariate logistic regression analysis showed that HIV-positive status was associated with significantly lower odds of antenatal complications (adjusted odds ratio (AOR) = 0.35, 95% CI: 0.22–0.55; p < 0.001). In contrast, pre-pregnancy ART initiation was independently associated with increased odds of antenatal complications (AOR = 1.68, 95% CI: 1.02–2.76; p = 0.041).

Unsuppressed viral load showed a non-significant trend toward increased risk (AOR = 1.94, 95% CI: 0.91–4.12; p = 0.085), while maternal age >35 years was not significantly associated with antenatal complications (p = 0.127) (Table 5).

3.6. Predictors of Low Birth Weight

HIV-positive status was an independent predictor of low birth weight (AOR = 1.88, 95% CI: 1.18–3.00; p = 0.008). Maternal age, pre-pregnancy ART initiation, and unsuppressed viral load were not significantly associated with low birth weight after adjustment (all p > 0.05) (Table 6).

3.7. Predictors of Neonatal ICU Admission

Low birth weight was the strongest predictor of neonatal ICU admission (AOR = 2.45, 95% CI: 1.46–4.11; p < 0.001). Neither HIV status nor pre-pregnancy ART initiation was independently associated with ICU admission after adjustment (p > 0.05 for both) (Table 7).

3.8. Neonatal Survival Analysis

Cox proportional hazards analysis demonstrated that HIV-positive status was associated with a significantly increased hazard of neonatal death (hazard ratio (HR) = 1.75, 95% CI: 1.12–2.71; p = 0.015).

Low birth weight was the strongest predictor of neonatal mortality, more than doubling the risk (HR = 2.40, 95% CI: 1.55–3.70; p < 0.001). Unsuppressed maternal viral load was also significantly associated with increased neonatal mortality (HR = 2.05, 95% CI: 1.13–3.73; p = 0.018). Pre-pregnancy ART initiation was not significantly associated with neonatal mortality (HR = 1.38; p = 0.172) (Table 8).

3.9. Kaplan–Meier Survival Analysis

Kaplan–Meier survival analysis demonstrated lower neonatal survival among infants born to HIV-positive mothers compared to those born to HIV-negative mothers. Survival curves diverged within the first week of life, indicating that most neonatal deaths occurred early in the postnatal period. By day 10, survival probability remained higher among HIV-negative infants (~98%) compared to HIV-exposed infants (~93%) (Figure 1).

4. Discussion

This study evaluated maternal and perinatal outcomes associated with maternal HIV infection in a high-prevalence setting at Nelson Mandela Academic Hospital, Eastern Cape, South Africa. The findings demonstrate that maternal HIV infection remains significantly associated with adverse maternal and neonatal outcomes despite the widespread availability of antiretroviral therapy (ART). These results highlight persistent disparities in maternal and neonatal health outcomes in the era of universal ART, particularly in resource-limited settings. The demographic profile of the study population showed that HIV-positive women were older and had higher parity compared to HIV-negative women. This is consistent with national epidemiological patterns indicating a higher HIV burden among older women [19,20,21,22]. Increased parity among HIV-positive women may reflect improved survival associated with long-term ART use, allowing extended reproductive lifespan, as well as potential differences in fertility patterns. These findings underscore the evolving demographic profile of women living with HIV in the ART era. In terms of maternal clinical outcomes, HIV-positive women had a higher prevalence of anaemia and hypertensive disorders of pregnancy. The elevated rate of anaemia (38%) is consistent with previous studies linking HIV infection to impaired haematological status, driven by chronic inflammation, ART-related effects, and nutritional deficiencies [23,24]. The increased prevalence of hypertensive disorders may reflect complex interactions between HIV-related immune dysregulation, endothelial dysfunction, and ART exposure. However, the observed lower adjusted odds of antenatal complications among HIV-positive women in multivariable analysis suggest a more nuanced relationship. This finding may be explained by increased clinical surveillance and more frequent healthcare contact among HIV-positive women engaged in ART programs, leading to earlier detection and management of complications. Antenatal care (ANC) utilization was suboptimal among HIV-positive women, with a substantial proportion initiating care late. Delayed ANC booking is a well-established determinant of adverse pregnancy outcomes, as it limits the timely initiation of ART and early identification of obstetric complications [25,26].

These findings highlight persistent structural and systemic barriers to care, including healthcare access challenges, socioeconomic constraints, and potential stigma associated with HIV. Strengthening integrated HIV–maternal health services and promoting early ANC engagement remain critical priorities. Neonatal outcomes were significantly worse among infants born to HIV-positive mothers, including lower birth weight, shorter gestational age, and higher rates of preterm birth, low Apgar scores, and stillbirth. These findings are consistent with both regional and global literature demonstrating the adverse impact of maternal HIV infection on fetal growth and development [27,28]. The underlying mechanisms are likely multifactorial, including placental insufficiency, chronic maternal inflammation, and impaired nutrient transfer. Importantly, low birth weight emerged as a key determinant of neonatal outcomes, independently predicting both neonatal ICU admission and mortality. This reinforces existing evidence that low birth weight is a critical marker of neonatal vulnerability, regardless of HIV exposure [29]. The survival analysis further demonstrated that HIV-positive status, low birth weight, and unsuppressed maternal viral load were significant predictors of neonatal mortality. Infants born to mothers with unsuppressed viral loads had more than double the risk of death, underscoring the critical importance of achieving and maintaining viral suppression during pregnancy [30,31]. Although the rate of vertical transmission was low (1.7%), reflecting the effectiveness of PMTCT programmes, gaps in viral load monitoring and treatment adherence remain key challenges that may contribute to adverse outcomes beyond transmission. The relationship between ART and pregnancy outcomes remains complex and warrants careful interpretation. While antenatal ART initiation was associated with modest improvements in birth weight, pre-pregnancy ART initiation was associated with increased odds of antenatal complications. This paradoxical finding may reflect confounding by indication, where women initiating ART prior to pregnancy may have more advanced HIV disease or longer cumulative exposure to treatment. Additionally, biological mechanisms such as immune reconstitution inflammatory syndrome (IRIS) and ART-related endothelial effects may contribute to adverse outcomes [32,33]. Despite these complexities, early and sustained ART remains the cornerstone of PMTCT strategies, and its benefits in reducing maternal morbidity and preventing vertical transmission clearly outweigh potential risks [34,35]. From a public health perspective, these findings emphasize the need for strengthened integration of HIV and maternal health services, improved access to early antenatal care, and enhanced monitoring of maternal health during pregnancy. Addressing these gaps is essential to achieving optimal maternal and neonatal outcomes in high HIV-burden settings.

4.1. Strengths and Limitations

This study has several strengths, including a relatively large sample size and the inclusion of both maternal and neonatal outcomes, allowing for a comprehensive assessment of HIV-related pregnancy outcomes in a high-burden setting. The use of multivariate regression and survival analysis enhances the robustness of the findings. However, several limitations should be considered. Missing viral load data (22.3%) and incomplete infant HIV testing limited the ability to fully evaluate PMTCT effectiveness. The retrospective design introduces the potential for information and documentation bias and precludes causal inference. Additionally, residual confounding may persist despite statistical adjustment. These limitations should be considered when interpreting the findings.

4.2. Recommendations

Based on these findings, several clinical and public health interventions are recommended. Strengthening the integration of HIV and antenatal care services is essential to ensure early ART initiation, routine viral load monitoring, and continuity of care. Community-based interventions and health education strategies should be prioritized to promote early ANC booking, particularly among high-risk populations. Enhanced screening and management of anaemia and hypertensive disorders in HIV-positive pregnant women are also needed. Expanding access to neonatal care services, particularly for preterm and low-birth-weight infants, may improve neonatal outcomes. Furthermore, prospective longitudinal studies are warranted to better understand the long-term safety and effects of ART exposure during pregnancy.

5. Conclusions

Maternal HIV infection remains a significant risk factor for adverse maternal and neonatal outcomes, despite substantial progress achieved through ART programmes. This study highlights important associations between HIV infection and anaemia, preterm birth, low birth weight, and increased neonatal mortality. Improving maternal and neonatal outcomes requires early ART initiation, sustained viral suppression, and strengthened integration of HIV and antenatal care services. Addressing these factors is critical for optimizing health outcomes in high HIV-burden, resource-limited settings.