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Abstract
Objectives To estimate the effect of HIV infection on the risk of preterm birth (PTB) and low birth weight (LBW) among Chinese pregnancy women.
Design A retrospective cohort study included HIV-positive pregnant women who gave birth to singletons in Chengdu between 2011 and 2020 and and HIV-negative pregnant women who delivered singletons at the Chengdu Women’s and Children’s Central Hospital in 2020.
Setting Data of pregnant women living with HIV were extracted from China’s Information System of Prevention of Mother-to-Child Transmission of HIV Management. Additionally, information for HIV-negative pregnant women was extracted from the electronic medical record system of the Chengdu Women’s and Children’s Central Hospital.
Participants 755 HIV-positive women and 15,094 HIV-negative pregnant women were included.
Primary outcome measures PTB and LBW rates, which were defined by gestational weeks and birth weight.
Results The incidences of PTB and LBW (13.51% and 14.17%, respectively) were significantly higher in the HIV-positive group compared with the HIV-negative group (6.82% and 4.65%). Propensity score matching was performed to improve comparability of the two groups, resulting in 1590 pregnancies with 558 HIV-positive and 1032 HIV-negative women in the final analysis. Conditional logistic regression was used to estimate the effect of maternal HIV status on adverse pregnancy outcomes. After propensity score matching and controlling the potential confounders, HIV infection was strongly associated with higher chances of LBW and PTB with adjusted odd ratios (95% confidence interval) of 2.53 (1.74 to 3.68) and 1.95 (1.33 to 2.85), respectively.
Conclusions HIV infection was significantly associated with increased risks of PTB and LBW in Chinese pregnant women. Future studies should focus on investigating the mechanisms underlying the association between HIV infection and adverse birth outcomes, and on identifying strategies to reduce the incidence of PTB and LBW in pregnant women living with HIV.
- Epidemiology
- EPIDEMIOLOGIC STUDIES
- HIV & AIDS
- Maternal medicine
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The use of propensity score matching to improve comparability of the HIV-positive and HIV-negative groups increases the validity of the results.
This study is the first to investigate the association between maternal HIV infection and adverse birth outcomes in a Chinese population, providing important evidence for policymakers and healthcare providers.
The large sample size and use of electronic health records from a major hospital in Chengdu increase the generalisability of the findings to other similar settings.
The study was limited by its retrospective cohort design, which precludes establishing a causal relationship between HIV infection and adverse birth outcomes.
Although the study controlled for several potential confounders, there may be unmeasured confounding factors that could have affected the results.
Introduction
Although the lives of the HIV-infected population are prolonged tremendously due to highly active antiretroviral therapy (ART), HIV infection remains a critical public health issue globally.1 It was reported that 36.8 million people were living with HIV worldwide in 2019, and the number of cases are still incessantly rising.2 An estimated 1.4 million HIV-infected pregnant women give birth each year. Fortunately, the use of ART during pregnancy and breast feeding has dramatically reduced the risk of vertical transmission of HIV3 offering hope for the effective elimination of new infant and child HIV infections. Between 2010 and 2020, the proportion of HIV-infected pregnant women receiving ART to prevent mother-to-child transmission (PMTCT) increased from 45% to 85%, resulting in a 54% reduction in new HIV infections among children during that period.4 In China, the vertical transmission rate declined from 7.4% to 3.6% between 2011 and 2020, as almost every pregnant woman has been covered by the national PMTCT programme over the past 10 years.5
The positive impact of PMTCT on reducing vertical transmission of HIV is widely acknowledged. However, the association between maternal HIV status, ART during pregnancy and pregnancy outcomes remains unclear and inconsistent across studies.6–10 Preterm delivery (PTD) and low birth weight (LBW) are the major adverse pregnancy outcomes (APOs) and are associated with a range of factors, including maternal age, nutrition and socioeconomic status. However, HIV infection during pregnancy may increase the risk of these adverse outcomes, particularly if the mother does not receive ART to PMTCT.6 Neonates with PTD and LBW suffer higher risks of perinatal morbidity and mortality and may at higher risk of poor neurodevelopmental and cardiometabolic outcomes across the life course.11 12 The findings of several previous studies indicated that maternal HIV infection could increase the risk of multiple adverse birth outcomes, incorporating preterm birth (PTB) and LBW.7–9 However, other studies10 documented no significant association, the increased risk of APOs in pregnant women living with HIV may be affected by poor socioeconomic status (older age, food insecurity and lower education level), pre-existing illnesses like anaemia and syphilis and other risk factors make HIV-exposed women more predisposed to APOs.13 Despite the potential impact on public health, few studies have definitively assessed the relationship between HIV infection and APOs in the Asian-Pacific region.
In China, studies have evaluated the prevalence of APOs in HIV-infected women, but none has investigated the relationship between them, especially in cohort studies. Therefore, it has not been thoroughly determined whether maternal HIV infection raises the risk of APOs in Chinese pregnant women.14 15 To address the research gaps, we conducted a retrospective cohort study among pregnant women from Chengdu City, China. Chengdu is a large city in Southwest China with 20.9 million residents,16 and the number of HIV/AIDS patients in Chengdu ranks first among all provincial capitals in China.17 Our aim was to assess the association between HIV infection and APOs, by compare the risk of APOs between HIV-infected pregnant women and a similar group of pregnancies who were not infected with HIV.
Materials and methods
Study design and data source
This retrospective cohort study compared the risks of PTB and LBW in pregnant women living with HIV to those of HIV-negative women. All pregnant women diagnosed with HIV before or during pregnancy and gaving birth to a live singleton infant between January 2011 and December 2020 in Chengdu were included in our study. Data on HIV-infected pregnancies were documented in China’s Information System of Prevention of Mother-to-Child Transmission (IPMTCT) of HIV Management, which is a nationwide, health facility-based case report system used to monitor and evaluate the effect of MTCT. The system involves all 31 provinces, municipalities and autonomous regions in China. Pregnant women living with HIV meeting the diagnostic criteria must be registered in the system and followed up through pregnancy and postpartum.
To form the control group, we obtained data on a group of HIV-negative pregnant women who delivered a singleton live birth between January and December 2020 at the Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology from the hospital’s electronic medical record system. This institution is a tertiary university-affiliated hospital with approximately 18 000 deliveries per year, accounting for nearly 10% of Chengdu city’s deliveries and provided healthcare and medical treatment for this region’s obstetrical population. A total of 15 437 HIV-negative pregnant women who gave birth to singleton infants in 2020 were identified from the information system, of whom 137 had incomplete occupational information, 32 had incomplete educational information and 175 had incomplete pregnancy information and were excluded from the analysis. Finally, 15 094 individuals were included in the study (online supplemental figure 1).
Supplemental material
The Medical Research Project of Chengdu Health Commission, grant number 2022076, provided funding for this investigation. The authors declare no known competing financial interests or personal relationships that could have influenced to influence the work reported in this paper. As our study did not involve direct patient recruitment, we were unable to obtain informed consent from patients directly.
Patient and public involvement
Patient and public involvement were not included in this study, as it is a retrospective cohort study that did not involve direct participation or input from patients or the public.
Exposure identification
Maternal HIV infection status was determined through a two-step process involving antibody testing and supplemental confirm testing. In accordance with China’s PMTCT protocols, all pregnant women with unknown HIV status initially undergo antibody screening tests at their first antenatal care (ANC) attendance, which include immunochromatography, immunofiltration, ELISA, chemiluminescence immunoassay and antibody–antigen combination detection assays. If the maternal antibody screening test was positive, supplementary tests are employed, including antibody confirmation test and nucleic acid test.
Covariates
Demographics involved maternal age, ethnicity (Han and minority), education (primary school or below, high school, university and above), marital status (married and unmarried), gravidity (nulligravid, 1–3 or above three times), parity (nulliparous or multiparous), first attend ANC occurred in the first trimester (yes or no), residential address (Chengdu or other regions), occupation (employed or unemployed).
Clinical characteristics and pregnancy outcome, including delivery mode (eutocia and caesarean), maternal syphilis status, anaemia, gestational hypertension, gestational diabetes, cardiac disease, liver disease, date of delivery, gestational weeks, neonatal gender and birth weight, were extracted from the hospital electronic registration system or IPMTCT of HIV Management.
Outcome
The primary outcomes of interest in this study were PTB and LBW. PTB was defined as a birth of an infant less than 37 gestational weeks. LBW was defined as birth weight <2500 g. The newborn’s weight in grams was measured within 1 hour from delivery using a calibrated electronic scale accurate to ±10 g when the baby was undressed. A binary outcome LBW was constructed by coded as ‘yes’ if birth weight <2500 g or ‘no’ otherwise.
Statistical analysis
To describe the data, frequency (n) and percentage (%) were used for categorical variables, and the mean and SD, or median and range were appropriately used for continuous variables.
We compared the baseline characteristics between pregnant women living with HIV and those without HIV using appropriate statistical tests. For categorical variables, we used either Person’s χ2 test or Fisher’s exact probability test, as appropriate. For continuous variables, we used either Student’s t-test or the Mann-Whitney U-test, depending on the distribution of the data. Given the heterogeneity in baseline characteristics, we used 1:2 propensity score (PS) matching (PSM) to control for baseline variables between pregnancies with and without HIV infection. Binary logistic regression was applied to calculate individual PSs with maternal HIV status as the model’s dependent variable. Independent variables included in the model were infant gender, maternal age, gravidity, parity, race, education, residential address, occupation, first prenatal visit time and marital status. We performed PS matching utilising the nearest neighbour matching algorithm without replacement with a maximum calibre of 0.1. Standard mean differences before and after matching were used to measure whether the performed matching worked, and a standardised mean difference plot indicated bias reduction after matching was processed.
After performing PS matching, we used paired t-tests to assess differences in continuous variables and McNemar’s tests for categorical variables in the matched data. Furthermore, we fitted conditional logistic regression to determine the potential factors associated with APOs. The regression models were adjusted for exposure factor of HIV status and all covariates, which presented significant relationships with PTB or LBW in the univariate analysis.
Additionally, we conducted two sensitivity analyses in our study to evaluate the robustness of our results. The first analysis included the delivery year as a variable in the fully adjusted model, and the second analysis involved PS matching using kernel matching.
Analyses were performed with Stata/SE V.17.0 (Stata Corporation, College Station, Texas) and R software (V.4.2.0, R Foundation for Statistical Computing). A two-tailed p value<0.05 was considered statistically significant.
Results
Study population
The cohort study included 755 pregnant women living with HIV who delivered live singletons between 2011 and 2020 in the exposure group and 15094 HIV-negative pregnancies as the control group. Maternal demographic and clinical characteristics stratified by HIV infection status are shown in table 1 and table 2, respectively.
Baseline characteristics of the study population stratified by maternal HIV status before and after propensity score matching
Descriptive analysis of clinical characteristics of the study population stratified by maternal HIV status before and after propensity matching.
The incidences of PTB and LBW were 13.51% and 14.17%, respectively, in the HIV-positive group, which were significantly higher than those of the HIV-negative group (6.82% and 4.65%). The p values for all comparisons were less than 0.001, indicating a statistically significant difference in PTB and LBW rates between the HIV-positive and HIV-negative groups.
Compared with HIV-negative pregnant women, those living with HIV were younger with a mean age of 28.19 years versus 30.22 years in the control group (p<0.001), and a higher proportion were from minority ethnicity (19.47% vs 3.90%, p<0.001). A significantly higher proportion of HIV-infective women were unemployed (61.59% vs 18.60%, p<0.001), unmarried (19.60% vs 0.26%, p<0.001) and primiparous (51.66% vs 35.90%, p<0.001). Women with a history of three or more pregnancies made up a larger fraction of the HIV-positive population (50.07% vs 25.97%, p<0.001). The majority of pregnant women living with HIV had completed high school (61.19%), while most HIV-negative women (74.94%) reported college degree or higher as their highest educational level (p<0.001).
Pregnant women living with HIV tend to have higher frequencies of syphilis (4.11% vs 0.34%, p<0.001) and cardiac disease (0.66% vs 0.08%, p<0.001) compared with the control group . Women with HIV also have a higher caesarean delivery rate (67.02% vs 55.99%, p<0.001). In contrast, the prevalence of gestational hypertension (2.12% vs 4.30%, p=0.004) and gestational diabetes (6.23% vs 9.19%, p<0.001) were significantly lower in the HIV-positive group compared with the control group.
No significant difference in neonatal gender was found between the two groups (p=0.112).
Demographic and clinical characteristics of the matched groups
Finally, a total of 1590 pregnancies, including 558 HIV-positive and 1032 HIV-negative women, were obtained by matching the baseline characteristics according to the 1:2 PS. As shown in table 1, the baseline demographic characteristics of the two groups were well balanced with respect to matched factors. The distribution of the PSs is illustrated in online supplemental figure 2, while online supplemental figure 3 displays the standardised mean difference between variables before and after PS matching.
Supplemental material
Supplemental material
Although there was no significant difference between the HIV-positive and control groups in terms of cardiac disease after PSM (p=0.243), the prevalence of gestational diabetes (7.53% vs 11.24%, p=0.019), gestational hypertension (2.51% vs 6.59%, p<0.001), liver disease (4.30% vs 7.46%, p=0.003) and syphilis (3.76% vs 0.87%, p<0.001) remained significantly different, as shown in table 2. Among the matched samples, a total of 171 pregnant women gave birth before 37 gestational weeks, and the rates of PTB were 13.08% and 9.50% in the HIV-positive and control groups, respectively. Additionally, 147 pregnant women delivered LBW infants, HIV-positive mothers were more likely to give birth to LBW infants compared with the control group (13.80% vs 6.78%).
Risk factors for LBW
As illustrated in online supplemental table 1, the results of the univariate analysis indicated that several factors may be the potential influent factors of LBW including maternal HIV status, area of residence and gestational hypertension. In the multivariate logistic regression analysis, three variables were found to be significantly associated with the risk of LBW (table 3). HIV-positive status was associated with a 2.53-fold (95% CI 1.74 to 3.68) increased risk of LBW. Women with gestational hypertension (aOR 4.13, 95% CI 1.55 to 10.97) and those residing outside of Chengdu (aOR 3.12 95% CI 1.37 to 7.08) also had a significantly higher risk of giving birth to LBW infants.
Supplemental material
Conditional logistic regression analysis of low birth weight adjusted for potential cofounders
Risk factors for PTB
Online supplemental table 2 summarises the results of univariate analysis examining the association between various characteristics and PTB. PTB is more likely occurred in women living with HIV, and those with gestational hypertension (22.83% vs 10.61%, p=0.023), gestational diabetes (20.63% vs 10.28%, p=0.002) and liver disease (26.42% vs 10.24%, p<0.001) during pregnancy. Interestingly, living in Chengdu appears to be a protective factor against PTB (10.08% vs 20.42%, p<0.001).
Supplemental material
Table 4 displays the results of the conditional logistic regression analysis examining the association between potential risk factors and PTB. After adjusting potential confounders, pregnant women living with HIV had 1.95 times risk of giving birth before 37 gestational weeks (aOR 1.95, 95% CI 1.33 to 2.85) compared with HIV-negative pregnancies. A significantly increased risk of PTB was observed among pregnant women who had gestational diabetes (aOR 2.95, 1.40 to 6.24) and liver disease (aOR 10.16, 95% CI 3.5 to 28.89). Pregnant women residing outside Chengdu was significantly associated with a higher risk of PTB (aOR 2.76, 95% CI 1.33 to 5.70).
Conditional logistic regression analysis of preterm birth adjusted for potential cofounders*
Sensitivity analysis
Incorporating delivery year as a covariate in the fully-adjusted model did not essentially alter the results. Pregnant women living with HIV had a 2.07 times higher risk of PTB (aOR 2.07, 95% CI 1.06 to 4.03) and a 2.92-fold increased risk of LBW (aOR 2.92, 95% CI 1.45 to 5.87) compared with HIV-negative pregnancies after further controlling the delivery year, as presented in online supplemental tables 3,4.
Supplemental material
Supplemental material
We also conducted PS matching using the kernel method, which yielded a matched subset of 755 pregnant women living with HIV and 4745 HIV-negative women. Although the differences in demographic and clinical characteristics between the two groups were weakened, they remained significant (online supplemental table 5). In the fully adjusted models using the matched data, the results showed that pregnant women living with HIV had a 2.93-fold higher risk of LBW (aOR 2.93, 95% CI 2.05 to 4.15), furthermore, those with gravidity above three times, gestational hypertension, gestational diabetes or liver disease were also at a significant higher risk of LBW (online supplemental table 6). Pregnant women living with HIV had a 1.68-fold higher risk of PTB (aOR 1.68, 95% CI 1.18 to 2.35), in addition, those residing outside of Chengdu or with gestational hypertension, gestational diabetes or liver disease were also at a higher risk of PTB (online supplemental table 7).
Supplemental material
Supplemental material
Supplemental material
Discussion
To the best of our knowledge, this study contained the largest samples to date to investigate the effects of maternal HIV infection status on the APOs in the Chinese HIV-positive pregnant population. LBW and PTB are important risk factors for postneonatal mortality and morbidity.18 Based on data from Chengdu over the previous decade, our study demonstrated that the PTB and LBW rates of HIV-positive women were 13.51% and 14.17%, respectively. In comparison to their HIV-negative counterparts, PTB and LBW rates were considerably higher in the HIV-positive population. These findings concur with the outcomes of most studies.19–21 However, few studies have examined, whether the increased PTB and LBW risk in Chinese pregnant women living with HIV were caused by HIV infection or relevant confounding factors, including maternal poor socioeconomic conditions, pre-existing illness, pregnancy complications and insufficient ANC. In our study, after further controlling the potential confounders by using PSM and multivariate logistics analysis, HIV infection is still strongly associated with higher chances of LBW and PTB with aOR of 2.53 and 1.95, respectively.
It was not difficult to find that there were significant differences in the baseline characteristics between the HIV+ and HIV− groups before PSM by maternal age, ethnicity, marital status, level of education, ANC, gravidity, and so on. After a 1:2 PSM analysis, there was a noticeable improvement in the comparability between the two groups, and the differences in most baseline characteristics diminished.
After PSM, our research suggested that the PTB rate was 13.08% in the HIV-infected group and 9.50% in the non-HIV-infected group. The conclusions of previous studies on the association of HIV infection with PTB are conflicting. This might differ significantly from the socio-economic situation, medical level and disease burden in different countries and regions.22 Concordant with our findings, several studies suggest that HIV infection was a risk factor for PTB.23 24 A study conducted in South Africa documented that HIV infection was associated with a 2.03-fold (95% CI 1.33 to 3.10) increased risk of PTB among 1554 mothers with live singleton births.23 The pooled result of another high-quality meta-analysis consisting of 14 prospective and 8 retrospective cohort studies confirmed that maternal HIV infection was substantially linked with PTB. The direction or significance level of the effect estimates was unaffected by the study’s design.24
The LBW rate was 13.80% vs 6.78% between the HIV+ group and HIV− group after PSM, the difference was statistically significant. Maternal HIV infection was an independent risk factor for neonatal LBW. A matched cohort study in Canada showed that HIV-positive women did not demonstrate a higher risk of PTB but had a higher risk of LBW.25 In our study, after multivariate analysis, the HIV+ group also had a higher risk of LBW than the HIV uninfected group with aOR of 1.96 (95% CI 1.40 to 2.75).
Exposure to HIV before or during pregnancy may increase the risk of APOs through various mechanisms. First, HIV infection damages the human immune system,26 and the low immune activation in HIV-positive women was associated with subsequently increased PTB risk. Compared with term controls, PTD subjects with HIV-positive had lower immune activation, in detail, including decreased CD8+T cell, monocyte cytokine, dendritic cell activation and lower level of inflammatory monocytes.27 Another study found that immunosuppression and a decrease in CD4+T cells in HIV-infected pregnancies may be attributed to LBW. In comparison to women with greater CD4+ cell counts, those with CD4+ cell counts <350 cells/mm3 had a higher chance of having LBW infants (RR 1.57, 95 % CI 1.16 to 2.12).28 Second, abnormal placenta and altered placental angiogenesis: lower placenta weight and smaller placenta area were examined in the HIV-infective mothers, both of which were significantly associated with lower infant birth weight.29 Placental angiogenic processes are critical for birth outcomes, and aberrant levels of two angiogenic factors throughout gestation were linked to APOs. Decreased concentration of placental growth factor was detected in pregnant women with neonatal underweight. Soluble endoglin acting as an antiangiogenic factor in the placenta was significantly higher in HIV-positive women destined to deliver preterm.30 Third, the ascending genital tract infection may be a potential mechanism of HIV-associated PTB. Through measuring the concentrations of genital-tract matrix-metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in HIV-positive and negative pregnant women, and exploring their correlations with inflammation and vaginal bacteria, researchers found that MMP-9 and TIMP-1 were positively associated with vaginal anaerobes and key proinflammatory cytokines, the ratio of MMP-9 to TIMP-1 increases in pregnancy and possibly leads to cervical remodelling as one mechanism underlying PTB.31
Strengths and limitations
Our analysis has several strengths. One of the advantages of this study is that a negative control group was set up to better illustrate the pregnancy outcomes of the HIV-infected and uninfected population. Furthermore, PS matching was used in the study to improve the comparability of the baseline between the two groups and that made the result more reliable. In addition, this study has some limitations: the study samples only originate from one city, which may restrict the extrapolation of the study results. The research object was from the same city，but the negative control group comes from a large hospital, and the time of enrolment of the control group is not completely consistent with the HIV-positive group. Due to incomplete historical data records, some important variables that may be related to outcomes such as CD4+ and viral load in the HIV+ group were not included in this study.
Conclusions
In this retrospective cohort study based on all pregnant women living with HIV with singleton birth in Chengdu, China from 2011 to 2020, HIV infection was significantly associated with increased risks of LBW and PTB.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Chengdu Women’s and Children’s Central Hospital Ethics Committee (number IEC-C-007-V.02). As this study had a retrospective design, obtaining consent for participation was not possible. However, the study was approved by the ethics committee, and all data were collected and analysed anonymously to ensure participant privacy and confidentiality. This study was approved by Chengdu Women’s and Children’s Central Hospital Ethics Committee ethics number 2022(101).
References
Supplementary materials
Supplementary Data
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Footnotes
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Contributors LY and YL designed the study. WX, SC contributed to the conception of the study and manuscript preparation. SY collected data. YL and JP performed the data analyses and wrote the manuscript. JP revised the manuscript critically and was responsible for the overall content. All the authors contributed to the final manuscript.
Funding This work was supported by Medical Research Project of Chengdu Health Commission grant number 2022076.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.