Abstract
Background
Maternal, obstetric and neonatal factors that increase the possibility of mother-to-child HIV transmission (MTCT) are known as mechanisms of transmission. Our aim was to determine the risk factors associated with MTCT in Mexico.
Methods
We conducted a case–control study from March to December 2015. Cases were 60 mothers with HIV infection who transmitted HIV to their children, and controls were 120 mothers with HIV infection whose children tested negative for HIV. Data were extracted from medical records and a self-reported questionnaire for each participant. To determine associations with MTCT, odds ratios (ORs) and 95% confidence intervals (CI) were obtained with the chi-squared test and a logistic-regression modeling.
Results
A total of 180 patients were included. HIV diagnosis for cases occurred after pregnancy in 88% of the patients, during pregnancy in 9%, and before pregnancy in 3% of patients. Among the controls, 38% of patients were diagnosed before pregnancy, 32% during pregnancy, and 30% after pregnancy. In multivariate analysis, the risk factors associated with MTCT were: absence of antiretroviral treatment during pregnancy (OR 5.21; 95% CI 1.24–16.11; p = 0.019); vaginal delivery (OR 3.2; 95% CI 1.27–8.26; p = 0.014); forceps-assisted delivery (OR 13.4; 95% CI 1.91–93.66; p = 0.009); breastfeeding (OR 6.23; 95% CI 2.27–17.05; p = <0.001) and the practice of mixed breastfeeding (OR 4.6; 95% CI 1.56–13.73; p = 0.006).
Conclusions
MTCT is preventable with early diagnosis; treatment initiation before pregnancy and avoidance breastfeeding could decrease the risk of transmitting HIV to their children.
Introduction
Globally, there were 1.3 million pregnant women with HIV in 2020, of which an estimated 85% received antiretroviral therapy (ART) to prevent mother to child transmission. New infections among children declined by more than a half (54%) from 2010 to 2020, due mainly to the increased provision of antiretroviral therapy to pregnant and breastfeeding women living with HIV. 1
In 2014, The Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the 95–95–95 targets. The aim was to diagnose 95% of all HIV-positive individuals, provide antiretroviral therapy (ART) for 95% of those diagnosed and achieve viral suppression for 95% of those treated by 2030. 2 One of the major benefits of the Fast-Track approach will be the projected avoidance of 5.9 million new infections in children. 3
Maternal, obstetric and neonatal factors that increase the possibility of MTCT are known as mechanisms of transmission. In the absence of intervention, the rate of transmission of HIV from a mother living with HIV to her child during pregnancy, labour, delivery or breastfeeding ranges from 15 to 45%. 4 Diagnosis of HIV is essential to enter the PMTCT continuum of care. The UNAIDS Spectrum model estimates a 0.3% risk of peripartum HIV transmission if a woman with HIV initiated ART prior to conception, a 1.4% risk when initiated at 14 weeks gestation, and an 8.2% risk when initiated less than 4 weeks from delivery. 5 Infant feeding interventions are known to be a significant factor in PMTCT. As HIV is present in breast milk, the MTCT rates in the absence of other interventions is between 20 and 45% for breastfed infants. 6 Gastrointestinal infections and malnutrition disrupt this maturational process and increase intestinal permeability, as does artificial feeding. This mechanism may account for the higher risk of HIV infection with mixed feeding, compared with exclusive breast-feeding. 7
In Mexico, 2020 estimates indicate that 76% of pregnant women living with HIV in Mexico were on ART compared with 84% in Latin America and 84.4% globally and the rate of vertical transmission is 2.6%.8,9 The prevalence of HIV infection among pregnant women in Mexico varies between 0.09% to 1.2%. The majority of HIV infection among children occurs through MTCT. An estimated 50%–70% of MTCT occur late in pregnancy or during birth. 10 Since 2001, Mexican National Action Plan on HIV and AIDS established the universal offer of HIV testing to pregnant women and the use of zidovudine as in the ACTG 076 protocol. 11 In Mexico, reports of MTCT transmission indicate a total of 202 cases from 2015–2020. Also, in 2020 alone, there were 620 notifications of pregnant women living with HIV in ART. 12 Pregnant woman should receive at least five prenatal consultations, starting preferably in the first 8 weeks of gestation. Public and private health services are obliged to offer an HIV test to all pregnant women and this should be done in the first 12 weeks or in the first prenatal consultation and in the third trimester. 13
To further our understanding of MTCT in Mexico, we attempted to determine the sociodemographic, maternal, obstetric and neonatal risk factors associated with MTCT at a reference hospital in Mexico.
Materials and methods
Design
A case–control study was conducted using two controls for each case at the Hospital de Infectología “La Raza” National Medical Center in Mexico City from March 1 to 31 December 2015. The HIV clinic is a tertiary level reference center for people with social security coverage. It offers diagnosis and treatment to patients with infectious diseases from eight states of the country, including Mexico City, Estado de Mexico, Morelos, Puebla, Queretaro, Veracruz, Guerrero and Hidalgo. The hospital has 128 beds for adults and children and an intensive care unit and monitors approximately 35 pregnant women living with HIV per year.
Patients
The cases were women with HIV infection who had children with HIV infection confirmed by PCR, with an HIV-1 RNA viral load ≥50 copies/mL at the first and fourth months after birth, or by meeting the 2007 AIDS definitions by the World Health Organization. 14 HIV-1 infection in mothers was confirmed by enzyme-linked immunosorbent assay and western blotting. The controls were women with HIV infection whose children were exposed to HIV during pregnancy but were uninfected. Lack of infection was confirmed by negative HIV-1 RNA viral load at the first and fourth months after birth, and the children were monitored by the pediatric infectious diseases department, with HIV-1 RNA viral load remaining negative until the infants reached 18 months of age. Controls were selected by consecutive sampling.
This study was evaluated by the local committee for scientific research 3502 with approval number R-2015–3502-149. Inclusion criteria were women living with HIV in Hospital de Infectología “La Raza” National Medical Center, older than 18 years old and given birth between 1998 and 2015 to a single child and who accepted to participate. All patients who fulfilled the selection criteria for cases and controls were identified and invited to participate in the investigation, selection was 2:1 ratio of controls: cases. The participants provided written informed consent before completing a sociodemographic questionnaire. Additional data were obtained from the medical records of the outpatient, HIV pediatric and HIV adult clinics.
Measurements
The participants’ clinical histories of antiretroviral regimens, CD4+ cell counts, HIV-1 RNA viral loads, and serum laboratory parameters were recorded. A questionnaire with demographic, socioeconomic, maternal, obstetric and neonatal characteristics was implemented. Characteristics included: area of residence; civil status; education; socioeconomic status using AMAI 8x7; 15 occupation; tobacco and alcohol consumption during pregnancy; drug use during pregnancy (cannabis, cocaine, amphetamines, etc.); number of sexual partners during pregnancy; engagement in oral sex, anal sex or both; use of condoms during pregnancy; HIV diagnosis time; AIDS criteria during pregnancy; 16 type of resolution; premature rupture of membranes; dystocia during childbirth; use of forceps; ART prophylaxis for the neonate; preterm birth; weight of neonates; breastfeeding and mixed breastfeeding; and coinfections such as human papilloma virus (HPV), active tuberculosis and hepatitis B and C virus.
Statistical analysis
Baseline characteristics were summarized by median and interquartile range (IQR) for continuous variables and proportion for categorical variables. For those patients with MTCT, the association with different factors was analyzed in bivariate analyses with the chi-squared test. Independent risk factors associated with MTCT were identified in a multivariate logistic-regression analysis, which included variables from bivariate analyses that had a p-value ≤0.05. All analyses were performed using SPSS software (Version 21.0, IBM, Armonk, NY, USA).
Results
A total of 180 patients were included (60 cases and 120 controls) (Figure 1). Demographic and socioeconomic characteristics are shown in Table 1. The median age of the cases was 24 years (IQR 21–29 years), and the median age of the controls was 25 years (IQR 22–30 years). Positive diagnoses of HPV infection occurred in 23 (38%) of MTCT cases and 22 (19%) of controls. Condom use during pregnancy was practiced in 4 (7%) cases and in 38 (32%) controls. Regarding maternal characteristics, 18 (30%) of the cases and 25 (21%) of the controls reported tobacco consumption during pregnancy; 18 (30%) of the cases and 24 (20%) of the controls reported alcohol consumption. Regarding illicit drug use, 6 (10%) of the cases and 6 (5%) of the controls reported drug use. The voluntary rapid test (VRT) for HIV was performed in 8 (13%) of the cases and 77 (64%) of the controls, amongst those who did not know their HIV diagnosis before pregnancy. Late diagnosis was referred as HIV diagnosis after 28 weeks of gestation. Regarding ART before pregnancy, 57 (95%) of cases and 42 (35%) of controls did not have treatment. Regarding obstetric characteristics, the delivery occurred at 40 weeks of gestation (WG) (IQR 38–40 weeks) in the case group and at 38 weeks (IQR 38–39 weeks) in the control group. At delivery, 11 (18%) of the cases were identified as premature; 16 (27%) of the cases and 13 (11%) of the controls had low birth weight (≤2500 g); breastfeeding occurred in 49 (82%) of the MTCT cases and 25 (21%) of the controls, with mixed breastfeeding in 31 (52%) and 9 (8%), respectively. Flowchart diagram describing the inclusion and exclusion of participants. Demographic, socioeconomic and clinical characteristics of cases and controls with and without mother-to-child transmission of HIV.
Bivariate analysis of sociodemographic and clinical factors associated with mother-to-child transmission of HIV.
ap-value from chi-squared test. PROM, premature rupture of the membranes.
Bivariate analysis of factors associated with virological and immunological status and treatment of pregnant women living with HIV.
ap-value from chi-squared test.
Multivariate analysis of factors associated with mother-to-child transmission of HIV.
aUnconditional logistic regression model. aOR, adjusted odds ratio.
Discussion
In this case–control study, we found that one of the major risk factors for MTCT is breastfeeding; other risk factors associated are related with the presence of virus in plasma and the transmission with the contact of blood such as vaginal delivery and mainly with forceps assistance; finally, these factors are related with the absence of ART during pregnancy.
We found both the case and control groups comprised young women who almost all had a single sexual partner. Notably, the prevalence of smoking during pregnancy was high (30% for cases and 21% for controls) compared with the global prevalence reported of 1.7% (95% CI 0·0–4·5). 17
In this study, 88% of women without ART during pregnancy had children with HIV infection (OR 5.21; 95% CI 1.24–16.11; p = 0.019). Worldwide, in the absence of ART the combined risk for MTCT in utero and intra-partum is 15–30%. 18 For instance, in a metanalysis including nine cohorts with 1115 mothers-infant pairs, the transmission rate for untreated women was 21.3% (95% CI 18.3–24.5). 19 Other studies have observed that when ART is started early, the rate of MTCT can be reduced. Data of the National Study of HIV in Pregnancy and Childhood (NSHPC) collected in the UK and Ireland described that the rate of MTCT declined from 2.1% in 2000–2001 to 0.46% (95% CI 0.21–0.86%) in 2010–2011 because of a combination of factors including earlier initiation of ART. 20
In this study, the prophylactic treatment that only included zidovudine against two regimens for pregnant women, which consisted of zidovudine/lamivudine or a combination of abacavir/lamivudine plus lopinavir/ritonavir, found that the risk for pregnant women was four times greater in women that only included zidovudine; compared with a clinical trial that showed an overall rate of intrapartum transmission at 3 months was 3.2%; the rate in the zidovudine-alone group (24 infants [4.8%]) was significantly higher than the rates in the two-drug group (11 infants [2.2%]) and the three-drug group (12 infants [2.4%]) (p = 0.046 for both comparisons). 21 Similar results were observed in a retrospective cohort study conducted in Spain, where patients treated with zidovudine alone had an 8.6-fold higher risk of MTCT compared to the 0.6% rate, and pregnant women who did not received treatment had 18.2 times greater risk of MTCT. 22
In our study population, the risk for MTCT that was associated with vaginal delivery was 8.44-times higher than that associated with cesarean delivery. The risk associated with vaginal delivery that was assisted by forceps was 13.24-times higher than with cesarean delivery or vaginal delivery without forceps, and the risk for MTCT associated with vaginal delivery assisted by forceps following premature rupture of the membranes (PROM) was 13.22-times higher than with all other types of delivery. In a study of MTCT in South Africa, 38.9% of children delivered by vaginal birth developed HIV infection, compared with 22.9% of those delivered by cesarean (OR 0.45; 95% CI 0.20–0.99). 23 In our population, no differences were observed between cesarean deliveries following PROM and non-cesarean deliveries, although the sample was too small to enable accurate comparison. For prevention of MTCT, elective cesarean delivery is generally recommended, and vaginal delivery is recommended only when prophylaxis with ART has reduced the viral load to undetectable levels. According with national recommendations, vaginal delivery by an HIV-positive mother is recommended when the woman is undergoing ART and has an HIV-1 RNA viral load ≤50 copies/mL, however, international recommendations like the US guidelines do not stipulate that the viral load must be undetectable for recommending vaginal delivery.24,25
Regarding neonatal feeding, in our study population, neonates who were breastfed had 3.0 times higher risk of HIV infection than those who were not breastfed. Mixed breastfeeding had 4.6 times higher risk for HIV infection. These findings are similar to the World Health Organization 26 review, who reported that exclusive breastfeeding during the first 6 months is associated with a 3 to 4 times lower risk of HIV transmission compared to mixed feeding. In studies in Ethiopia, HIV-exposed children who had been mixed breastfed were 10 times more likely to get acquire HIV than those who had been exclusive breastfed or replacement fed.27,28
In Kenya, breastfeeding is recommended, because of high malnutrition rates; but breastfeeding by mothers who are seropositive for HIV is not recommended in Mexico; 29 however, accumulating evidence has shown that giving antiretroviral drugs to the mother or the infant can significantly reduce the risk of HIV transmission through breastfeeding. Here, we found that a high proportion of mothers in the MTCT group breastfed. Notably, a high proportion of mothers in this group also had a late diagnosis of HIV infection, so there was no opportunity to advise against breastfeeding, or to reduce its risk through administration of ART.
Our study has some limitations. In some of the cases, the women had delivered many years before the study, and the data they reported at the time of the questionnaire might not have been accurate. Some of the confidence intervals in the multivariate analysis are large due to small sample size. Although the study was conducted at a single hospital, that hospital is a reference center that serves a diverse population and is representative of Mexico. Despite these limitations, to the best of our knowledge, this is the first report in a Mexican population to identify risk factors associated with MTCT.
MTCT can be largely prevented if a number of documented strategies are applied. In Mexico, there is an uncomplete application of preventive measures designed to achieve a zero-transmission rate. HIV testing should be offered for every woman in childbearing age, including pregnant women in the first and third trimester of pregnancy. HIV detection in early pregnancy will improve the prenatal care and it will decrease the risk of MTCT. The health-care system in Mexico should expand the number of hospital centers with staff trained to provide comprehensive care, early diagnosis, and ART during pregnancy. In addition, safe delivery practices and the avoidance of breastfeeding and mixed feeding are mandatory for decreasing MTCT.
Footnotes
Acknowledgements
The authors wish to acknowledge all the patients who kindly gave consent to participate in this study. The authors also wish to thank the study staff in the Infectious Diseases Department and the study participants and their families and caregivers for their participation in the study.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
