Email updates

Keep up to date with the latest news and content from BMC Pediatrics and BioMed Central.

Open Access Research article

Pregnancy loss and role of infant HIV status on perinatal mortality among HIV-infected women

Hae-Young Kim12, Prisca Kasonde3, Mwiya Mwiya3, Donald M Thea4, Chipepo Kankasa3, Moses Sinkala5, Grace Aldrovandi6 and Louise Kuhn12*

Author Affiliations

1 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

2 Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 W 168th St, New York, NY, USA

3 University Teaching Hospital, University of Zambia, Lusaka, Zambia

4 Center for International Health and Development, Boston University of School of Public Health, Boston, USA

5 Lusaka District Health Management Team, Lusaka, Zambia

6 Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Los Angeles, USA

For all author emails, please log on.

BMC Pediatrics 2012, 12:138  doi:10.1186/1471-2431-12-138

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2431/12/138


Received:7 May 2012
Accepted:17 August 2012
Published:31 August 2012

© 2012 Kim et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

HIV-infected women, particularly those with advanced disease, may have higher rates of pregnancy loss (miscarriage and stillbirth) and neonatal mortality than uninfected women. Here we examine risk factors for these adverse pregnancy outcomes in a cohort of HIV-infected women in Zambia considering the impact of infant HIV status.

Methods

A total of 1229 HIV-infected pregnant women were enrolled (2001–2004) in Lusaka, Zambia and followed to pregnancy outcome. Live-born infants were tested for HIV by PCR at birth, 1 week and 5 weeks. Obstetric and neonatal data were collected after delivery and the rates of neonatal (<28 days) and early mortality (<70 days) were described using Kaplan-Meier methods.

Results

The ratio of miscarriage and stillbirth per 100 live-births were 3.1 and 2.6, respectively. Higher maternal plasma viral load (adjusted odds ratio [AOR] for each log10 increase in HIV RNA copies/ml = 1.90; 95% confidence interval [CI] 1.10–3.27) and being symptomatic were associated with an increased risk of stillbirth (AOR = 3.19; 95% CI 1.46–6.97), and decreasing maternal CD4 count by 100 cells/mm3 with an increased risk of miscarriage (OR = 1.25; 95% CI 1.02–1.54). The neonatal mortality rate was 4.3 per 100 increasing to 6.3 by 70 days. Intrauterine HIV infection was not associated with neonatal morality but became associated with mortality through 70 days (adjusted hazard ratio = 2.76; 95% CI 1.25–6.08). Low birth weight and cessation of breastfeeding were significant risk factors for both neonatal and early mortality independent of infant HIV infection.

Conclusions

More advanced maternal HIV disease was associated with adverse pregnancy outcomes. Excess neonatal mortality in HIV-infected women was not primarily explained by infant HIV infection but was strongly associated with low birth weight and prematurity. Intrauterine HIV infection contributed to mortality as early as 70 days of infant age. Interventions to improve pregnancy outcomes for HIV-infected women are needed to complement necessary therapeutic and prophylactic antiretroviral interventions.

Keywords:
Perinatal mortality; Infant mortality; Risk factors; Adverse pregnancy outcome; HIV infection; Vertical transmission

Background

In 2009, an estimated 1.4 million pregnant women were living with HIV in low- and middle-income countries. About 91% of those women in need of antiretroviral drugs for preventing mother-to-child transmission were in sub-Saharan Africa and 54% of women are estimated to have received the prophylactic drugs with recent scale-up [1]. Besides the risk of HIV transmission, maternal HIV infection is associated with increased risk of adverse pregnancy outcomes. For example, a meta-analysis of 31 studies showed almost a four-fold increased risk of stillbirth among HIV-infected compared to uninfected women [2], although some studies have not observed this [3,4].

Several studies in sub-Saharan African countries have also shown that infants born to HIV-infected women have a significantly increased risk of low birth weight (LBW) [4-7], preterm birth [5,6], neonatal mortality [7] and infant mortality [7-9]. Generally, markers of more advanced maternal disease, such as low CD4 cell counts and high plasma viral loads, are associated with these endpoints [9-11]. However, since these markers are also strongly related to HIV transmission [12-14], it is not clear whether infant HIV infection is a cause or a consequence of these adverse events. One study that separated HIV infections by their timing found that preterm birth was associated with intrapartum but not with intrauterine infection, suggesting prematurity as a risk factor for intrapartum infection rather than a cause of preterm delivery [15]. In some studies, intrauterine-infected children had smaller weight-for-gestation than expected, suggesting some growth consequences of early intrauterine HIV infection [16,17].

HIV-infected infants have a substantially higher risk of infant mortality compared to uninfected but exposed infants [18,19]. In addition, infants infected intrauterine or intrapartum have a worse prognosis than those infected through breastfeeding [19-21]. But it is unclear whether perinatally-acquired HIV infection will influence infant survival within the first months after birth. Since LBW and preterm birth are the major risk factors for neonatal and early infant mortality in all populations regardless of HIV status, separating out independent effects of these inter-related perinatal variables is complex and requires large sample sizes [22,23]. One large study in Tanzania found that among infants born to HIV-infected mothers, LBW, not infant HIV infection, was the strongest risk factor for neonatal mortality [21].

Here we investigate risk factors for miscarriage, stillbirth, neonatal mortality and early mortality among a cohort of pregnant HIV-infected women followed as part of a study in Lusaka, Zambia. We aim to identify independent contributions of advanced maternal disease and infant HIV status to adverse pregnancy and neonatal outcomes and focus on whether the timing of infant HIV infection influences the risk of these adverse outcomes.

Methods

Study design

We report a secondary analysis of data collected as part of the Zambia Exclusive Breastfeeding Study (ZEBS), a randomized clinical trial to examine whether exclusive breastfeeding to 4 months, followed by abrupt weaning, could reduce postnatal HIV transmission and child mortality. The study protocol and primary results have been reported elsewhere [24-26]. Briefly, a total of 1435 HIV-positive pregnant women were recruited at two antenatal care clinics in Lusaka between May 2001 and September 2004 if they intended to breastfeed, accepted to take single-dose nevirapine to prevent perinatal HIV transmission and consented to be assigned to either of the study and control groups. Antiretroviral therapy (ART) only became available in the public sector as the study was nearing completion. Written informed consent was obtained from all study participants. The study was approved by human subjects committees at all collaborating institutions.

Study procedures

Socioeconomic and clinical data were collected at enrollment. Maternal blood samples were drawn at enrollment to test for CD4 cell counts (FACSCount; BD Immunocytometry Systems), hemoglobin level (Hemocue system), and plasma viral load (Roche Amplicor 1.5; Roche). All women with positive results of routine syphilis screening test (RPR) were treated with penicillin. Two subsequent antenatal visits were scheduled before delivery. Data on the circumstances of miscarriages and stillbirths were collected from medical records if available or from interview with the mothers. Gestational week at delivery was calculated from the estimated gestational week at enrollment, which was based on clinical examination (fundal height) and self-report of last menstrual period (LMP). In cases of discrepant gestational age estimates, the LMP date was used. Heel stick blood samples of infants were obtained at clinic visits scheduled at birth, 1 week and 5 weeks. DNA was extracted from each infant’s blood sample and tested for HIV by real-time polymerase chain reaction (PCR). All positive test results were confirmed by testing at least two samples. To rule out false negative test results due to an inadequate sample, amplification of the beta-globin gene was performed to ensure adequate cell numbers. Home visits were scheduled at 4 days after birth and 2, 3 and 7 weeks post-partum. Study participants who did not return for the scheduled antenatal or clinic visits were tracked and followed by home-visit teams.

Study variables

The primary outcomes of interest were miscarriage, stillbirth, neonatal mortality (infant’s death <28 days) and early mortality (infant’s death <70 days). Miscarriage was defined as spontaneous abortion of pregnancy occurring before 24 gestational weeks, and stillbirth as fetal death occurring at 24 gestational weeks or later. Low birth weight (LBW) was defined as birth weight <2500 g, and preterm birth as having <34 weeks of gestation. This cut-off was selected since systematic under-estimation of gestational age by 2–3 weeks was indicated by the birth weight distribution. 30 infants did not have birth weight data mainly due to delivery at home. Their birth weights were predicted based on their weights measured at 1 week.

Maternal body mass index (BMI) at 1 month postpartum was used as a predictor since women were enrolled at different gestational weeks and often quite late in pregnancy. 123 women who missed the one month visit were included into models as a separate group. Breastfeeding was defined as having stopped only if cessation occurred before the illness preceding infant’s death or loss to follow up. Stopping breastfeeding was considered as a fixed-covariate and a time-dependent variable. After November 2003, cotrimoxazole prophylaxis was introduced for women with CD4 cell counts <200 cells/mm3 and the effects of cotrimoxazole were reported elsewhere [27]. If women experienced weight loss, >30 days of diarrhea, fever or cough in the six months prior to enrollment, or had history of thrush or tuberculosis, women were considered as being symptomatic according to World Health Organization criteria [28]. Further, each symptom was individually examined.

The timing of HIV transmission was stratified into three groups: 1) intrauterine transmission (IU) 2) intrapartum/early post-partum transmission (IP/ePP) and 3) no infection within 42 days after birth (NI). IU transmission was presumed if PCR results were positive within 3 days of birth. IP/ePP transmission was presumed if the PCR results were positive between 4 and 42 days after birth. If PCR results were negative at least for 42 days after birth, then the infants were presumed not to be infected within 42 days (NI). Mortality among the three groups with different timing of HIV transmission was compared. The cut-off point of early mortality was chosen at 70 days to measure the effect of IU and IP infection over the 6 weeks period after the neonatal period. Those with no PCR results were considered to be of unknown HIV status.

Statistical analysis

Mantel-Haenszel relative risk (RR) of each factor on each outcome was examined and reported with 95% Confidence Intervals (CIs). For adjusted analysis, multivariable logistic regression was fitted. Variables with p-value < .10 in univariable analysis were included and were retained if significant (p-value <0.05) and their odds ratios (ORs) were reported with 95% CIs. Kaplan-Meier methods were used to calculate mortality rates for IU, IP/ePP and NI infants and Cox Proportional Hazards models to examine risk factors of neonatal mortality and early mortality [29]. Unadjusted and adjusted hazard ratios (HRs) were reported with 95% CIs. Continuous and categorical variables were compared across groups by two sided-Wilcoxon tests or t-tests and χ2 statistics, respectively. All statistical analyses were performed by SAS (version 9.2).

Sensitivity analysis

Sensitivity analysis was performed to examine whether infants with unknown HIV status biased the results. First, we assumed that all infants with unknown status are IU, IP or NI. Next we estimated the probability of IU or IP transmission in the infants of unknown HIV status among those who died or who were lost to follow up separately based on a logistic regression model predicting transmission from maternal CD4 cell counts and plasma viral load. Finally, we calculated the expected neonatal and early mortality rates that would have occurred had these transmission rates occurred in each group of IU, IP and NI infants.

Results

Cohort description

Of 1435 HIV-positive women in the study, 11 women were not pregnant, 191 withdrew or were lost to follow up and four women died before delivery. Of 1229 women, 3.4% were enrolled during the first trimester and 62.7% during the second (median 26 weeks; IQR 20–31). There were 36 miscarriages and 30 stillbirths. Thus, 1163 women gave birth to 1185 live-born infants (26 non-singleton births including 21 pairs of twins both born alive). For 53 women, live-births were known to have occurred but no delivery or follow-up data were available. Compared to all 1163 live-born infants, the ratio of miscarriage and stillbirth per 100 live-births were 3.1 (95% CI 2.2–4.3) and 2.6 (95% CI 1.8–3.7), respectively. Among 1132 live-born infants with delivery records from 1110 mothers, 14.3% had LBW, and 16.3% were preterm. The probabilities of neonatal (<28 days) and early (<70 days) mortality were 0.043 (n = 47, 95% CI 0.032–0.057) and 0.063 (n = 67, 95% CI 0.050–0.079), respectively (Table 1). No woman with miscarriage or stillbirth had started ART and only 6 women started ART during pregnancy and 3 within 70 days post-partum.

Table 1. Frequencies of adverse pregnancy outcomes among 1229 HIV-infected pregnant women recruited in Lusaka, Zambia

Risk factors for miscarriage and stillbirth

Risk factors for miscarriage or stillbirth were examined (Table 2). CD4 cell counts <350 cells/mm3 and history of miscarriage were associated with an increased risk of miscarriage. For stillbirth, plasma viral load ≥50,000/ml and symptomatic HIV disease were significant risk factors as well as no previous pregnancies. In multivariable analysis, only CD4 cell counts <350 cells/mm3 was significantly associated with miscarriage. The odds ratio for decreasing CD4 cell counts by 100 cells/mm3 was 1.25 (95% CI 1.02–1.54, p = 0.03). For stillbirth, plasma viral load (adjusted OR [AOR] for each log10 increase in HIV RNA copies/ml = 1.90; 95% CI 1.10–3.27), being symptomatic (AOR = 3.19; 95% CI 1.46–6.97) and no previous pregnancy (AOR = 2.71; 95% CI 1.16–6.31) remained as significant risk factors.

Table 2. Risk factors for miscarriage and stillbirth among a cohort of 1229 HIV-infected womena

Risk factors for LBW and preterm birth

Risk factors for LBW and preterm birth are shown in Table 3. Higher plasma viral load, BMI <18.5 kg/m2 and swollen glands in more than one place were associated with both LBW and premature birth. In addition, women with CD4 cell counts <350 cells/mm3 had an increased risk of having LBW infants (RR = 1.57; 95% CI 1.16–2.12) compared to women with higher CD4 cell counts. Infants born to mothers with hemoglobin <10 g/dl, clinical symptoms or history of tuberculosis were more likely to be LBW. Less formal education was associated with preterm birth and women aged >30 years had a lower risk of preterm birth than women aged 20–30 years.

Table 3. Risk factors for low birth weight (<2500g) and preterm birth among 1132 live-born infantsa

In multivariable analysis, maternal plasma viral load (AOR for each log10 increase = 1.30; 95% CI 1.03–1.66), BMI <18.5 kg/m2 (AOR = 2.35; 95% CI 1.49–3.70), hemoglobin <10g/dl (AOR = 1.50; 95% CI 1.04–2.16), a history of swollen glands in more than one place (AOR = 1.64; 95% CI 1.02–2.63) or tuberculosis (AOR = 1.85; 95% CI 1.11–3.06) were each independently associated with a higher risk of LBW. For preterm birth, BMI <18.5 kg/m2 was the strongest risk factor (AOR = 1.96; 95% CI 1.27–3.04). History of swollen glands (AOR = 1.77; 95% CI 1.14–2.73) and less formal education (AOR = 1.42; 95% CI 1.00–2.02) were independently associated with preterm birth. Maternal age >30 years was still associated with reduced risk of preterm birth (AOR = 0.62; 95% CI 0.38–1.00).

Risk factors for neonatal and early mortality

Risk factors for neonatal and early mortality are shown in Table 4. Preterm birth, LBW, APGAR scores and cesarean delivery were strongly associated with an increased risk of both neonatal and early mortality in univariable analysis. History of tuberculosis and >30 days of diarrhea were significant risk factors for both neonatal and early mortality. Relative risks of these factors were higher for neonatal mortality than for early mortality. Maternal health factors, namely CD4 cell counts <350 cells/mm3, hemoglobin <10 g/dl, higher plasma viral load, and BMI <18.5 kg/m2 were significantly associated with an increased risk of early mortality, but not with neonatal mortality.

Table 4. Risk factors for neonatal mortality (<28 days) and early mortality (<70 days) among 1132 live-born infantsa

Maternal death <70 days was associated with an increased risk of both neonatal and early mortality but many of these deaths occurred after infant death. Restricting only to maternal deaths occurring before infant death (18/1132; 1%), the association with early mortality was attenuated. Stopping breastfeeding <70 days was a significant risk factor for neonatal and early mortality. When fitted as a time-dependent variable, the association was further strengthened for both neonatal mortality (HR = 15.02; 95% CI 5.20–43.43) and early mortality (HR = 15.37; 95% CI 7.39–31.97). Infants born to mothers aged <20 years had a two-fold increased risk of neonatal and early mortality and having more than one child aged 5–16 years living in the household was associated with a lower risk of early mortality.

In multivariable analysis, LBW, stopping breastfeeding and young maternal age were significantly associated with both neonatal and early mortality. Preterm birth was only associated with neonatal mortality and low maternal CD4 cell counts (<350 cells/mm3) only with early mortality (Table 5, Model 1).

Table 5. Multivariate analysis of risk factors for neonatal and early mortalitya

Effects of infant HIV status

Among the 1132 infants, 50 infants had no HIV test results. Of 1082 infants with a known HIV status, 64 infants (5.9%) were IU infected. Another 64 infants (5.9%) were IP/ePP infected including 10 infants with indeterminate HIV status at birth but tested HIV-positive by 42 days. 863 infants were followed up and not infected at least for 42 days. 69 infants were lost to follow up but confirmed HIV-negative prior to 42 days and another 22 infants were HIV-negative at birth or 1 week but died before 42 days. These were included as NI infants, giving a total of 954 NI infants (88.2%).

Neonatal mortality rates were 5.0 per 100 live-born infants (95% CI 1.7–14.8) in IU infants, 1.6 (95% CI 0.2–10.6) in IP/ePP infants and 2.2 (95% CI 1.3–3.3) in NI infants. By 70 days after birth, early mortality increased to 13.7 per 100 (95% CI 7.1–25.5) in IU infants, 4.8 (95% CI 1.6–14.1) in IP/ePP infants and 3.5 (95% CI 2.5–5.0) in NI infants. Infants with IU infection had a non-significant elevation in mortality by 28 days compared to NI infants (HR = 2.29; 95% CI 0.68–7.70). The risk associated with IU infection increased when mortality through 70 days was considered (HR = 3.93; 95% CI 1.81–8.53). Model 2 in Table 5 shows the associations between IU and IP/ePP transmission and neonatal and early mortality in multivariable model. IU infection remained significantly associated with early mortality (AHR = 2.76; 95% CI 1.25–6.08) after adjustment for LBW, preterm birth, stopping breastfeeding, and having more than a child aged 5–16 years. IP/ePP infection was not significantly associated with early mortality and cannot be directly examined in relation to neonatal mortality since survival to a subsequent test was a component of the definition of intrapartum infection. Major causes of neonatal and early mortality were similar among the three groups; pneumonia, acute diarrhea and septicemia.

When we examined the mortality between 28 and 70 days, the risk of the mortality among IU infants was further elevated compared to NI infants (HR = 6.82; 95% CI 2.40–19.35) and still significant after adjustment for LBW and cessation of breastfeeding (AHR = 6.36; 95% CI 2.22–18.27). Non-significant increase in mortality was observed among IP/ePP infants (HR = 2.34; 95% CI 0.52–10.43).

To consider whether risk factors for neonatal and early mortality were modified by infant HIV status, we stratified the analysis by infant HIV status. In multivariable model restricting to 128 infected infants, only LBW was associated with neonatal mortality (HR = 16.63; 95% CI 1.73–160.16) and LBW (AHR = 16.13; 95% CI 4.23–61.48) and stopping breastfeeding (AHR = 8.15; 95% CI 1.62–40.92) with early mortality. Among 954 uninfected infants, LBW (AHR = 6.99; 95% CI 2.61–18.71) and preterm birth (AHR = 2.64; 95% CI 1.00–6.99) were significantly associated with neonatal mortality. LBW (AHR = 6.47; 95% CI 3.13–13.34) and stopping breastfeeding (AHR = 9.52; 95% CI 3.65–24.85) were significantly associated with early mortality as seen in whole population.

Sensitivity analysis

The 50 infants with unknown HIV status had lower birth weights and higher mortality rates than IU, IP and NI infants. 23 infants (46%) died by 28 days and 24 infants (48%) by 70 days. To determine the extent of bias, we performed a sensitivity analysis including these infants under different assumptions (Table 6).

Table 6. Sensitivity analyses for the 50 infants with unknown HIV status

The predicted probability of HIV transmission was 6.8% for IU and 6.9% for IP in the 24 infants who died before 70 days and 4.4% for IU and 4.0% for IP in the 26 infants lost to follow up. Assuming these transmission rates among the infants with unknown HIV status, we calculated neonatal mortality rates of 7.3% in IU, 3.9% in IP and 4.1% in NI groups. Early mortality rates were 15.6% in IU, 7.1% in IP and 5.5% in NI groups among the 1132 infants. After this imputation, the adjusted HRs of neonatal mortality and early mortality among IU transmitted infants were 1.66 (95% CI 0.65–4.29) and 2.09 (95% CI 1.05–4.17) compared to NI infants, respectively (Model 4). This is similar to the results excluding the infants of unknown HIV status suggesting that the original approach was reasonable.

Discussion

This study documents that women with advanced HIV disease are not only more likely to transmit HIV but also have an increased risk of miscarriage and stillbirth and infants born to these mothers have an increased risk of neonatal and early mortality. High rates of neonatal and early mortality are primarily attributable to low birth weight and preterm birth, both also increased among women with advanced disease. It is only after the neonatal period that the infant’s HIV status begins to make a significant contribution to excess mortality.

In this study, the risks of miscarriage and stillbirth were 31 and 26 per 1000 live-born births, respectively. From another cohort study in Lusaka, Zambia, the estimated rate of stillbirth was 21 per 1000 live-born births where 75.2% of the participating women were HIV-uninfected [30]. We found that among HIV-infected women, miscarriage was associated with CD4 cell counts <350 cells/mm3. This result is similar to other studies [31,32]. In a South African cohort study, women with CD4 cell counts <250 cells/mm3 had a two-fold increased risk of the adverse outcome (antenatal heath, miscarriage or stillbirth) compared to those with CD4 cell counts >500 cells/mm3[31]. Another study in India reported that symptomatic women had a significantly increased rate of miscarriage, compared to asymptomatic women [32].

In our study, high plasma viral load was significantly associated with stillbirth among HIV-infected women. Many studies have reported increased risk of stillbirth in HIV-infected women compared to HIV-negative women [2], but only two studies have examined risk factors associated with stillbirth among HIV-infected pregnant women [3,33]. A study in Tanzania found that elevated CD3 count, but not other markers such as CD4 or CD8 counts, was associated with stillbirth [33]. In the cohort conducted in four cities in sub-Saharan Africa, the risk of stillbirth was correlated with decreasing CD4 count [3] but not with plasma viral load categorized into ≥100,000 copies/ml or less. In our analysis, the mean baseline plasma viral load of mothers who delivered stillbirths was significantly higher (median value 76,560 vs. 39,783 copies/ml, p = 0.01) thus fitting it as a continuous variable (log scale) seemed to be more accurate. Furthermore, symptomatic women had a more than a three-fold increased risk of stillbirth compared to asymptomatic women, suggesting that maternal disease progression may play an important role in perinatal outcomes.

Some previous studies have tried to document HIV status of pregnancy losses [34-36]. One study which did so by in situ hybridization showed that 60% of the spontaneous fetal losses (6/10) were associated with HIV transmission to the fetus [35]. It is possible that advanced maternal disease might have increased pregnancy losses via intrauterine transmission [37,38] but we could not directly examine such mechanism. Since ART only became available towards the end of the study, 52 out of 66 women (79%) who had miscarriages or stillbirths should have received ART under the current WHO guidelines but did not. Although certain ART regimens may increase the risk of adverse pregnancy outcomes [39,40], it also reduces the risk of perinatal transmission and improves maternal health [41]. Timely ART for HIV-infected pregnant women may result in a net improvement in these perinatal outcomes.

Our data indicate that HIV infection acquired during pregnancy begins to contribute to excess mortality as early as 70 days but mostly only after the neonatal period, independent of LBW and early cessation of breastfeeding. After the neonatal period, IU-infected infants had more than a six-fold increased risk of mortality compared to NI infants through 70 days. Prior studies have not as precisely considered the timing of early mortality of infected infants [19,20] nor separated IU transmission from IP/ePP transmission [21]. Some studies have found IU-infected infants to have onset of symptoms in first few months of life and faster disease progression than those infected at delivery or later [15,42,43]. Despite recent scale-up, only 15% of HIV-exposed infants had access to early infant diagnosis and one-third of infants diagnosed of HIV did not receive appropriate antiretroviral treatment in 2011 [44]. Our results re-emphasize the crucial role of early infant diagnosis in order to initiate therapy for infected infants given their rapid progression [45,46].

LBW was previously associated with infant death between 8 weeks and 6 months of life [9], post-neonatal death (29–365 days) and infant mortality [21] among HIV-infected children as well as among HIV-exposed uninfected [22]. Among perinatally-infected infants, the effect of LBW on infant survival dominates the neonatal period but persists thereafter even once HIV-related disease contributes to infant mortality. In our study, high maternal viral load and low hemoglobin were the most significant predictors of LBW and preterm birth as observed in other studies [4,16,47]. Advanced maternal disease seems to indirectly affect early infant survival via the risk of LBW and premature birth. Thus to complement antiretroviral interventions, other interventions such as providing cotrimoxazole [27] or multivitamin supplements during pregnancy [48] may need to be considered to improve overall birth outcomes.

Early breastfeeding cessation was a significant risk factor for both neonatal and early mortality. Breastfeeding has a significant role in infant survival for all infants including those born to HIV-infected women [20,25,26]. Maternal death was also related to infant mortality and is closely related to cessation of breastfeeding. However, we found breastfeeding to be a strong protector of infant survival independent of confounding effects of maternal health and survival.

Some social factors significantly affected infant survival. Infants with more than one sibling aged 5–16 years had decreased rates of early mortality. This may reflect families with greater birth spacing or substantial care provided by an older sibling. Teenage pregnancy was associated with an increased risk of neonatal and early mortality. In the general population, some studies have reported adverse associations between teenage pregnancy and perinatal mortality, largely attributable to preterm birth [49-51], while others have not [52]. In our study, maternal age <20 years was associated with neonatal mortality independent of preterm birth.

The study has several limitations. First, most of study participants were enrolled into the study during second or third trimester thus miscarriages and stillbirths occurring in earlier gestational ages are excluded resulting in underestimated rates of these outcomes. Our study thus has limited capacity to comment on the predictors of early pregnancy loss. However, most early pregnancy loss is due to chromosomal abnormalities and is unlikely to be influenced by maternal HIV status [53]. Second, distinguishing between miscarriage and stillbirth is difficult particularly with inaccuracies in estimates of gestational age. Nevertheless, similar factors were associated with both of these adverse outcomes hence the consequence of misclassification seems to be limited. Third, HIV status could not be determined for some infants. However, we examined the extent of bias in sensitivity analyses which suggested that these exclusions did not appreciably affect the results. Finally, the cut-off of 70 days might have been too early to see any adverse effects of IP/ePP infection but this analysis aimed to examine how rapidly intrauterine and perinatally-acquired HIV infection affect infant survival.

Conclusion

Women with more advanced HIV disease had a higher risk of pregnancy loss and perinatal mortality. Advanced maternal HIV disease affected infant health and survival directly via the risk of HIV transmission and indirectly via LBW and prematurity. The effect of intrauterine infection in the infant was apparent by 70 days but excess neonatal mortality was primarily attributed to LBW and preterm birth independent of infant HIV status. Interventions to improve maternal health as well as pregnancy outcomes for HIV-infected women may be necessary to complement the currently recommended prophylactic and therapeutic antiretroviral regimens.

Competing interests

The authors declare that they have no competing interests.

Authors contributions

The authors’ responsibilities were as follows - LK, DMT, and GA: conceptualization and design; MS, CK, MM, DMT, and LK: study implementation and management; GA: laboratory assays; HYK and LK: analysis and statistics; and HYK and LK: draft of the manuscript. All authors: interpretation of data and revision of manuscript for critical content. All authors read and approved the final manuscript.

Acknowledgements

The study was supported by the National Institute for Child Health and Human Development, National Institutes of Health (R01 HD39611 and R01 HD 40777) for the Zambia Exclusive Breastfeeding Study; the Centers for Disease Control and Prevention (CDC), Global AIDS Program (GAP); Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) (GA is a recipient of the EGPAF Scientist Award); and USAID Country Research Activity Award (GHS-A-00-00020-00). The funders had no role in the design and conduct of the study, in the collection of the data, the interpretation of the data and in the preparation, review and approval of the manuscript. We thank the Zambian families who participated in the research and all the study staff and volunteers.

References

  1. World Health Organization: Towards universal access: Scaling up priority HIV/AIDS interventions in the health sector: progress report 2010. World Health Organization, Geneva; 2010. OpenURL

  2. Brocklehurst P, French R: The association between maternal HIV infection and perinatal outcome: a systematic review of the literature and meta-analysis.

    Brit J Obstet Gynaec 1998, 105:836-848. PubMed Abstract | Publisher Full Text OpenURL

  3. Chi BH, Wang L, Read JS, Taha TE, Sinkala M, Brown ER, Valentine M, Martinson F, Goldenberg RL: Predictors of stillbirth in Sub-Saharan Africa.

    Obstet Gynecol 2007, 110:989-997. PubMed Abstract | Publisher Full Text OpenURL

  4. Braddick MR, Kreiss JK, Embree JE, Datta P: Impact of maternal HIV infection on obstetrical and early neonatal outcome.

    AIDS 1990, 4:1001-1005. PubMed Abstract | Publisher Full Text OpenURL

  5. Castetbon K, Ladner J, Leroy V, Chauliac M, Karita E, De Clercq A, Van de Perre P, Dabis F, Pregnancy, Study Group HIV: Low birthweight in infants born to African HIV-infected women: relationship with maternal body weight during pregnancy.

    J Trop Pediatrics 1999, 45:152-157. Publisher Full Text OpenURL

  6. Temmerman MCE, Ndinya-Achola J, Plummer FA, Coppens M, Piot P: Maternal human immunodeficiency virus-1 infection and pregnancy outcome.

    Obstet Gynecol 1994, 83:495-501. PubMed Abstract | Publisher Full Text OpenURL

  7. Ryder RW, Nsa W, Hassig SE, Behets F, Rayfield M, Ekungola B, Nelson AM, Mulenda U, Francis H, Mwandagalirwa K, et al.: Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire.

    N Engl J Med 1989, 320:1637-1642. PubMed Abstract | Publisher Full Text OpenURL

  8. Taha T, Dallabetta G, Canner J, Chiphangwi J, Liomba G, Hoover D, Miotti P: The effect of human immunodeficiency virus infection on birth weight, and infant and child mortality in urban Malawi.

    Int J Epidemiol 1995, 24:1022-1029. PubMed Abstract | Publisher Full Text OpenURL

  9. Zijenah LS, Moulton LH, Iliff P, Nathoo K, Munjoma MW, Mutasa K, Malaba L, Zvandasara P, Ward BJ, Humphrey J, ZVITAMBO Study Group: Timing of mother-to-child transmission of HIV-1 and infant mortality in the first 6 months of life in Harare, Zimbabwe.

    AIDS 2004, 18:273-280. PubMed Abstract | Publisher Full Text OpenURL

  10. Lambert G, Thea DM, Pliner V, Steketee RW, Abrams EJ, Matheson P, Thomas PA, Greenberg B, Brown TM, Bamji M, Kalish ML: Effect of maternal CD4 + cell count, acquired immunodeficiency syndrome, and viral load on disease progression in infants with perinatally acquired human immunodeficiency virus type 1 infection.

    J Pediatr 1997, 130:890-897. PubMed Abstract | Publisher Full Text OpenURL

  11. Abrams EJ, Wiener J, Carter R, Kuhn L, Palumbo P, Nesheim S, Lee F, Vink P, Bulterys M, Perinatal AIDS Collaborative Transmission Study (PACTS) Group: Maternal health factors and early pediatric antiretroviral therapy influence the rate of perinatal HIV-1 disease progression in children.

    AIDS 2003, 17:867-877. PubMed Abstract | Publisher Full Text OpenURL

  12. Thea DM, Steketee RW, Pliner V, Bornschlegel K, Brown T, Orloff S, Matheson PB, Abrams EJ, Bamji M, Lambert G, et al.: The effect of maternal viral load on the risk of perinatal transmission of HIV-1.

    AIDS 1997, 11:437-444. PubMed Abstract | Publisher Full Text OpenURL

  13. Garcia PM, Kalish LA, Pitt J, Minkoff H, Quinn TC, Burchett SK, Kornegay J, Jackson B, Moye J, Hanson C: Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission.

    N Engl J Med 1999, 341:394-402. PubMed Abstract | Publisher Full Text OpenURL

  14. Mofenson LM, Lambert JS, Stiehm ER, Bethel J, Meyer WA, Whitehouse J, Moye J, Reichelderfer P, Harris DR, Fowler MG: Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine.

    N Engl J Med 1999, 341:385-393. PubMed Abstract | Publisher Full Text OpenURL

  15. Kuhn L, Steketee R, Weedon J, Abrams E, Lambert G, Bamji M, Schoenbaum E, Farley J, Nesheim S, Palumbo P, et al.: Distinct risk factors for intrauterine and intrapartum human immunodeficiency virus transmission and consequences for disease progression in infected children.

    J Infect Dis 1999, 179:52-58. PubMed Abstract | Publisher Full Text OpenURL

  16. Dreyfuss ML, Msamanga GI, Spiegelman D, Hunter DJ, Urassa EJ, Hertzmark E, Fawzi WW: Determinants of low birth weight among HIV-infected pregnant women in Tanzania.

    Am J Clin Nutr 2001, 74:814-826. PubMed Abstract | Publisher Full Text OpenURL

  17. Kuhn L, Abrams EJ, Matheson PB, Thomas PA, Lambert G, Bamji M, Greenberg B, Steketee RW, Thea DM: New York City Perinatal HIVTCSG: Timing of maternal-infant HIV transmission: associations between intrapartum factors and early polymerase chain reaction results.

    AIDS 1997, 11:429-435. PubMed Abstract | Publisher Full Text OpenURL

  18. Newell M-L, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F: Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis.

    Lancet 2004, 364:1236-1243. PubMed Abstract | Publisher Full Text OpenURL

  19. Marinda E, Humphrey JH, Iliff PJ, Mutasa K, Nathoo KJ, Piwoz EG, Moulton LH, Salama P, Ward BJ, The Zvitambo Study Group: Child mortality according to maternal and infant HIV status in Zimbabwe.

    Pediatr Infect Dis J 2007, 26:519-526. PubMed Abstract | Publisher Full Text OpenURL

  20. Fox MP, Brooks D, Kuhn L, Aldrovandi G, Sinkala M, Kankasa C, Mwiya M, Horsburgh R, Thea DM: Reduced mortality associated with breast-feeding-acquired HIV infection and breast-feeding among HIV-infected children in Zambia.

    J Acq Immun Def Synd 2008, 48:90-96. Publisher Full Text OpenURL

  21. Wei R, Msamanga GI, Spiegelman D, Hertzmark E, Baylin A, Manji KM, Fawzi WW: Association between low birth weight and infant mortality in children born to human immunodeficiency virus 1-infected mothers in Tanzania.

    Pediatr Infect Dis J 2004, 23:530-535. PubMed Abstract | Publisher Full Text OpenURL

  22. McCormick MC: The contribution of low birth weight to infant mortality and childhood morbidity.

    N Engl J Med 1985, 312:82-90. PubMed Abstract | Publisher Full Text OpenURL

  23. Simmons LE, Rubens CE, Darmstadt GL, Gravett MG: Preventing Preterm Birth and Neonatal Mortality: exploring the Epidemiology, Causes, and Interventions.

    Semin Perinatol 2010, 34:408-415. PubMed Abstract | Publisher Full Text OpenURL

  24. Thea DM, Vwalika C, Kasonde P, Kankasa C, Sinkala M, Semrau K, Shutes E, Ayash C, Tsai W-Y, Aldrovandi G, Kuhn L: Issues in the design of a clinical trial with a behavioral intervention–the Zambia exclusive breast-feeding study.

    Control Clin Trials 2004, 25:353-365. PubMed Abstract | Publisher Full Text OpenURL

  25. Kuhn L, Aldrovandi GM, Sinkala M, Kankasa C, Semrau K, Mwiya M, Kasonde P, Scott N, Vwalika C, Walter J, et al.: Effects of early, abrupt weaning on HIV-free survival of children in Zambia.

    N Engl J Med 2008, 359:130-141. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  26. Kuhn L, Sinkala M, Semrau K, Kankasa C, Kasonde P, Mwiya M, Hu CC, Tsai WY, Thea Donald M, Aldrovandi Grace M: Elevations in mortality associated with weaning persist into the second year of life among uninfected children born to HIV-infected mothers.

    Clin Infect Dis 2010, 50:437-444. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  27. Walter J, Mwiya M, Scott N, Kasonde P, Sinkala M, Kankasa C, Kauchali S, Aldrovandi GM, Thea Donald M, Kuhn L: Reduction in preterm delivery and neonatal mortality after the introduction of antenatal cotrimoxazole prophylaxis among HIV-infected women with low CD4 cell counts.

    J Infect Dis 2006, 194:1510-1518. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  28. World Health Organization: Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. World Health Organization, Geneva; 2010. OpenURL

  29. Allison PD: Survival analysis using the SAS system: a practical guide. SAS Institue Inc., Cary, NC; 1995. OpenURL

  30. Stringer EM, Vwalika B, Killam WP, Giganti MJ, Mbewe R, Chi BH, Chintu N, Rouse D, Goldenberg RL, Stringer JS: Determinants of stillbirth in Zambia.

    Obstet Gynecol 2011, 117:1151-1159. PubMed Abstract | Publisher Full Text OpenURL

  31. Rollins NC, Coovadia HM, Bland RM, Coutsoudis A, Bennish ML, Patel D, Newell M-L: Pregnancy outcomes in HIV-infected and uninfected women in rural and urban South Africa.

    J Acq Immun Def Synd 2007, 44:321-328. Publisher Full Text OpenURL

  32. Kumar RM, Uduman SA, Khurranna AK: Impact of maternal HIV-1 infection on perinatal outcome.

    Int J Gynecol Obstet 1995, 49:137-143. Publisher Full Text OpenURL

  33. Kupka R, Kassaye T, Saathoff E, Hertzmark E, Msamanga GI, Fawzi WW: Predictors of stillbirth among HIV-infected Tanzanian women.

    Acta Obstet Gynecol Scand 2009, 88:584-592. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  34. Soeiro R, Rubinstein A, Rashbaum WK, Lyman WD: Maternofetal transmission of AIDS: frequency of human immunodeficiency virus type 1 nucleic acid sequences in human fetal DNA.

    J Infect Dis 1992, 166:699-703. PubMed Abstract | Publisher Full Text OpenURL

  35. Langston C, Lewis DE, Hammill HA, Popek EJ, Kozinetz CA, Kline MW, Hanson IC, Shearer WT: Excess intrauterine fetal demise associated with maternal human immunodeficiency virus infection.

    J Infect Dis 1995, 172:1451-1460. PubMed Abstract | Publisher Full Text OpenURL

  36. Brossard Y, Aubin JT, Mandelbrot L, Bignozzi C, Brand D, Chaput A, Roume J, Mulliez N, Mallet F, Agut H, et al.: Frequency of early in utero HIV-1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses.

    AIDS 1995, 9:359-366. PubMed Abstract OpenURL

  37. Magder LS, Mofenson L, Paul ME, Zorrilla CD, Blattner WA, Tuomala RE, LaRussa P, Landesman S, Rich KC: Risk factors for in utero and intrapartum transmission of HIV.

    J Acquir Immune Defic Syndr 2005, 38:87-95. PubMed Abstract | Publisher Full Text OpenURL

  38. Jourdain G, Mary J-Y, Le Coeur S, Ngo-Giang-Huong N, Yuthavisuthi P, Limtrakul A, Traisathit P, Mcintosh K, Lallemant M: Risk factors for in utero or intrapartum mother-to-child transmission of human immunodeficiency virus type 1 in Thailand.

    J Infect Dis 2007, 196:1629-1636. PubMed Abstract | Publisher Full Text OpenURL

  39. Lopez M, Figueras F, Hernandez S, Lonca M, Garcia R, Palacio M, Coll O: Association of HIV infection with spontaneous and iatrogenic preterm delivery: effect of HAART.

    AIDS 2012, 26:37-43. PubMed Abstract | Publisher Full Text OpenURL

  40. Tuomala RE, Shapiro DE, Mofenson LM, Bryson Y, Culnane M, Hughes MD, O'Sullivan MJ, Scott G, Stek AM, Wara D, Bulterys M: Antiretroviral therapy during pregnancy and the risk of an adverse outcome.

    N Engl J Med 2002, 346:1863-1870. PubMed Abstract | Publisher Full Text OpenURL

  41. Shapiro RL, Hughes MD, Ogwu A, Kitch D, Lockman S, Moffat C, Makhema J, Moyo S, Thior I, McIntosh K, et al.: Antiretroviral regimens in pregnancy and breast-feeding in Botswana.

    N Engl J Med 2010, 362:2282-2294. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  42. Mphatswe W, Blanckenberg N, Tudor-Williams G, Prendergast A, Thobakgale C, Mkhwanazi N, McCarthy N, Walker BD, Kiepiela P, Goulder P: High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis.

    AIDS 2007, 21:1253-1261. PubMed Abstract | Publisher Full Text OpenURL

  43. Shearer WT, Quinn TC, LaRussa P, Lew JF, Mofenson L, Almy S, Rich K, Handelsman E, Diaz C, Pagano M, et al.: Viral load and disease progression in infants infected with human immunodeficiency virus type 1.

    N Engl J Med 1997, 336:1337-1342. PubMed Abstract | Publisher Full Text OpenURL

  44. The Working Group on Pediatric Care Treatment and the Interagency Task team on Prevention and Treatment of HIV infection in Pregnant Women, Mothers and their Children: Pediatric advocacy toolkit: For improved pediatric HIV diagnosis, care and treatment in high HIV prevalence countries and regions. WHO and UNICEF, Geneva; 2011. OpenURL

  45. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, Jean-Philippe P, McIntyre JA: Early antiretroviral therapy and mortality among HIV-infected infants.

    N Engl J Med 2008, 359:2233-2244. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  46. Goetghebuer T, Haelterman E, Le Chenadec J, Dollfus C, Gibb D, Judd A, Green H, Galli L, Ramos JT, Giaquinto C, et al.: Effect of early antiretroviral therapy on the risk of AIDS/death in HIV-infected infants.

    AIDS 2009, 23:597-604. PubMed Abstract | Publisher Full Text OpenURL

  47. Mehta S, Manji KP, Young AM, Brown ER, Chasela C, Taha TE, Read JS, Goldenberg RL, Fawzi WW: Nutritional indicators of adverse pregnancy outcomes and mother-to-child transmission of HIV among HIV-infected women.

    Am J Clin Nutr 2008, 87:1639-1649. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  48. Fawzi WW, Msamanga GI, Spiegelman D, Urassa EJN, McGrath N, Mwakagile D, Antelman G, Mbise R, Herrera G, Kapiga S, et al.: Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania.

    Lancet 1998, 351:1477. PubMed Abstract | Publisher Full Text OpenURL

  49. Olausson PO, Cnattingius S, Haglund B: Teenage pregnancies and risk of late fetal death and infant mortality.

    BJOG 1999, 106:116-121. Publisher Full Text OpenURL

  50. Gilbert WM, Jandial D, Field NT, Bigelow P, Danielsen B: Birth outcomes in teenage pregnancies.

    J Matern Fetal Neonatal Med 2004, 16:265-270. PubMed Abstract | Publisher Full Text OpenURL

  51. Chen X-K, Wen SW, Fleming N, Yang Q, Walker MC: Increased risks of neonatal and postneonatal mortality associated with teenage pregnancy had different explanations.

    J Clin Epidemiol 2008, 61:688-694. PubMed Abstract | Publisher Full Text OpenURL

  52. Smith GCS, Pell JP: Teenage pregnancy and risk of adverse perinatal outcomes associated with first and second births: population based retrospective cohort study.

    BMJ 2001, 323:476. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  53. Kline J, Stein Z, Susser M: Conception to Birth: Epidemiology of Prenatal Development (Monographs in Epidemiology and Biostatistics). Oxford University Press, New York; 1989. OpenURL

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2431/12/138/prepub