Purpose of review: The introduction of combination ART to prevent mother-to-child-transmission (MTCT) has substantially decreased MTCT rates. However, there are concerns regarding safety of ART exposure for the mother, pregnancy outcome and infant. Changing MTCT prevention guidelines, with expanded eligibility, have led to a rapid increase of ART-treated women and exposed infants in high prevalence regions.
Recent findings: Recent studies confirm that ART in HIV-infected mothers decreases disease progression and mortality, also after delivery. However extended duration of ART, especially HAART, during pregnancy has also been associated with premature delivery, small-for-gestational age (SGA) infants and pregnancy complications including hypertension. In the uninfected infant, ART exposure was associated with levels of hematologic and immunological markers, which, in high microbial regions, may be clinically relevant, especially in combination with premature birth and SGA. Altered mitochondrial functioning is reported in ART-exposed children although clinical implications remain difficult to discern.
Summary: The benefit of ART in the prevention of MTCT is beyond doubt, but there are reports on adverse effects on pregnancy outcome and infant currently also from high prevalence regions. Further research regarding safety is urgently required, as the number of pregnant women on ART and exposed uninfected infants is rapidly increasing.
aAfrica Centre for Health and Population Studies, University of KwaZulu-Natal, KwaZulu-Natal, South Africa
bFaculty of Medicine, University of Southampton, Southampton, UK
cDivision of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital
dDepartment of Experimental Immunology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Correspondence to Professor Marie-Louise Newell, MB, MSc, PhD, FMedSci, Africa Centre for Health and Population Studies, P.O Box 198 Mtubatuba, 3935 South Africa. Tel: +27 035 550 7509; fax: +27 035 550 7565; e-mail: firstname.lastname@example.org
Antiretroviral drugs are successfully used in HIV-infected women while pregnant, to delay disease progression and to prevent mother-to-child transmission (PMTCT). HIV prevalence among women is highest in sub-Saharan, in particular Southern, Africa, settings with high fertility and limited treatment-regimen choices. Current WHO guidelines recommend a combination of at least three drugs (HAART) for pregnant women with a CD4 cell count below 350 cells/μl, for life; for women with less advanced HIV, PMTCT can be HAART or zidovudine (ZDV) prophylaxis from early pregnancy with single dose nevirapine (NVP) and emtricitabine/tenofovir (Truvada) during labour , with infants receiving oral daily NVP for at least 6 weeks, or throughout breastfeeding for up to 1 year (WHO option A). Alternatively, several countries now recommend PMTCT HAART for all pregnant and breastfeeding women, irrespective of CD4 cells count (WHO Option B), or for life (WHO Option B+). Intensification of PMTCT will further substantially reduce the risk of MTCT, making vertically acquired HIV rare and improve maternal health by delaying disease progression, in turn positively affecting morbidity and mortality in their infants. However, this intensive and prolonged PMTCT regimen, and increasing numbers of women now becoming pregnant while already on HAART, will substantially increase the duration of exposure during fetal and early life for children born to HIV-infected mothers.
Concern has previously been expressed regarding the potential impact of HAART during pregnancy on pregnancy outcome, the infected child and mother, and exposed uninfected children. However, such adverse effects have not been well quantified in high HIV-prevalence settings, in which malnutrition and other comorbidities may serve to exacerbate any fetal effects of ART, and there is little understanding as to any underlying mechanisms. With the substantial roll-out of PMTCT programmes in areas of high HIV prevalence, especially in sub-Saharan Africa, recent data on the health of women on HAART, their pregnancy outcomes and impact of ART exposure on infant health, summarized in this review based on research from both high and low prevalence regions, add to this debate.
IMPACT OF ANTIRETROVIRAL THERAPY ON MATERNAL HEALTH
In high prevalence settings, HIV is the leading cause of death in women of childbearing ages, but treatment with HAART of pregnant women substantially decreases mortality [2,3▪] (Table 1). Recently, postpartum disease progression among women receiving HAART during pregnancy and for 6 months during breastfeeding was assessed and reported to be significantly lower than in women receiving zidovidine during pregnancy and single dose NVP during labour/delivery [4▪]. The effect was limited to the duration of HAART exposure.
Specific ART-related adverse effects have been described in HIV-infected pregnant women. NVP, frequently used as part of combination ART and previously associated with adverse liver and skin reactions in pregnant women with higher (≥250 cells) CD4 cell counts, was explored in a systematic review . NVP in pregnancy was associated with severe hepatotoxicity, including clinical hepatitis and increased transaminases at more than 10× the upper limit, but not severe cutaneous reactions. NVP-associated serious adverse events occurred soon (<10 weeks) after ART initiation and waned after cessation. However, in a large systematic review of 20 studies including 3582 pregnant women from 14 countries, the frequency of adverse events associated with NVP use in pregnant women, although high, was no higher than reported for NVP in the general adult population . Pregnant women with a high CD4 cell count may be at increased risk of adverse events, but evidence supporting this association is weak.
MTCT rates at 6 weeks have been reduced to 2–4% in high-prevalence regions where pregnant women access antenatal care and, when diagnosed with HIV infection during (or before) pregnancy, are offered ART to prevent MTCT or treatment to delay HIV-disease progression when eligible [12–14]. The virtual elimination of vertically acquired HIV through the use of HAART is increasingly achievable, although operational challenges remain; including early identification of HIV infection in pregnancy to allow optimal effect of HAART .
Recent papers add to the knowledge base relating to potential adverse pregnancy outcome in HIV-infected pregnant women and HAART exposure; in particular, the risk of premature delivery or small-for-gestational age (SGA) infants may be associated both with maternal HIV-infection and HAART exposure [14,16▪]. The effect of HIV infection was assessed in a nonrandomized intervention cohort [16▪], before HAART availability; HIV-infected women more commonly had SGA infants than uninfected women (18.1 vs. 15.1%), but percentages preterm (<37 weeks) were similar (21.8 vs. 20.9%). Allowing for other variables associated with outcome, infant mortality was significantly increased in SGA infants, but no difference in infant mortality was observed between the preterm and term infants.
There have been reports from Europe, USA and more recently from Africa, of increased risk of premature delivery with HAART. A successful pregnancy depends on a delicate equilibrium between maternal and fetal immune systems, which may be affected by infections or drugs thereby triggering preterm labour and delivery. HAART affects the maternal immune system, including plasma cytokine profiles and T-helper subsets associated with initiation of labour/delivery, and could also induce metabolic changes, resulting in, for example, hypertension or preeclampsia, and preterm delivery.
In a recent article from Botswana [7▪], rates of stillbirth, premature delivery, SGA infants and neonatal death were recorded in HIV-infected and uninfected women. Of more than 33 000 women, about 30% HIV-infected, rates of all adverse pregnancy outcomes were significantly higher in HIV-infected than uninfected women. Among HIV-infected women, those who continued HAART from before pregnancy were 20% more likely to deliver prematurely, 80% more likely to have SGA infants and 50% more likely to have a stillbirth than women in whom HAART was initiated during pregnancy; women who initiated HAART during pregnancy were at increased risk of adverse pregnancy outcome compared with women who were treated with only ZDV for PMTCT. Maternal hypertension, more frequent in women with continued HAART than in those initiating HAART or ZDV alone during pregnancy, was associated with SGA infant and stillbirth. However, in a small Spanish study , the overall preterm delivery (<37 weeks) rate in HIV-infected women was more than double that in matched controls, which was shown to be associated with the use of HAART during the second half of pregnancy but not with HAART initiated prior to the pregnancy.
In an article from Switzerland , linking the records of HIV-infected pregnant women with records of the same women in adult care before pregnancy and allowing for sociodemographic variables, the risk of premature delivery was increased by 80% in women who received mono/dual ART during pregnancy and more than doubled in those on HAART, compared with infected women who did not receive ART during pregnancy. In this study, there was no evidence for any confounding effects of maternal clinical, demographic or lifestyle characteristics.
The mechanism underlying premature delivery is unknown; an immune reconstruction inflammatory syndrome-induced response in the mother has been suggested, which is in line with the findings from Lopez et al. However, results from Chen et al.[7▪] that women on HAART from before pregnancy were most at risk of premature delivery would suggest an alternative mechanism. Overall these data illustrate determination of the optimal timing of initiation of HAART is complex: initiation of HAART before or in early pregnancy may prevent most MTCT but could lead to adverse pregnancy outcome. Further research into the mechanisms explaining these effects is urgently required .
Specific concern has been raised regarding the use of tenofovir in pregnant women, which is increasingly used in PMTCT. Gibb et al.[17▪], using data from Uganda and Zambia, showed that the frequency of congenital abnormalities was not associated with Tenofovir use (Table 2). Efavirenz has been associated with central nervous system (CNS) malformations in cynomolgus monkeys with in-utero exposure and subsequently there have been several case reports of CNS malformations (mainly neural tube defects) in infants exposed to efavirenz. In a recent systematic review , the pooled prevalence of overall birth defects for women exposed to first trimester efavirenz (2.0%) was similar to that for women exposed to non-efavirenz-based regimens (2.9%) and in the general population (6%). Incidence of neural tube defects remains low (0.07%), but this estimate is derived from a small sample. In-utero exposure to high doses of delavirdine in rats was associated with ventricular septal defects and use of this drug should be avoided in pregnancy or in women planning to become pregnant until further data is available.
ANTIRETROVIRAL THERAPY EXPOSURE IN FETAL AND EARLY LIFE AND INFANT HEALTH
One recurring observation relating to HAART exposure in fetal and early life is mitochondrial toxicity, in particular with ZDV, although studies have reported conflicting results and questions regarding a potential association and mechanism remain. Ross et al. investigated placental material, umbilical cord blood and infant peripheral blood on 20 HIV/ART exposed and 26 unexposed infants (Table 2). HIV-exposed infants showed reduced umbilical cord blood mitochondrial enzyme expression with increased infant peripheral blood mitochondrial DNA levels, the latter possibly reflecting a compensatory mechanism to overcome HIV/ART-associated mitochondrial toxicity. A similar study by Hernandez et al. detected reduced mitochondrial DNA levels, maternal and fetal mitochondrial protein synthesis and maternal glycerol-3-phosphate+ complex III function. HAART exposure was one trimester longer in the Spanish study and demographics differed between the two studies, which may have affected the results. Fatty acid oxidation also depends on oxidative phosphorylation. A large study (N = 2731) by Kirmse et al.[21▪] showed that in addition to an increase in mitochondrial disorders in ART and HIV-exposed infants, acylcarnitine levels were also altered with an increase in fatty acid oxidation disorders. In a sub-analysis comparing children born to HIV-infected women with and without ART exposure, acylcarnitine levels were only altered upon ART exposure suggesting a specific effect of ART and not HIV [21▪].
Whether the described abnormalities have clinical ramifications remains uncertain. Neurologic abnormalities have been described and concern regarding psychomotor development has been raised. In a large USA study, Mental Developmental Index (MID) and Psychomotor Developmental Index (PDI) were lower in children born to HIV-infected women compared to the general population. Reassuringly, ART exposure did not affect MID and PDI in children with a normal birth weight, however in children with a low birth weight ART exposure negatively affected MDI and PDI . Other organs such as the heart may be affected. In a USA study  on 216 uninfected children born to HIV-infected women before ART availability and 136 uninfected, HAART exposed children, showed that fetal HAART exposure was associated with reduced left ventricle mass, as well as an increased left ventricle fractional shortening up to 2 years of age; these effects were more pronounced in girls than in boys. The authors concluded that fetal ART exposure may impair myocardial growth and be associated with improved left ventricle functioning up to 2 years of age. The combination of antiretroviral compounds seems to be associated with increased mitochondrial toxicity in rodents, potentially explaining its absence in ZDV-only exposed infants. Whether the thinner heart muscle could lead to increased cardiovascular diseases (heart failure) at later ages needs to be investigated. Further studies of potential pathways and with longer follow-up and appropriate controls are needed to assess clinical consequences.
Haematological abnormalities associated with HAART exposure in fetal and early life have been previously described. In-utero exposure was associated specifically with long-term changes in neutrophil levels, while anaemia generally resolves after cessation of ART. The effects of neonatal ART prophylaxis was recently investigated in a German/Austrian study addressing the safety of 2, rather than 6-week ZDV prophylaxis in PMTCT . The only serious side-effect was anaemia, which resolved when neonatal ZDV treatment ceased. In the HPTN040 trial , evaluating three postpartum ART regimen to the infant in the absence of maternal ART during pregnancy, infants who received only ZDV for 6 weeks postpartum were more likely to acquire infection intra-partum than children who received 6 weeks ZDV and either three doses of oral NVP in the first 8 days of life or 2 weeks nelfinavir and lamivudine. However, a dose-dependent effect was observed with serious adverse events, mainly neutropenia and anaemia, more frequently detected in the three than in the two and one regimen group.
Whether the long-term effects of ART exposure in-utero on haematological stem cells may affect immunity against infections is unknown, however to date there have not been any alarming observations from low-prevalence countries with long-term experience with HAART. Nevertheless, this may be different in high HIV-prevalence countries. Furthermore, the effects on the immune system with fetal exposure to maternal HIV infection and HAART may be cumulative. Altered vaccine responses in terms of specific immune globulin production and cellular responses have been described [30,31]. Some studies reported more severe disease progression with more prominent sequelae of common infections with (intra-cellular) pathogens in HIV-exposed infants compared with infants born to healthy mothers . For example, a study from Zambia showed that HIV-exposed infants infected with cytomegalovirus (CMV) were shorter, had a reduced head circumference and delayed psychomotor development than CMV-infected infants born to healthy mothers, suggesting more severe sequelae of CMV infection in HIV-exposed infants . Increased risks of postoperative infectious complications in HIV-exposed children, in particularly sepsis and pneumonia [29,33,34], have also been reported. Most studies reporting increased infections were performed in nonbreastfeeding or mixed-feeding populations, which could potentially affect the results .
Evidence suggesting that even if there is an effect of HAART on the developing fetus’ immune system, the overall impact may not be clinically relevant, comes from a recent report on more than 9000 mothers of 12 000 children in a rural surveillance area in South Africa [3▪]. Infant mortality rates declined substantially after the rollout of ART programmes in the area. Allowing for other factors associated with child mortality, mortality in children of HIV-infected mothers on HAART was not significantly different from that in children of HIV-negative mothers. These findings highlight the importance of maternal HIV treatment with direct benefit of improved survival among all children up to 5 years of age.
With changing ART regimens with new ART compounds novel adverse effects may arise. In HIV-infected infants and adults tenofovir use is associated with a decreased bone mineral density and the fetus may be similarly affected. In the DART sub-study [17▪] in pregnant women who received HAART with or without tenofovir, there were no bone fractures during an average of 25 months of follow-up, no renal toxicity and no evidence of growth delay in the tenofovir-exposed children. Siberry et al. did not detect differences between tenofovir-exposed infants and not exposed infants regarding length, weight and head circumference at birth, although at 1 year of age length and head circumference were marginally reduced. Another ART compound increasingly used is ritonavir-boosted lopinavir and adrenal insufficiency has been reported in children exposed to ritonavir-boosted lopinavir as PMTCT prophylaxis .
The benefit of HAART in improving maternal and infant health by reducing MTCT and prolonging survival is unparalleled compared to any other HIV PMTCT intervention. However, although HAART is overall relatively safe, questions remain about the effect on immunological and metabolic pathways in the mother and infant and their potential relation to the risk of adverse pregnancy outcomes, especially preterm delivery, SGA, immunity and metabolic disorders in the infant, and particularly in resource-limited settings where malnutrition and co-morbidities may exacerbate any effect of ART on the fetus and young infant. The recent development with extending exposure to HAART beyond birth in high-prevalence, resource-limited settings to prevent transmission via breastfeeding [35,36], and increasing duration of ART exposure in infants and mothers, urgently requires long-term follow-up studies monitoring mothers and infants to ensure optimal care.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 519).
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