Abstract
Introduction
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without antiretroviral treatment, the risk of HIV transmission from infected mothers to their children is 15% to 30% during gestation or labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads, advanced disease, or both, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood. Mixed feeding practices (breast milk plus other liquids or solids) and prolonged breastfeeding are also associated with increased risk of mother-to-child transmission of HIV.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother-to-child transmission of HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
Results
We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, micronutrient supplements, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breastfeeding is the norm.
Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15% to 30% during pregnancy and labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding.
HIV-2 is rarely transmitted from mother to child.
Transmission is more likely in mothers with high viral loads, advanced HIV disease, or both.
Without antiretroviral treatment (ART), 15% to 35% of vertically infected infants die within the first year of life.
The long-term treatment of children with ART is complicated by multiple concerns regarding the complications associated with life-long treatment, including adverse effects of antiretroviral drugs, difficulties of adherence across the developmental trajectory of childhood and adolescence, and the development of resistance.
From a paediatric perspective, successful prevention of MTCT and HIV-free survival for infants remain the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, to the baby immediately after birth, or to the mother and baby reduce the risk of intrauterine and intrapartum MTCT of HIV-1 and when given to the infant after birth and to the mother or infant during breastfeeding reduce the risk of postpartum MTCT of HIV-1.
Reductions in MTCT are possible using multidrug ART regimens.
Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.
Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1% to 2%.
Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. There is evidence that short courses of antiretroviral drugs have confirmed efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.
The development of viral resistance in mothers and infants after single-dose nevirapine and other short-course regimens that include single-dose nevirapine is of concern. An additional short-course of antiretrovirals with a different regimen during labour and early postpartum, and the use of HAART, may decrease the risk of viral resistance in mothers, and in infants who become HIV-infected despite prophylaxis.
World Health Organization guidelines recommend starting prophylaxis with antiretroviral drugs from as early as 14 weeks' gestation, or as soon as possible if women present late in pregnancy, in labour, or at delivery.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission).
The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin seems no more effective than immunoglobulin without HIV antibody at reducing HIV-1 MTCT risk.
Vaginal microbicides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that supplementation with vitamin A reduces the risk of HIV-1 MTCT, and there is concern that postnatal vitamin A supplementation for mother and infant may be associated with increased risk of mortality.
We don't know whether micronutrients are effective in prevention of MTCT of HIV as we found no RCT evidence on this outcome.
Avoidance of breastfeeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education.
The risk of breastfeeding-related HIV transmission needs to be balanced against the multiple benefits that breastfeeding offers. In resource-poor countries, breastfeeding is strongly associated with reduced infant morbidity and improved child survival.
Exclusive breastfeeding during the first 6 months may reduce the risk of HIV transmission compared with mixed feeding, while retaining most of its associated benefits.
In a population where prolonged breastfeeding is usual, early, abrupt weaning may not reduce MTCT or HIV-free survival at 2 years compared with prolonged breastfeeding, and may be associated with a higher rate of infant mortality for those infants diagnosed as HIV-infected at <4 months of age.
Antiretrovirals given to the mother or the infant during breastfeeding can reduce the risk of HIV transmission in the postpartum period.
World Health Organization guidelines recommend that HIV-positive mothers should exclusively breastfeed for the first 6 months, after which time appropriate complementary foods can be introduced. Breastfeeding should be continued for the first 12 months of the infant's life, and stopped only when an adequate diet without breast milk can be provided.
Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
Clinical context
About this condition
Definition
Mother-to-child transmission (MTCT) of HIV infection is defined as transmission of HIV from an infected mother to her child during gestation, labour, or postpartum through breastfeeding. HIV-1 infection is frequently transmitted from mother to child, although HIV-2 is rarely transmitted in this way. Infected children rarely have symptoms or signs of HIV at birth, but usually develop them over subsequent months.
Incidence/ Prevalence
A review of 13 cohort studies estimated the risk of MTCT of HIV in the absence of antiretroviral treatment (ART) to be 15% to 20% in Europe, 15% to 30% in the USA, and 25% to 35% in Africa. The risk of transmission is estimated to be 15% to 30% during pregnancy, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. The Joint United Nation's Programme on HIV/AIDS (UNAIDS) estimates that more than 2 million children are infected with HIV-1 worldwide, and that more than 1000 new HIV infections are transmitted daily from mothers to infants. Of these, more than 80% are in sub-Saharan Africa, where almost 400,000 children were newly infected with HIV in 2008 alone.
Aetiology/ Risk factors
Transmission of HIV to infants is more likely if the mother has a high viral load. Based on polymerase chain reaction (PCR) results of infants at 6 weeks of age, a Tanzanian study reported that a maternal viral load of 50,000 copies/mL or more at delivery was associated with a 4-fold increase in the risk of early transmission (OR 4.21, 95% CI 1.59 to 11.13; P = 0.004). Other maternal risk factors include low CD4+ count, advanced HIV disease, sexually transmitted diseases, chorioamnionitis, prolonged rupture of membranes, vaginal mode of delivery, and obstetric events with bleeding (episiotomy, perineal laceration, and intrapartum haemorrhage). Estimations of the timing of MTCT of HIV-1 during pregnancy indicate that the probability of transmission in non-breastfeeding populations (80%) is highest during late pregnancy (3% at <14 weeks, 3% at 14–28 weeks, 14% at 28–36 weeks, 50% at 36 weeks to labour, and 30% during labour). Prolonged breastfeeding poses a significant additional risk for MTCT, with about 60% of total transmissions occurring during pregnancy, and 40% via breast milk in breastfeeding populations. With the use of effective drug regimens to reduce pre-partum and intrapartum MTCT of HIV, prolonged breast or mixed feeding without continued antiretroviral prophylaxis or treatment becomes the predominant route of transmission. Observational studies have found that mixed feeding (breast milk in combination with other liquids or solids) is associated with a significantly higher risk of postnatal transmission compared with exclusive breastfeeding; prospective cohort studies have reported early mixed feeding (during the infants' first 6 months) to be associated with increased risk of postnatal MTCT of 4.03 (95% CI 0.98 to 16.61; 2060 infants in Zimbabwe who were HIV-negative at 6 weeks) and 6.30 (95% CI 1.1 to 36.4; 622 infants from Cote d'Ivoire who were HIV-negative at or after 30 days). One study also found that prolonged exclusive breastfeeding (beyond 6 months) was associated with an increased risk of postnatal MTCT compared with formula feeding (622 infants from Cote d'Ivoire who were HIV-negative at or after 30 days; increase in risk of MTCT of 7.5, 95% CI 2.0 to 28.2; P = 0.003). Late postnatal transmission (beyond 6 months) contributes substantially to overall MTCT, with prolonged breastfeeding (beyond 6 months) and maternal disease progression (as measured by CD4+ count) identified as risk factors. Data from a small retrospective case series in China (104 women who acquired HIV-1 through postnatal blood transfusion) showed a potential increased risk of MTCT when mothers seroconverted during breastfeeding after becoming infected with HIV-1 through postnatal blood transfusion (MTCT risk 35.8%, 95% CI 26.7% to 44.9%). Data from a meta-analysis of individual patient data found a 2-fold increase in the risk of postnatal transmission among women with CD4+ counts of less than 200 cells/mm3.
Prognosis
The natural history of HIV infection in infancy is variable. It has been estimated that 25% of infants infected with HIV progress rapidly to AIDS or death within the first year of life, although some survive beyond 12 years of age, even in the absence of ART. One collaborative European study that documented the natural history of disease in the absence of ART reported 15% mortality during infancy, and 28% mortality by the age of 5 years. In one prospective cohort study carried out in France, 2% of perinatally infected children (data reported for 348 HIV-1-infected children) displayed no immunological or clinical symptoms by the age of 10 years. The study found that the mother's clinical status during pregnancy, prematurity of the infant, and the child's initial CD4+ and CD8+ counts were associated with disease progression. However, the prognosis of African children with vertically acquired HIV infection seems significantly worse. One meta-analysis of individual patient data for children born to HIV-infected mothers in Africa (3468 children in analysis) estimated that, of the 707 HIV-infected children, 35.2% would have died by 1 year of age, and 52.5% by 2 years of age. By comparison, the study estimated that 4.9% of uninfected children would have died by 1 year of age and 7.6% by 2 years of age. Stage of disease was a significant predictor of mortality; a prospective cohort study (213 infants with HIV) from Zambia found that infants infected with HIV in the intrauterine (0–3 days postpartum) or intrapartum/early postpartum (4–40 days) periods had a significantly higher risk of mortality at 12 months compared with children with late postpartum infection (>40 days) (HR for late postpartum infection v intrauterine infection 0.27, 95% CI 0.15 to 0.50; for intrapartum/early postpartum v late postpartum infection; P = 0.006). On a population level, HIV accounts for 4% of overall child deaths in sub-Saharan Africa, and each year causes 210,000 child deaths across the continent. Five countries (Botswana, Namibia, Swaziland, Zambia, and Zimbabwe) reported HIV-attributable mortality in excess of 30/1000 in children under the age of 5 years.
Aims of intervention
To reduce MTCT of HIV and improve infant survival, with minimal adverse effects.
Outcomes
HIV infection status of the child; infant HIV-free survival at 2 years; infant morbidity and mortality; adverse effects in mothers, infants, or both.
Methods
Clinical Evidence search and appraisal October 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to October 2009, Embase 1980 to October 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, including open studies and any number of individuals, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. For the option of antiretroviral treatments for the prevention of intrauterine and intrapartum transmission, we have included RCTs in which treatment was given to the mother during gestation or labour; some RCTs include treatment for the infant. For the option of antiretroviral treatments for the prevention of postpartum transmission, we have included RCTs here that carried out an analysis of infants who were diagnosed as HIV negative at birth. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table 1.
GRADE evaluation of interventions for HIV: mother-to-child transmission
| Important outcomes | HIV transmission, infant mortality, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of measures to reduce mother-to-child transmission of HIV? | |||||||||
| 3 (2498) | HIV transmission | Antiretrovirals v placebo in a breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of non-breastfeeding women in largest RCT (25% of women) |
| 3 (2498) | Infant mortality | Antiretrovirals v placebo in a breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological limitations (incomplete reporting of results). Directness point deducted for inclusion of non-breastfeeding women in largest RCT (25% of women) |
| 1 (222) | HIV transmission | Different durations of regimens using the same antiretrovirals v each other in a breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (222) | Infant mortality | Different durations of regimens using the same antiretrovirals v each other in a breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (2346) | HIV transmission | Different antiretroviral regimens v each other in a breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological limitations (early termination of 1 RCT due to poor recruitment). Directness points deducted for use of a composite outcome in 1 RCT (includes mortality) |
| 4 (2346) | Infant mortality | Different antiretroviral regimens v each other in a breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (early termination of 1 RCT due to poor recruitment). |
| 3 (984) | HIV transmission | Antiretrovirals v placebo in a non-breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (984) | Infant mortality | Antiretrovirals v placebo in a non-breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results) |
| 1 (1437) | HIV transmission | Different durations of regimens using the same antiretrovirals v each other in a non-breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results) |
| 1 (1109) | Infant mortality | Different durations of regimens using the same antiretrovirals v each other in a non-breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results) |
| 4 (4165) | HIV transmission | Different antiretroviral regimens v each other in a non-breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (short follow-up in 1 study) |
| 4 (4643) | Infant mortality | Different antiretroviral regimens v each other in a non-breastfeeding population (prevention of intrauterine and intrapartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (short follow-up in 1 study and incomplete reporting of results) |
| 3 (2632) | HIV transmission | Different short-term antiretroviral regimens v each other (prevention of postpartum MTCT) | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for methodological limitations (incomplete reporting of results in 1 RCT, subgroup analysis in 2 RCTs, and 1 RCT may have been underpowered to detect a clinically important difference for this outcome). Consistency point deducted for inconsistent results for the same regimen |
| 3 (5053) | Infant mortality | Different short-term antiretroviral regimens v each other (prevention of postpartum MTCT) | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for methodological limitations (incomplete reporting of results in 1 RCT, and subgroup analysis in 2 RCTs). Consistency point deducted for inconsistent results for the same regimen |
| 2 (5053) | HIV transmission | Short-term antiretroviral regimens v extended antiretroviral regimens (prevention of postpartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results in 1 RCT, 1 RCT may have been underpowered to detect a clinically important difference for this outcome and there were differences among groups in usual care) |
| 2 (5053) | Infant mortality | Short-term antiretroviral regimens v extended antiretroviral regimens (prevention of postpartum MTCT) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results in 1 RCT, and differences among groups in usual care in 1 RCT) |
| 1 (425) | HIV transmission | Formula feeding v breastfeeding alone | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (425) | HIV-free survival | Formula feeding v breastfeeding alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results) |
| 1 (425) | Infant mortality | Formula feeding v breastfeeding alone | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (1200) | HIV transmission | Formula feeding plus antiretrovirals v breastfeeding plus antiretrovirals for infants | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results and open-label RCT) |
| 1 (1200) | Infant mortality | Formula feeding plus antiretrovirals v breastfeeding plus antiretrovirals for infants | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results and open-label RCT) |
| 1 (958) | HIV transmission | Early cessation of breastfeeding v prolonged breastfeeding | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results and low adherence to recommended protocol in both groups) |
| 1 (958) | HIV-free survival | Early cessation of breastfeeding v prolonged breastfeeding | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (incomplete reporting of results and low adherence to recommended protocol in both groups) |
| 1 (132) | Infant mortality | Early cessation of breastfeeding v prolonged breastfeeding | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and methodological limitations (incomplete reporting of results and for subgroup analysis, and low adherence to recommended protocol in both groups) |
| 1 (436) | HIV transmission | Elective caesarean section v vaginal delivery | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for differences in interventions between groups |
| 1 (501) | HIV transmission | HIV hyperimmune globulin v immunoglobulin without HIV antibody | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (1 RCT potentially underpowered to detect a clinically important difference) |
| 2 (708) | HIV transmission | Vaginal microbicides v no microbicides | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (randomisation flaws in included RCTs, and for 1 RCT being underpowered to detect a clinically meaningful difference) |
| 2 (215) | Infant mortality | Vaginal microbicides v no microbicides | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for methodological limitations (randomisation flaws in included RCTs, and for 1 RCT being underpowered to detect a clinically meaningful difference) |
| 4 (6517) | HIV transmission | Vitamin A supplements v placebo/control | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for heterogeneity among RCTs in meta-analysis |
| 1 (3708) | Infant mortality | Vitamin A supplements v placebo/control | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological limitations (incomplete reporting of data). Directness point deducted for using a composite outcome |
| 1 (815) | Infant mortality | Micronutrient supplements v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological limitations (incomplete reporting and for short follow-up [6 months]). Directness point deducted for administration of maternal co-intervention throughout pregnancy (multivitamins) |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies.Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Human immunodeficiency virus type 1 (HIV-1)
is the most common cause of HIV disease throughout the world.
- Human immunodeficiency virus type 2 (HIV-2)
is predominantly found in West Africa and is more closely related to the simian immunodeficiency virus than to HIV-1.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Chloe A Teasdale, International Center for AIDs Care & Treatment Programs, Columbia University, New York, USA.
Ben J Marais, UKWANDA Centre for Rural Health and the Department of Paediatrics and Child Health, Stellenbosch University, South Africa.
Elaine J Abrams, Columbia University, New York, USA.
References
- 1.John GC, Kreiss J. Mother-to-child transmission of human immunodeficiency virus type 1. Epidemiol Rev 1996;18:149–157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Adjorlolo-Johnson G, De Cock KM, Ekpini E, et al. Prospective comparison of mother-to-child transmission of HIV-1 and HIV-2 in Abidjan, Ivory Coast. JAMA 1994;272:462–466. [PubMed] [Google Scholar]
- 3.Peckham C, Gibb D. Mother-to-child transmission of the human immunodeficiency virus. N Engl J Med 1995;333:298–302. [DOI] [PubMed] [Google Scholar]
- 4.Working Group on MTCT of HIV. Rates of mother-to-child transmission of HIV-1 in Africa, America and Europe: results of 13 perinatal studies. J Acquir Immune Defic Syndr 1995;8:506–510. [DOI] [PubMed] [Google Scholar]
- 5.Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000;283:1167–1174. [DOI] [PubMed] [Google Scholar]
- 6.UNAIDS/WHO. AIDS epidemic update: November 2009. http://data.unaids.org/pub/Report/2009/JC1700_Epi_Update_2009_en.pdf (last accessed 2 December 2010). [Google Scholar]
- 7.Mofenson LM. Epidemiology and determinants of vertical HIV transmission. Semin Pediatr Infect Dis 1994;5:252–256. [Google Scholar]
- 8.Khouri YF, McIntosh K, Cavacini L, et al. Vertical transmission of HIV-1: correlation with maternal viral load and plasma levels of CD4 binding site anti-gp 120 antibodies. J Clin Invest 1995;95:732–737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Fawzi W, Msamanga G, Renjifo B, et al. Predictors of intrauterine and intrapartum transmission of HIV-1 among Tanzanian women. AIDS 2001;15:1157–1165. [DOI] [PubMed] [Google Scholar]
- 10.Nair P, Alger L, Hines S, et al. Maternal and neonatal characteristics associated with HIV infection in infants of seropositive women. J Acquir Immune Defic Syndr 1993;6:298–302. [PubMed] [Google Scholar]
- 11.Minkoff H, Burns DN, Landesman S, et al. The relationship of the duration of ruptured membranes to vertical transmission of human immunodeficiency virus. Am J Obstet Gynecol 1995;173:585–589. [DOI] [PubMed] [Google Scholar]
- 12.European Collaborative Study. Risk factors for mother-to-child transmission of HIV-1. Lancet 1992;339:1007–1012. [DOI] [PubMed] [Google Scholar]
- 13.Mofenson LM. A critical review of studies evaluating the relationship of mode of delivery to perinatal transmission of human immunodeficiency virus. Pediatr Infect Dis J 1995;14:169–176. [DOI] [PubMed] [Google Scholar]
- 14.Jamieson D, Sibailly TS, Sadek R, et al. HIV-1 viral load and other risk factors for mother-to-child transmission in a breastfeeding population in Cote d'Ivoire. J Acquir Immune Defic Syndr 2003;34:430–436. [DOI] [PubMed] [Google Scholar]
- 15.Kourtis AP, Lee FK, Abrams EJ, et al. Mother-to-child transmission of HIV-1: timing and implications for prevention. Lancet Infect Dis 2006;6:726–732. [DOI] [PubMed] [Google Scholar]
- 16.Iliff PJ, Piwoz EG, Tavengwa NV, et al. Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival. AIDS 2005;19:699–708. [DOI] [PubMed] [Google Scholar]
- 17.Becquet R, Ekouevi DK, Menan H, et al. Early mixed feeding and breastfeeding beyond 6 months increase the risk of postnatal HIV transmission: ANRS 1201/1202 Ditrame Plus, Abidjan, Cote d'Ivoire. Prev Med 2008;47:27–33. [DOI] [PubMed] [Google Scholar]
- 18.Coutsoudis A, Dabis F, Fawzi W, et al. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004;189:2154–2166. [DOI] [PubMed] [Google Scholar]
- 19.Liang K, Gui X, Zhang YZ, et al. A case series of 104 women infected with HIV-1 via blood transfusion postnatally: high rate of HIV-1 transmission to infants through breast-feeding. J Infect Dis 2009;200:682–686. [DOI] [PubMed] [Google Scholar]
- 20.European Collaborative Study. Natural history of vertically acquired human immunodeficiency virus-1 infection. Pediatrics 1994;94:815–819. [PubMed] [Google Scholar]
- 21.Warszawski J, Lechenadec J, Faye A, et al. Long-term nonprogression of HIV infection in children: evaluation of the ANRS prospective French Pediatric Cohort. Clin Infect Dis 2007;45:785–794. [DOI] [PubMed] [Google Scholar]
- 22.Newell ML, Coovadia H, Cortina-Borja M, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004;364:1236–1243. [DOI] [PubMed] [Google Scholar]
- 23.Fox MP, Brooks D, Kuhn L, et al. Reduced mortality associated with breast-feeding-acquired HIV infection and breast-feeding among HIV-infected children in Zambia. J Acquir Immune Defic Syndr 2008;48:90–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Kinney MV, Kerber KJ, Black RE, et al. Sub-Saharan Africa's mothers, newborns, and children: where and why do they die? PLoS Med 2010;7:e1000294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Walker N, Schwartlander B, Bryce J. Meeting international goals in child survival and HIV/AIDS. Lancet 2002;360:284–289. [DOI] [PubMed] [Google Scholar]
- 26.Volmink J, Siegfried NL, van der Merwe L, et al. Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2006. [Google Scholar]
- 27.Shapiro RL, Thior I, Gilbert PB, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana. AIDS 2006;20:1281–1288. [DOI] [PubMed] [Google Scholar]
- 28.Thistle P, Spitzer RF, Glazier RH, et al. A randomized, double-blind, placebo-controlled trial of combined nevirapine and zidovudine compared with nevirapine alone in the prevention of perinatal transmission of HIV in Zimbabwe. Clin Infect Dis 2007;44:111–119. [DOI] [PubMed] [Google Scholar]
- 29.Chi BH, Sinkala M, Mbewe F, et al. Single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial.[see comment]. Lancet 2007;370:1698–1705. [DOI] [PubMed] [Google Scholar]
- 30.Chi BH, Chintu N, Cantrell RA, et al. Addition of single-dose tenofovir and emtricitabine to intrapartum nevirapine to reduce perinatal HIV transmission. J Acquir Immune Defic Syndr 2008;48:220–223. [DOI] [PubMed] [Google Scholar]
- 31.Wiktor SZ, Ekpini E, Karon JM, et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cote d'Ivoire: a randomised trial. Lancet 1999;353:781–785. [DOI] [PubMed] [Google Scholar]
- 32.Dabis F, Msellati P, Meda N, et al. Six-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d'Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. Lancet 1999;353:786–792. [DOI] [PubMed] [Google Scholar]
- 33.Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet 2002;359:1178–1186. [DOI] [PubMed] [Google Scholar]
- 34.Thistle P, Gottesman M, Pilon R, et al. A randomized control trial of an Ultra-Short zidovudine regimen in the prevention of perinatal HIV transmission in rural Zimbabwe. Cent Afr J Med 2004;50:79–84. [PubMed] [Google Scholar]
- 35.Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795–802. [DOI] [PubMed] [Google Scholar]
- 36.Brooks Jackson J, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18 month follow-up of the HIVNET 012 randomised trial. Lancet 2003;362:859–868. [DOI] [PubMed] [Google Scholar]
- 37.Thior I, Lockman S, Smeaton LM, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. JAMA 2006;296:794–805. [DOI] [PubMed] [Google Scholar]
- 38.Connor EM, Sperling RS, Gelber RD, et al. Reduction of maternal–infant transmission of human immunodeficiency type 1 with zidovudine treatment. N Engl J Med 1994;331:1173–1180. [DOI] [PubMed] [Google Scholar]
- 39.Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Lancet 1999;353:773–780. [DOI] [PubMed] [Google Scholar]
- 40.Limpongsanurak S, Thaithumyanon P, Chaithongwongwatthana S, et al. Short course zidovudine maternal treatment in HIV-1 vertical transmission: randomized controlled multicenter trial. J Medical Assoc Thai 2001;84:S338–S345. [PubMed] [Google Scholar]
- 41.Lallemant M, Jourdain G, Le Couer S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. N Engl J Med 2000;343:982–991. [DOI] [PubMed] [Google Scholar]
- 42.Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission. A randomized trial. JAMA 2002;288:189–198. [DOI] [PubMed] [Google Scholar]
- 43.Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis 2003;187:725–735. [DOI] [PubMed] [Google Scholar]
- 44.Lallemant M, Jourdain G, Le Coeur S, et al. Single dose perinatal nevirapine plus standard zidovudine to prevent mother to child transmission of HIV-1 in Thailand. N Engl J Med 2004;351:217–228. [DOI] [PubMed] [Google Scholar]
- 45.Gray G, Violari A, McIntyre J, et al. Antiviral activity of nucleoside analogues during short-course monotherapy or dual therapy: its role in preventing HIV infection in infants. J Acquir Immune Defic Syndr 2006;42:169–176. [DOI] [PubMed] [Google Scholar]
- 46.McKoy JM, Bennett CL, Scheetz MH. Hepatotoxicity associated with long- versus short-course HIV-prophylactic nevirapine use: a systematic review and meta-analysis from the Research on Adverse Drug events And Reports (RADAR) project. Drug Safety 2009;32:147–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Briand N, Lallemant M, Jourdain G, et al. Haematological safety of perinatal Zidovudine in pregnant HIV-1-infected women in Thailand secondary analysis of a randomized trial. PLoS Clinical Trials 2007;2:e11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Shekelle P, Maglione M, Geotz MB, et al. Antiretroviral (ARV) drug resistance in the developing world. Evid Rep Technol Assess (Full Rep) 2007;(156):1–74. [PMC free article] [PubMed] [Google Scholar]
- 49.McIntyre JA Martison N, Gray GE, et al. Single dose nevirapine combined with a short course of combivir for prevention of mother to child transmission of HIV-1 can significantly decrease the subsequent development of maternal and infant resistant virus. Antivir Ther 2005;10:S4. [Google Scholar]
- 50.McIntyre JA, Hopley M, Moodley D, et al. Efficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: a randomized clinical trial. PLoS Med 2009;6:e1000172. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.World Health Organization. Rapid advice: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. November 2009. http://www.who.int/hiv/pub/mtct/rapid_advice_mtct.pdf (last accessed 2 December 2010). [Google Scholar]
- 52.Six Week Extended-Dose Nevirapine (SWEN) Study Team, Bedri A, Gudetta B, et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet 2008;372:300–313. [DOI] [PubMed] [Google Scholar]
- 53.Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med 2008;359:119–129. [DOI] [PubMed] [Google Scholar]
- 54.Taha ET, Kumwenda N, Gibbons A, et al. Short post-exposure prophylaxis in newborn babies to reduce mother- to-child transmission of HIV-1: NVAZ randomized clinical trial. Lancet 2003;362:1171–1177. [DOI] [PubMed] [Google Scholar]
- 55.Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting: a randomized controlled trial. JAMA 2004;292:202–209. [DOI] [PubMed] [Google Scholar]
- 56.Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers. AIDS 2005,19:1289–1297. [DOI] [PubMed] [Google Scholar]
- 57.Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med 2010;362:2271–2281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med 2010;362:2282–2294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir Immune Defic Syndr 2008;48:315–323. [DOI] [PubMed] [Google Scholar]
- 60.Peltier CA, Ndayisaba GF, Lepage P, et al. Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda. AIDS 2009;23:2415–2423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir Immune Defic Syndr 2009;52:406–416. [DOI] [PubMed] [Google Scholar]
- 62.Mbori-Ngacha D, Nduati R, John G, et al. Morbidity and mortality in breastfed and formula-fed infants of HIV-1-infected women: a randomized clinical trial. JAMA 2001;286:2413–2420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Kuhn L, Aldrovandi GM, Sinkala M, et al. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med 2008;359:130–141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Nduati R, Richardson BA, John G, et al. Effect of breastfeeding on mortality among HIV-1 infected women: a randomised trial. Lancet 2001;357:1651–1655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Breastfeeding and HIV International Transmission Study Group. Mortality among HIV-1-infected women according to children's feeding modality: an individual patient data meta-analysis. J Acquir Immune Defic Syndr 2005;39:430–438. [DOI] [PubMed] [Google Scholar]
- 66.Taha TE, Kumwenda NI, Hoover DR, et al. The impact of breastfeeding on the health of HIV-positive mothers and their children in sub-Saharan Africa. Bull World Health Organ 2006;84:546–554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007;369:1107–1116. [DOI] [PubMed] [Google Scholar]
- 68.World Health Organization. Rapid advice: revised WHO principles and recommendations on infant feeding in the context of HIV. November 2009. http://www.searo.who.int/LinkFiles/HIV-AIDS_Rapid_Advice_Infant_feeding(web).pdf (last accessed 2 December 2010). [Google Scholar]
- 69.Hartmann SU, Berlin CM, Howett MM. Alternative modified infant-feeding practices to prevent postnatal transmission of human immunodeficiency virus type 1 through breast milk: Past, present, and future. J Hum Lact 2006;22:75–88. [DOI] [PubMed] [Google Scholar]
- 70.Read JS, Newell ML. Efficacy and safety of cesarean delivery for prevention of mother-to-child transmission of HIV-1. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2004. [DOI] [PubMed] [Google Scholar]
- 71.Brocklehurst P. Interventions for reducing the risk of mother-to-child transmission of HIV infection. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date not reported. [Google Scholar]
- 72.Wiysonge CS, Shey MS, Shang J, et al. Vaginal microbicides for preventing mother-to-child transmission of HIV infection - no evidence of an effect or evidence of no effect? South Afr Med J 2007;97:530–533. [PubMed] [Google Scholar]
- 73.Wiysonge CS, Shey MS, Shang JD, et al. Vaginal disinfection for preventing mother-to-child transmission of HIV infection. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005. [DOI] [PubMed] [Google Scholar]
- 74.Wiysonge CS, Shey M, Kongnyuy E, et al. Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection. In: The Cochrane Library, Issue 4, 2009. Chichester, UK: John Wiley & Sons, Ltd. Search date 2008. [Google Scholar]
- 75.Humphrey JH, Iliff PJ, Marinda ET, et al. Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. J Infect Dis 2006;193:860–871. [DOI] [PubMed] [Google Scholar]
- 76.Semba RD, Miotti PG, Chiphangwi JD, et al. Maternal vitamin A deficiency and mother-to-child transmission of HIV-1. Lancet 1994;343:1593–1597. [DOI] [PubMed] [Google Scholar]
- 77.Fawzi WW, Msamanga G, Hunter D, et al. Randomized trial of vitamin supplements in relation to vertical transmission of HIV-1 in Tanzania. J Acquir Immune Defic Syndr 2000;23:246–254. [DOI] [PubMed] [Google Scholar]
- 78.Kumwenda N, Miotti PG, Taha TE, et al. Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi. Clin Infect Dis 2002;35:618–624. [DOI] [PubMed] [Google Scholar]
- 79.Fawzi WW, Msamanga GI, Spiegelman D, et al. A randomized trial of multivitamin supplements and HIV disease progression and mortality. N Engl J Med 2004;351:23–32. [DOI] [PubMed] [Google Scholar]
- 80.Kupka R, Mugusi F, Aboud S, et al. Randomized, double-blind, placebo-controlled trial of selenium supplements among HIV-infected pregnant women in Tanzania: effects on maternal and child outcomes. Am J Clin Nutr 2008;87:1802–1808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Villamor E, Aboud S, Koulinska IN, et al. Zinc supplementation to HIV-1-infected pregnant women: Effects on maternal anthropometry, viral load, and early mother-to-child transmission. Eur J Clin Nutr 2006;60:862–869. [DOI] [PubMed] [Google Scholar]