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Interventions for preventing late postnatal mother-to-child transmission of HIV

  1. Tara Horvath1,*,
  2. Banyana C Madi2,
  3. Irene M Iuppa1,
  4. Gail E Kennedy1,
  5. George W Rutherford1,
  6. Jennifer S. Read3

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 19 SEP 2008

DOI: 10.1002/14651858.CD006734.pub2

How to Cite

Horvath T, Madi BC, Iuppa IM, Kennedy GE, Rutherford GW, Read JS. Interventions for preventing late postnatal mother-to-child transmission of HIV. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006734. DOI: 10.1002/14651858.CD006734.pub2.

Author Information

  1. 1

    University of California, San Francisco, Global Health Sciences, San Francisco, California, USA

  2. 2

    SADC secretariat, HIV and AIDS Unit, Gaborone, Botswana

  3. 3

    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Pediatric, Adolescent, and Maternal AIDS Branch, Center for Research for Mothers and Children, Bethesda, MD, USA

*Tara Horvath, Global Health Sciences, University of California, San Francisco, 50 Beale Street, Suite 1200, San Francisco, California, 94105, USA. thorvath@psg.ucsf.edu.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 JAN 2009

SEARCH

 
Characteristics of included studies [ordered by study ID]
Coovadia 2007

MethodsNon-randomized intervention cohort study


ParticipantsHIV-infected and uninfected pregnant women attending antenatal clinics in KwaZulu Natal were enrolled into a non-randomized intervention cohort study if they were 16 years of age or older, planned to stay in the study area for at least 3 months after delivery, and provided written informed consent.  Uninfected women were included to establish the effect of HIV status on adherence to exclusive breastfeeding and other infant feeding practices. 


InterventionsExclusive breastfeeding (antenatal counseling regarding infant feeding options, home visits 3-4 times during first 2 weeks of life, and every 2 weeks thereafter until the infant was 6 months old. 


OutcomesHIV status:

1276 infants with complete feeding data. 

14.1 (95%CI: 12.0-16.4) of exclusively breastfed infants infected with HIV by age 6 weeks and 19.5% (17.0-22.4) by 6 months;  the risk was significantly associated with maternal CD4 cell counts below 200 cells/mm3 (adjusted HR 3.79; 2.35-6.12) and birth weight < 2500 grams (1.81; 1.07-3.06).  Breast infants who also received solid food during their first six months of life were significantly more likely to acquire infection than were exclusively breastfed children (HR 10;87; 1.51-78.00; p=0.018), as were infants who at 12 weeks received both breast milk and formula milk (1.82; 0.98-3.36; p=0.057). 

Mortality:

Cumulative 3-month mortality was15.1% (7.63-28.73) in infants given replacement feeds vs. 6.1% (4.74-7.92) among exclusively breastfed infants (HR 2.06; 1.00-4.27, p=0.51).


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?NoNot a randomized controlled trial

Allocation concealment?NoNot a randomized controlled trial

Blinding?
All outcomes
NoThis study was not blinded.

Incomplete outcome data addressed?
All outcomes
Yes"Data for nevirapine uptake and ingestion were inconsistent and are not included in any analysis."

Free of selective reporting?YesNo problems apparent

Free of other bias?YesNo problems apparent

Fawzi 2002

MethodsRandomized controlled trial


ParticipantsPregnant women presenting to public antenatal clinics (in the era before interventions to prevent MTCT of HIV were available locally) between 12 and 27 weeks gestation who resided in Dar es Salaam, Tanzania, and who intended to stay in the city until after delivery and for at least 1 year thereafter were enrolled. Median age ˜24 years;  CD4 count ˜ 420


InterventionsEligible women were randomly assigned in a two-by-two factorial design to receive a daily oral dose of one or four regimens from enrolment and throughout the pregnancy and lactation periods:

  1. vitamin A alone (30 mg beta-carotene plus 5000 IU preformed vitamin A)
  2. multivitamins excluding vitamin A (20 mg B1, 20 mg B2, 25 mg B6, 100 mg niacin, 50 micrograms B12, 500 mg vitamin C, 30 mg vitamin E, 0.8 mg folic acid)
  3. multivitamins including vitamin A in the same doses as above
  4. placebo


At delivery, women in groups 1 and 3 received an additional oral dose of vitamin A (200,000 IU), and women in groups 2 and 4 received placebo.

Those infants whose mothers received multivitamins were compared to infants whose mothers did NOT receive multivitamins.  Similarly, those infants whose mothers received vitamin A were compared to infants whose mothers did NOT receive vitamin A.


OutcomesHIV infection status:

Multivitamins (vitamins B, C, and E) had no effect on the overall risk of HIV transmission (RR = 1.04; 95%CI: 0.82-1.32; p = 0.76).  Multivitamins were associated with non-statistically significant reductions in transmission through breastfeeding. 

More cases of HIV infection were observed among children of mothers in the vitamin A arm compared with those who did not receive vitamin A  (RR=1.38; 95%CI: 1.09-1.76; p = 0.009). 

Mortality:

Multivitamins (vitamins B, C, and E) had a modest and not statistically significant reduction in mortality by 24 months or the combined risks of infection and mortality among children. 


NotesNot all study details were provided in this publication.  "Details of the study design have been published [9,10]" (referring to Fawzi 2000 and Fawzi 1998). Fawzi 2000 says: "Details of the study design have been published elsewhere (10,11)" (referring to Fawzi 1999 and Fawzi 1998).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Unclear"We assigned women randomly to receive a daily oral dose." (From Fawzi 1999)

Allocation concealment?NoNot addressed

Blinding?
All outcomes
Yes"We realized that unblinding, whether real or based on an impression or perception that may develop among subjects or staff, is more likely to occur if regimens are color-coded or bear simple numeric codes. To minimize this risk, we provided the regimen in bottles labeled with the subjects’ names and identification numbers, and made active tablets and placebo indistinguishable, so that neither the subjects nor the investigators could identify which subjects were randomized to the same regimen." (From Fawzi 1999)

Incomplete outcome data addressed?
All outcomes
Yes"We also developed a system for tracking the survival of all women not in active follow-up, by visiting their homes regularly and asking questions of neighbors, relatives, and friends. Through these methods, we have kept loss to follow-up down to about 5% per year. We anticipated these inevitable losses, and other losses due to mortality, and factored them in our sample-size calculation." (From Fawzi 1999)

Free of selective reporting?YesNo problems apparent.

Free of other bias?YesNo problems apparent.

Kuhn 2008

MethodsRandomized controlled trial


ParticipantsHIV-infected women were recruited from two antenatal clinics in Lusaka, Zambia that offered VCT and the two dose nevirapine prophylaxis regimen (one dose to mother, one dose to infant) prophylaxis.  Pregnant women (less than 38 weeks gestation) were recruited.  Women could volunteer if they intended to breastfeed for any length of time, accepted treatment with nevirapine, and agreed to be randomly assigned to the intervention or control group.  Exclusion criteria were severe pregnancy complications (e.g., pre-eclampsia), previous cesarean delivery, and HIV-related conditions requiring hospitalization.

Median CD4 count of mothers at baseline was ˜330 cells/mm3.  The maternal plasma viral load (median) was about 36,000-41,000 copies/mL.  Slightly over a third of the women were eligible for antiretroviral therapy.  The mean age was 26 years.  84-85% were married.  Over half of mothers had no schooling or only primary school education.

3216 women and 3276 infants were enrolled, and infants underwent randomization at birth;  of 3276 infants assigned an intervention, 3106 were included in the primary analysis;  of these, 2389 reached the HIV infection endpoint OR did not have HIV infection and were under follow-up or completed follow-up.

Median maternal age was ˜26 years.  ˜2/3 had < grade 8 education;  median CD4 count was ˜400; ˜2/3 presented early (>4 hours before delivery)


InterventionsEarly, abrupt weaning

Participants were randomly assigned to one of two groups.  The experimental intervention encouraged women to breastfeed exclusively to 4 months and then to stop breastfeeding abruptly, or as rapidly as possible.  Women in the control group were encouraged to breastfeed exclusively to 6 months, gradually introduce complementary foods, and continue to breastfeed for a duration of their own choice (standard practice).


OutcomesChild mortality rates were similar by 24 months in the two groups:  23.9% in the intervention group and 24.6% in the control group (p = 0.96). 

There was no significant difference in HIV-free survival between the two groups according to the intention-to-treat analysis:  at 24 months of age, 68.4% of children in the intervention group and 64.0% in the control group were alive and not infected with HIV (p = 0.13)

Among uninfected children who were still being breastfed at 4 months, there was no significant difference between the groups in HIV-free survival at 24 months:  83.9% of the children in the intervention group survived to 24 months without HIV infection, as compared with 80.7% in the control group (p = 0.27).  Between 4 and 24 months, rates of postnatal HIV transmission were not significantly different (6.2% in the intervention group and 8.8% in the control group, p = 0.19), and mortality among uninfected children was similar in the two groups (0.7% in the intervention group and 11.7% in the control group, p = 0.71). 


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?YesUse of a computer algorithm with randomized permuted block design within each site

Allocation concealment?No"Participants were informed of their assignment at the next (usually second-month) visit to ensure sufficient time for preparation."

Blinding?
All outcomes
NoThis study was not blinded.

Incomplete outcome data addressed?
All outcomes
Yes"Home-visit teams tracked the participants who did not return for appointments. Information about children’s deaths was sought from hospital and clinic records and from interviews with caretakers and health care personnel. The circumstances of all deaths were reviewed to identify the causes of death."

Free of selective reporting?YesNo problems apparent

Free of other bias?YesNo problems apparent

Kumwenda 2008

MethodsRandomized controlled trial


ParticipantsPregnant women who presented for either antenatal or delivery services at specific health centers in Blantyre, Malawi were offered HIV counseling and testing.  All women with HIV infection, except those late presenters whose HIV infection was not identified until after they gave birth, received a single intrapartum dose of nevirapine.  Women could be enrolled in the trial if they had HIV infection, were at least 18 years of age (although women <18 years of age could be enrolled if they consented and a guardian gave permission), were pregnant or had given birth within the previous 24 hours at one of the study clinics, were a resident of the study area, were willing to return for postnatal follow-up visits for up to 2 years, and intended to breastfeed.  The study excluded infants with life-threatening conditions requiring immediate care.  Mothers were counseled to breastfeed exclusively for six months and to consider weaning thereafter.


InterventionsArm 1:  single dose nevirapine PLUS 1 week of zidovudine (control regimen)

Arm 2:  control regimen PLUS daily nevirapine starting at age 7 days until the age of 14 weeks

Arm 3:  control regimen PLUS daily nevirapine with zidovudine starting at age 7 days until the age of 14 weeks

The control regimen was single dose nevirapine PLUS 1 week of zidovudine. (Those women who enrolled early enough received one dose of intrapartum nevirapine; some women (approximately 30%) presented too late to receive intrapartum nevirapine.)


OutcomesHIV infection status:

Of 3016 infants, 255 were found to have HIV infection (242 confirmed and 13 presumptive).

Among infants who were not infected at birth, between the ages of 6 weeks and 18 months, the control group had consistently higher rates of HIV infection, as compared with both extended-prophylaxis groups. 

At 9 months, the estimated rate of HIV infection (primary end point) was 10.6% in the control group, 5.2% extended nevirapine group (P < 0.001), 6.4% in extended dual prophylaxis group (P = 0.002).  There were no significant differences between the two extended-prophylaxis groups. 

The estimated protective efficacy of the extended prophylaxis regimens were:

6 weeks:   

  • Nevirapine:  67% (95%CI: 43-81)
  • Nevirapine + Zidovudine:  69% (95%CI: 45-83)


14 weeks: 

  • Nevirapine:  67% (95%CI: 49-79)
  • Nevirapine + Zidovudine:  66% (95%CI: 48-78)


6 months: 

  • Nevirapine:   60% (95%CI: 42-73)
  • Nevirapine + Zidovudine:  49% (95%CI: 27-64)


9 months: 

  • Nevirapine:   51% (95%CI: 30-66)       
  • Nevirapine + Zidovudine:  40% (95%CI: 16-57)


Mortality:

No statistically significant differences in mortality by study arm.

HIV-free survival was significantly better through the age of 9 months in both extended prophylaxis groups, and through the age of 15 months in the extended nevirapine group.


NotesAdverse effects:

Infants receiving nevirapine + zidovudine prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) deemed possibly related to a study drug.  There was no difference in adverse events between the control group and the nevirapine only prophylaxis group.


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Randomization procedures employed permutated block algorithms of sizes 9 and 12, stratified by study clinic. A computer generated randomization list assigned infants to the appropriate treatment arms using a 1:1:1 allocation ratio. Randomization numbers were placed in sequentially labeled and sealed envelopes." (From Kumwenda 2008)

Allocation concealment?NoNot addressed

Blinding?
All outcomes
NoThis study was not blinded.

Incomplete outcome data addressed?
All outcomes
Yes"All Grade 3-4 toxicities, rashes Grade 2B or higher and ALT levels Grade 2 or higher were considered serious. Serious adverse events, including deaths and hospitalizations, were reported to the University of Malawi, Johns Hopkins University, and CDC Institutional Review Boards (IRBs). Abnormal clinical and laboratory findings were followed until resolution to Grade 2 or lower. Infants discontinued from study drug(s) were followed for the study duration." (From Kumwenda 2008 Supplement)

Free of selective reporting?YesNo problems apparent

Free of other bias?YesNo problems apparent.

Nduati 2000

MethodsRandomized controlled trial


ParticipantsPregnant women attending 4 Nairobi antenatal clinics (in the era before interventions to prevent MTCT of HIV were available locally) were offered counseling and serologic testing for HIV.  Seropositive women were invited to attend the research clinic at Kenyatta National Hospital.  Women were eligible if they resided in Nairobi and had access to municipal-treated water.  Women were randomized to breastfeed or formula feed at about 32 weeks.   

Of 2315 HIV seropositive women, 1708 (74%) returned to receive their results.  Of these, 425 (25%) were enrolled (18% of all seropositive pregnant women). 

Median age of enrolled women = 23 years.  61% of women living in a 1-room home, 74% sharing a toilet with other households, 5% owning a refrigerator.  All women had access to clean water, 76% had access to flush sanitation.  At 32 weeks gestation, 47/381 women (12%) had CD4 < 200 cells/mm3.  Median plasma viral load at this visit was 42,360 copies/mL. 


InterventionsFormula feeding instead of breastfeeding. Those randomized to formula feeding were compared to those randomized to breastfeeding.


OutcomesHIV status:

The cumulative probability of HIV infection at 24 months was 36.7% (95% CI: 29.4-44.0%) in the breastfeeding arm and 20.5% (95%CI: 14.0-27.0%) in the formula arm (p = 0.001).

Morbidity:

Mbori-Ngacha 2001 addresses morbidity:

Of 401 live born, singleton or first-born twin infants of randomized HIV-seropositive mothers, 371 were included in the analysis of morbidity and mortality. 

Incidence of diarrhea during the 2 years of follow-up was similar in formula and breastfeeding arms (155 vs 149 per 100 person-years, respectively).  The incidence of pneumonia was identical in the 2 groups (62/100 person years).  There were no significant differences in incidence of other recorded illnesses.

Mortality

The 2-year mortality rates in both arms were similar: (breastfeeding arm:  24.4% (95%CI: 18.2-30.7%) vs. formula feeding arm: 20.0% (95%CI: 14.4-25.6%); p = 0.30

The rate of HIV-free survival at 2 years was significantly lower in the breastfeeding arm than in the formula feeding arm (58.0% vs. 70.0%, respectively, p = 0.02).


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"Women were randomized to breastfeed or formula feed at about 32 weeks using computer-generated block randomization."

Allocation concealment?NoNot applicable

Blinding?
All outcomes
NoThis study was not blinded.

Incomplete outcome data addressed?
All outcomes
Yes"We did not present secondary analyses of self-reported feeding behavior and HIV transmission or mortality, because feeding practices may be associated with confounding variables that affect primary study outcomes."

Free of selective reporting?YesNo problems apparent

Free of other bias?Unclear"Because more than one quarter of women in the formula arm admitted to noncompliance with feeding modality, our estimated breast milk transmission rate is an underestimate."

SWEN 2008

MethodsRandomized controlled trial


ParticipantsPregnant women who presented to antenatal and delivery facilities in Addis Ababa, Ethiopia, Pune, India, and Kampala, Uganda, who were identified as HIV-infected, were offered the local standard of care for prevention of MTCT of HIV and provided infant feeding counseling, consistent with WHO/UNICEF guidelines. Women were eligible for study enrolment if they indicated an intention to breastfeed their infants and provided informed consent.


InterventionsIn Arm 1 (control arm) of the trials, 200 mg nevirapine was provided to women in labor and 2 mg/kg to infants shortly after birth.  In Arm 2 of the trials, this two-dose nevirapine regimen was provided in addition to infant dosing of 5 mg nevirapine each day starting at age 7 days through six weeks of life.  The risk of HIV infection and death at 6 weeks and 6 months of age in infants who were HIV-uninfected at birth was estimated.  The analysis included data for 1887 infants. 


OutcomesAt six weeks of age, more children in the single-dose nevirapine group than the extended-dose nevirapine group were infected (relative risk:  0.54; 0.34-0.86; p=0.009).  However, at six months of age, the risk of transmission was similar (relative risk 0.80; 0.58-1.10; p=0.16).  HIV-free survival was higher in the extended prophylaxis arm, at both six weeks (p = 0.008) and six months (p = 0.03). 


Notes


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?Yes"For all three countries, block randomisation was used with treatment assignments generated by computer at a central data coordinating centre at Johns Hopkins University. The randomisation list was provided to study pharmacists only in each country."

Allocation concealment?Unclear"Study products were administered by pre-filled amber oral syringes in Ethiopia and Uganda and by opaque dropper bottles in India, after training of mothers by study pharmacists .A number of specific study procedures were implemented to introduce some degree of masking of study staff and care givers. Specifically, none of the study investigators or staff, with the exception of the study pharmacists and a member of the central data management team, had access to the randomization assignments for study participants." Because study pharmacists knew the randomization assignments, however, and worked directly with the mothers, it is possible that allocation was not sufficiently well concealed.

Blinding?
All outcomes
No"This study was not blinded"; However, "[t]he reliability of the HIV PCR results were assessed through a centralised quality assurance programme, coordinated by the laboratory of one of the authors (JBJ) at Johns Hopkins School of Medicine, which included blinded retesting of samples from HIV-infected infants and a random sample of HIV-uninfected infants. Final infant infection status was assigned for each country by a blinded study investigator and results from all three countries were subsequently reviewed by a fourth blinded investigator (JBJ) to ensure consistency across the countries.

Incomplete outcome data addressed?
All outcomes
Yes"Since many infant deaths occurred at home or outside of the study clinics, information about the cause of these deaths was limited to verbal autopsy interviews of mothers and other family members. Thus, HIV status at the time of death was not available for infants who could have become HIV positive between their last study visit and their death. 38 (72%) of the deaths occurred among infants for whom their last HIV screening test was negative by HIV PCR. However, the mean time from this last study visit until death was 13·8 (SD 17·7) days, decreasing the likelihood that we failed to identify HIV-infected infants before their death. We assessed the distribution of mortality by sex, because of an imbalance between study groups at baseline, but there was no significant difference between males and females in terms of the distribution of overall mortality (data not shown). We found no differences between groups in other factors that might be associated with infant mortality, including maternal age, maternal CD4 cell count, maternal viral load (available in India and Uganda), maternal education level, parity, gravidity, and gestational age at enrolment (data not shown)."

Free of selective reporting?YesNo problems apparent.

Free of other bias?YesNo problems apparent.

Thior 2006

MethodsRandomized controlled trial


Participants1200 HIV-infected women were randomized.  Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. Median maternal age = 26.78 years; 55% had water tap in the yard, 37% used communal standpipe; 74% cited private latrine/house as the most used sanitation facility; 24% had electricity in the home; the maternal baseline CD4 count was 366 cells/mm3 and the median maternal baseline plasma viral load was 4.35 log10 copies/mL


InterventionsMothers were instructed to initiate and complete weaning when the infant was between five and six months of age.  Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus 6 months of zidovudine) or formula feeding plus 1 month of infant zidovudine (formula fed). Infants received zidovudine syrup 4 mg/kg/12 hours from birth until 1 month of age in all infants, and discontinued at 1 month in the formula-fed group.  For the breastfed plus zidovudine group, infant zidovudine prophylaxis continued from 1 to 2 months of age at 4 mg/kg/8 hours, and from 2 to 6 months of age (while still breastfeeding) at 6 mg/kg/8 hours.

(All mothers received zidovudine 300 mg orally twice daily from 34 weeks gestation and during labor.). 

Mothers and infants were randomized to receive single-dose nevirapine or placebo.


OutcomesMorbidity:

The rates of grade 3 or higher signs or symptoms (17.6% vs. 13.1%; P = 0.03) and of hospitalization (20.3% vs. 15.6%, P = 0.04) by 7 months were significantly higher among infants in the formula-fed group than in the breastfed plus zidovudine group.  

Mortality:

Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed) vs. 86 infants (15.1% breastfed plus zidovudine) (P = 0.60). 

Cumulative infant mortality at 7 months was significantly higher for the formula-fed group than for the breastfed plus zidovudine group (9.3% vs. 4.9%; p = 0.003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P = 0.21). 

Therefore, breastfeeding with zidovudine prophylaxis for six months was associated with a lower mortality rate at 7 months, but both strategies had comparable HIV-free survival at 18 months.


NotesAdverse effects:

The rate of grade 3 or higher laboratory abnormality associated with zidovudine toxicity was significantly higher in the breastfed plus zidovudine group than in the formula-fed group (24.7% vs. 14.8%) (P < 0.001).


Risk of bias

ItemAuthors' judgementDescription

Adequate sequence generation?YesCentralized randomization to both part 1 and part 2 groups occurred at study enrolment (34 weeks gestation), using permuted blocks of size 8 within each site.

Allocation concealment?UnclearProbably done, but exactly how is unclear.

Blinding?
All outcomes
NoThis study was not blinded.

Incomplete outcome data addressed?
All outcomes
NoNot addressed.

Free of selective reporting?UnclearPossibly some post-randomization selection bias.

Free of other bias?YesNo problems apparent.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Becquet 2006Not a randomized clinical trial (prospective cohort study); mothers had received antiretrovirals perinatally.

Becquet 2008Not a randomized clinical trial (open-labeled cohort study); mothers had received antiretrovirals perinatally.

Bobat 1997Not a randomized clinical trial (prospective cohort study).

Dabis 1999This study addressed in utero/intrapartum transmission (not a trial addressing prevention of late postnatal transmission)

Embree 2000Not a randomized clinical trial (longitudinal observational cohort study).

Gray 2005This study addresses prevention of peripartum transmission of HIV.  Was not designed (and did not address) late postnatal/breastfeeding transmission of HIV.

Guay 1999This study addressed in utero/intrapartum transmission (not a trial addressing prevention of late postnatal transmission)

Iliff 2005This is analysis of data regarding infant feeding (data came from a randomized trial addressing a different topic), i.e., this is an analysis of prospectively collected data regarding infant feeding modalities and infant HIV infection status.

Kilewo 2008Not a randomized clinical trial (prospective cohort study).

Miotti 1999Not a randomized clinical trial (prospective cohort study).

SIMBA 2003Abstract only - manuscript was never published.  Authors of the study were contacted, but no further information was obtained.

 
Table 1. Examples of search strategies

PubMED: Date range: 1 January 1980 - 15 July 2008

#11Search #3 AND #4 AND #9

#10Search #3 AND #4 AND #9

#9Search #7 OR #8

#8Search (infant feeding) OR (infant nutrition) OR (infant feeding options) OR (exclusive breastfeeding) OR (exclusive breast-feeding) OR (exclusive breast feeding) OR (formula feeding) OR (early weaning) OR (abrupt weaning) OR (wet nursing) OR (milk bank) OR (milk banks) OR (expressed breast milk) OR (expressed human milk) OR (replacement feeding)

#7Search #5 AND #6

#6Search pasteurization OR pasteurization OR (heat treatment) OR sterilisation OR sterilization OR decontamination

#5Search (breast milk) OR (breast milks) OR (human milk)

#4Search (mother-to-child transmission) OR (mother to child transmission) OR (adult-to-child transmission) OR (adult to child transmission) OR (maternal-to-child transmission) OR (maternal to child transmission) OR (breast milk transmission) OR (breast-milk transmission) OR (vertical transmission) OR (disease transmission, vertical)

#3Search #1 AND #2

#2Search randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ( placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT human [mh])

#1Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MESH:NoExp]

EMBASE: Date range: 1 January 1980 - 15 July 2008

#1(((('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection') OR ('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection')) OR (('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection') OR ('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection'))) OR ((('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection') OR ('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection')) OR (('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection') OR ('human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection')))) OR ((((('human immunodeficiency virus'/exp OR 'human immunodeficiency virus') OR ('human immunodeficiency virus'/exp OR 'human immunodeficiency virus')) OR (('human immunodeficiency virus'/exp OR 'human immunodeficiency virus') OR ('human immunodeficiency virus'/exp OR 'human immunodeficiency virus'))) OR ((('human immunodeficiency virus'/exp OR 'human immunodeficiency virus') OR ('human immunodeficiency virus'/exp OR 'human immunodeficiency virus')) OR (('human immunodeficiency virus'/exp OR 'human immunodeficiency virus') OR ('human immunodeficiency virus'/exp OR 'human immunodeficiency virus'))))) OR (hiv:ti OR hiv:ab) OR ('hiv-1':ti OR 'hiv-1':ab) OR ('hiv-2':ti OR 'hiv-2':ab) OR ('human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab) OR ('human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab) OR ('human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab) OR ('human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab) OR ('acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab) OR ('acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab) OR ('acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab) OR ('acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab)

#2(random*:ti OR random*:ab) OR (factorial*:ti OR factorial*:ab) OR (cross?over*:ti OR cross?over:ab OR crossover*:ti OR crossover*:ab) OR (placebo*:ti OR placebo*:ab) OR (((doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab))) OR (((singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab))) OR (assign*:ti OR assign*:ab) OR (volunteer*:ti OR volunteer*:ab) OR ((((('crossover procedure'/exp OR 'crossover procedure') OR ('crossover procedure'/exp OR 'crossover procedure')) OR (('crossover procedure'/exp OR 'crossover procedure') OR ('crossover procedure'/exp OR 'crossover procedure'))) OR ((('crossover procedure'/exp OR 'crossover procedure') OR ('crossover procedure'/exp OR 'crossover procedure')) OR (('crossover procedure'/exp OR 'crossover procedure') OR ('crossover procedure'/exp OR 'crossover procedure'))))) OR ((((('double-blind procedure'/exp OR 'double-blind procedure') OR ('double-blind procedure'/exp OR 'double-blind procedure')) OR (('double-blind procedure'/exp OR 'double-blind procedure') OR ('double-blind procedure'/exp OR 'double-blind procedure'))) OR ((('double-blind procedure'/exp OR 'double-blind procedure') OR ('double-blind procedure'/exp OR 'double-blind procedure')) OR (('double-blind procedure'/exp OR 'double-blind procedure') OR ('double-blind procedure'/exp OR 'double-blind procedure'))))) OR ((((('single-blind procedure'/exp OR 'single-blind procedure') OR ('single-blind procedure'/exp OR 'single-blind procedure')) OR (('single-blind procedure'/exp OR 'single-blind procedure') OR ('single-blind procedure'/exp OR 'single-blind procedure'))) OR ((('single-blind procedure'/exp OR 'single-blind procedure') OR ('single-blind procedure'/exp OR 'single-blind procedure')) OR (('single-blind procedure'/exp OR 'single-blind procedure') OR ('single-blind procedure'/exp OR 'single-blind procedure'))))) OR ((((('randomized controlled trial'/exp OR 'randomized controlled trial') OR ('randomized controlled trial'/exp OR 'randomized controlled trial')) OR (('randomized controlled trial'/exp OR 'randomized controlled trial') OR ('randomized controlled trial'/exp OR 'randomized controlled trial'))) OR ((('randomized controlled trial'/exp OR 'randomized controlled trial') OR ('randomized controlled trial'/exp OR 'randomized controlled trial')) OR (('randomized controlled trial'/exp OR 'randomized controlled trial') OR ('randomized controlled trial'/exp OR 'randomized controlled trial'))))) OR (allocat*:ti OR allocat*:ab)

#3 #1 AND #2

#4 'mother-to-child transmission' OR 'mother to child transmission' OR 'adult-to-child transmission' OR 'adult to child transmission' OR 'maternal-to-child transmission' OR 'maternal to child transmission' OR 'breast milk transmission' OR 'breast-milk transmission' OR ('vertical transmission'/exp OR 'vertical transmission') OR 'vertical disease transmission'

#5 ('breast milk'/exp OR 'breast milk') OR 'breast milks' OR ('human milk'/exp OR 'human milk')

#6 pasteurisation OR ('pasteurization'/exp OR 'pasteurization') OR ('heat treatment'/exp OR 'heat treatment') OR ('sterilisation'/exp OR 'sterilisation') OR ('sterilization'/exp OR 'sterilization') OR ('decontamination'/exp OR 'decontamination')

#7 #5 AND #6

#8 ('infant feeding'/exp OR 'infant feeding') OR ('infant nutrition'/exp OR 'infant nutrition') OR 'infant feeding options' OR 'exclusive breastfeeding' OR 'exclusive breast-feeding' OR 'exclusive breast feeding' OR ('formula feeding'/exp OR 'formula feeding') OR 'early weaning' OR 'abrupt weaning' OR 'wet nursing' OR ('milk bank'/exp OR 'milk bank') OR ('milk banks'/exp OR 'milk banks') OR 'expressed breast milk' OR 'expressed human milk' OR 'replacement feeding'

#9 #7 OR #8

#10 #3 AND #4 AND #9

Cochrane CENTRAL Controlled Trials Register: Date range: 1 January 1980 - 15 July 2008

#1(HIV INFECTIONS) OR HIV OR HIV OR HIV-1* OR HIV-2* OR HIV1 OR HIV2 OR (HIV INFECT*) OR (HUMAN IMMUNODEFICIENCY VIRUS) OR (HUMAN IMMUNEDEFICIENCY VIRUS) OR (HUMAN IMMUNO-DEFICIENCY VIRUS) OR (HUMAN IMMUNE-DEFICIENCY VIRUS) OR ((HUMAN IMMUN*) AND (DEFICIENCY VIRUS)) OR (ACQUIRED IMMUNODEFICIENCY SYNDROME) OR (ACQUIRED IMMUNEDEFICIENCY SYNDROME) OR (ACQUIRED IMMUNO-DEFICIENCY SYNDROME) OR (ACQUIRED IMMUNE-DEFICIENCY SYNDROME) OR ((ACQUIRED IMMUN*) AND (DEFICIENCY SYNDROME)) OR (VIRAL SEXUALLY TRANSMITTED DISEASES)

#2(MOTHER-TO-CHILD TRANSMISSION) OR (MOTHER TO CHILD TRANSMISSION) OR (ADULT-TO-CHILD TRANSMISSION) OR (ADULT TO CHILD TRANSMISSION) OR (MATERNAL-TO-CHILD TRANSMISSION) OR (MATERNAL TO CHILD TRANSMISSION) OR (BREAST MILK TRANSMISSION) OR (BREAST-MILK TRANSMISSION) OR (VERTICAL TRANSMISSION) OR (VERTICAL DISEASE TRANSMISSION)

#3(BREAST MILK) OR (BREAST MILKS) OR (HUMAN MILK)

#4PASTEURIZATION OR PASTEURIZATION OR (HEAT TREATMENT) OR STERILISATION OR STERILIZATION OR DECONTAMINATION

#5(#3 AND #4)

#6(INFANT FEEDING) OR (INFANT NUTRITION) OR (INFANT FEEDING OPTIONS) OR (EXCLUSIVE BREASTFEEDING) OR (EXCLUSIVE BREAST-FEEDING) OR (EXCLUSIVE BREAST FEEDING) OR (FORMULA FEEDING) OR (EARLY WEANING) OR (ABRUPT WEANING) OR (WET NURSING) OR (MILK BANK) OR (MILK BANKS) OR (EXPRESSED BREAST MILK) OR (EXPRESSED HUMAN MILK) OR (REPLACEMENT FEEDING)

#7(#5 OR #6)

#8(#1 AND #2 AND #7)