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

 

Characteristics of included studies [ordered by study ID]

Coovadia 2007

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Methods	Non-randomized intervention cohort study
Participants	HIV-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.
Interventions	Exclusive 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.
Outcomes	HIV 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/mm^3 (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
Item	Authors' judgement	Description
Adequate sequence generation?	No	Not a randomized controlled trial
Allocation concealment?	No	Not a randomized controlled trial
Blinding? All outcomes	No	This 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?	Yes	No problems apparent
Free of other bias?	Yes	No problems apparent

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Fawzi 2002

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Methods	Randomized controlled trial
Participants	Pregnant 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
Interventions	Eligible 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: vitamin A alone (30 mg beta-carotene plus 5000 IU preformed vitamin A) 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) multivitamins including vitamin A in the same doses as above 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.
Outcomes	HIV 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.
Notes	Not 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
Item	Authors' judgement	Description
Adequate sequence generation?	Unclear	"We assigned women randomly to receive a daily oral dose." (From Fawzi 1999)
Allocation concealment?	No	Not 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?	Yes	No problems apparent.
Free of other bias?	Yes	No problems apparent.

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Kuhn 2008

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Methods	Randomized controlled trial
Participants	HIV-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)
Interventions	Early, 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).
Outcomes	Child 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
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Use 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	No	This 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?	Yes	No problems apparent
Free of other bias?	Yes	No problems apparent

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Kumwenda 2008

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Methods	Randomized controlled trial
Participants	Pregnant 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.
Interventions	Arm 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.)
Outcomes	HIV 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.
Notes	Adverse 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
Item	Authors' judgement	Description
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?	No	Not addressed
Blinding? All outcomes	No	This 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?	Yes	No problems apparent
Free of other bias?	Yes	No problems apparent.

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Nduati 2000

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Methods	Randomized controlled trial
Participants	Pregnant 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.
Interventions	Formula feeding instead of breastfeeding. Those randomized to formula feeding were compared to those randomized to breastfeeding.
Outcomes	HIV 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
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	"Women were randomized to breastfeed or formula feed at about 32 weeks using computer-generated block randomization."
Allocation concealment?	No	Not applicable
Blinding? All outcomes	No	This 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?	Yes	No 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."

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SWEN 2008

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Methods	Randomized controlled trial
Participants	Pregnant 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.
Interventions	In 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.
Outcomes	At 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
Item	Authors' judgement	Description
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?	Yes	No problems apparent.
Free of other bias?	Yes	No problems apparent.

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Thior 2006

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Methods	Randomized controlled trial
Participants	1200 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
Interventions	Mothers 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.
Outcomes	Morbidity: 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.
Notes	Adverse 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
Item	Authors' judgement	Description
Adequate sequence generation?	Yes	Centralized 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?	Unclear	Probably done, but exactly how is unclear.
Blinding? All outcomes	No	This study was not blinded.
Incomplete outcome data addressed? All outcomes	No	Not addressed.
Free of selective reporting?	Unclear	Possibly some post-randomization selection bias.
Free of other bias?	Yes	No problems apparent.

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Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Becquet 2006	Not a randomized clinical trial (prospective cohort study); mothers had received antiretrovirals perinatally.
Becquet 2008	Not a randomized clinical trial (open-labeled cohort study); mothers had received antiretrovirals perinatally.
Bobat 1997	Not a randomized clinical trial (prospective cohort study).
Dabis 1999	This study addressed in utero/intrapartum transmission (not a trial addressing prevention of late postnatal transmission)
Embree 2000	Not a randomized clinical trial (longitudinal observational cohort study).
Gray 2005	This study addresses prevention of peripartum transmission of HIV.  Was not designed (and did not address) late postnatal/breastfeeding transmission of HIV.
Guay 1999	This study addressed in utero/intrapartum transmission (not a trial addressing prevention of late postnatal transmission)
Iliff 2005	This 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 2008	Not a randomized clinical trial (prospective cohort study).
Miotti 1999	Not a randomized clinical trial (prospective cohort study).
SIMBA 2003	Abstract only - manuscript was never published.  Authors of the study were contacted, but no further information was obtained.

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Table 1. Examples of search strategies

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PubMED: Date range: 1 January 1980 - 15 July 2008
#11	Search #3 AND #4 AND #9
#10	Search #3 AND #4 AND #9
#9	Search #7 OR #8
#8	Search (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	Search #5 AND #6
#6	Search pasteurization OR pasteurization OR (heat treatment) OR sterilisation OR sterilization OR decontamination
#5	Search (breast milk) OR (breast milks) OR (human milk)
#4	Search (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)
#3	Search #1 AND #2
#2	Search 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])
#1	Search 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)
#4	PASTEURIZATION 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)

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