Tenofovir (all routes except local)

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Bagkeris
2015 		Ukraine
2000 - 2012
prospective cohort 		The European Collaborative Study (ECS) in EuroCoord, a continuing cohort study. Exposure to Tenofovir-based regimens during pregnancy (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Exposure to zidovudine or lamivudine-based regimens during pregnancy (unspecified regimens). 		2nd and/or 3rd trimester 124 / 2204 Starting ART: mostly during second or third trimester of pregnancy (95%).
Not specified.
Bérard (Controls exposed to other ARV)
2017 		Canada
1998 - 2015
population based cohort propective 		The Quebec Pregnancy Cohort Pregnant women with prescription fillings of Tenofovir-based regimens during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women with prescription fillings of non-Tenofovir-based regimens during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). 		1st trimester 53 / 145 Addition of cases of malformations of all regimens including Tenofovir versus all other regimens (TableS6).
The Quebec Public Prescription Drug Insurance database (drug name, start date, dosage, duration).
Bérard (Controls unexposed, disease free)
2017 		Canada
1998 - 2015
population based cohort propective 		The Quebec Pregnancy Cohort Pregnant women with prescription fillings of Tenofovir-based regimens during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, disease free
Pregnancies without antiretroviral exposure during the first trimester. 		1st trimester 53 / 214042 Among the 214 042 pregnancies unexposed to antiretrovirals during the first trimester, 169 pregnancies were HIV positive (99,9%).
The Quebec Public Prescription Drug Insurance database (drug name, start date, dosage, duration).
Bérard (Controls unexposed, sick)
2017 		Canada
1998 - 2015
population based cohort propective 		The Quebec Pregnancy Cohort Pregnant women with prescription fillings of Tenofovir-based regimens during the first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant HIV positive women without antiretroviral exposure during the first trimester. 		1st trimester 53 / 169
The Quebec Public Prescription Drug Insurance database (drug name, start date, dosage, duration).
Brogly
2010 		USA
1993 - 2000
prospective cohort 		The Pediatric AIDS Clinical Trials Group (PACTG), a multisite US cohort of children born to HIV-infected women. Live-born children exposed to Tenofovir during the 1st trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Live-born children unexposed to Tenofovir during the 1st trimester (included ARV unexposed children, children exposed to ARV in labor only, children unexposed to Tenofovir but to other ARV, and children exposed to Tenofovir in the 2nd and/or 3rd trimester only). 		1st trimester 45 / 1988
Not specified.
Calitri
2014 		Italy
2001 - 2012
prospective cohort 		The Italian Register for HIV infection in Children (ITLR), a nationwide, multicentre, prospective study set up by the Italian Association of Paediatrics. Pregnancies in women that received Tenofovir-based regimens during pregnancy. exposed to other treatment, sick
Pregnancies in women that received non-Tenofovir-based regimens during pregnancy. 		during pregnancy (anytime or not specified) 12 / 14
Center enroll all children born to HIV-infected mothers and forward data to 2 coordinating center, using specific individual forms for registration and followup. The registration form includes notably treatment with antiretroviral therapy during pregnancy.
Caniglia
2018 		Botswana
2004 - 2015
retrospective cohort 		The combined dataset of birth outcomes surveillance studies in six government maternity sites (~ 45% of births nationwide). Pregnant women with pre-conception initiation of tenofovir, emtricitabine, efavirenz (TDF/FTC/EFV) (historical comparison). exposed to other treatment, sick
Pregnant women with pre-conception initiation of zidovudine, lamivudine, nevirapine (ZDV/3TC/NVP) (historical comparison). 		during pregnancy (anytime or not specified) 1108 / 637 Data reported for historical comparison ("The risks of adverse birth outcomes were similar in the contemporaneous comparison and the historical comparison.")
ART start date, ART regimen were collected via the obstetric cards.
Celen
2013 		Turkey
2010 - 2012
retrospective cohort 		A retrospective study conducted in six hopitals in South-east Anatolia, Turkey. Pregnant women with active hepatitis B infection treated with Tenofovir 300 mg orally once a day from week 18 to 27 of gestation. unexposed, sick
Untreated pregnant women with active hepatitis B infection. 		2nd and/or 3rd trimester 21 / 24 Maternal outcomes (Elevated creatinine kinase, Spontaneous abortion, VaginitisArrhythmia Anemia Proteinuria) not reported because most of them occurred before treatment.
Not specified.
Chang
2019 		Taiwan
2011 - 2016
prospective cohort 		The PreMIT Study (Prevention of Mother-to-Infant Transmission of HBV), an open-labeled, non-randomized controlled trial recruiting in 14 collaborative hospitals. Pregnant women that received an oral dose of 300 mg of tenofovir disoproxil fumarate daily starting at 30‐32 weeks of gestation and continuing until post‐partum week 4. unexposed, sick
Pregnant women that did not receive any anti‐viral therapy. 		3rd trimester 110 / 91
Women were invited to join the trial and could choose to participate in either the control or the tenofovir group based on their willingness.
Chen
2015 		Taiwan
2011 - 2013
prospective cohort 		The PreMIT Study (Prevention of Mother-to-Infant Transmission of HBV), an open-labeled, non-randomized controlled trial recruiting in 14 collaborative hospitals. Pregnant women who received Tenofovir 300 mg once daily initiated from gestational week 30-32 until 1 month following delivery. unexposed, sick
Pregnant women who did not receive antiviral therapy. 		late pregnancy 62 / 56 For 2 outcomes (preterm and caesarean section), data were updated by Chang 2019 and thus not reported here.
The TDF group received treatment (NOS).
Chetty
2018 		South Africa
2010 - 2015
retrospective cohort 		Antenatal clinics in the Hlabisa HIV Treatment and Care Programme, northern KwaZulu-Natal. Singleton live births exposed to Tenofovir-(lamivudine (3TC)/emtricitabine(FTC))-efavirenz (EFV) initiated in pregnancy (TDF-3TC-EFV (30.5%); TDF-FTC-EFV (69.6%)). exposed to other treatment, sick
Singleton live births exposed to Zidovudine (ZDV) initiated in pregnancy 		during pregnancy (anytime or not specified) 959 / 528 Preconception and post-conception ARV initiation were studied by authors. Only post-conception ARV initiation was reported here (more exposed pregnancies).
Clinic staff collected antenatal data. Dates of ART initiation or change were retrieved from the HIV clinical database.
Chi
2007 		Zambia
2005 - 2007
randomized controlled trial 		An open-label randomised trial in Lusaka, Zambia. Pregnant women assigned to receive in labour a single oral dose of 300 mg tenofovir disoproxil fumarate with 200 mg emtricitabine under direct observation. unexposed, sick
Pregnant women assigned to receive any intervention above the standard of care. 		late pregnancy 200 / 199
Pregnant women were randomised to receive oral tenofovir and emtricitabine, given under direct observation or no intervention above the standard of care.
Colbers
2015 		Europe
2010 - 2013
prospective cohort 		A non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe (PANNA network). Pregnant patients on ritonavir-boosted atazanavir (ATV/r) 300/ 100 mg with Tenofovir (and other nucleoside reverse transcriptase inhibitors (NRTIs)). exposed to other treatment, sick
Pregnant patients on ritonavir-boosted atazanavir (ATV/r) 300/ 100 mg without Tenofovir (and other nucleoside reverse transcriptase inhibitors (NRTIs)). 		during pregnancy (anytime or not specified) 19 / 10 Other NRTIs taken were: emtricitabine (n=20), lamivudine (n=10), zidovudine (n=6) and abacavir (n=4). One patient also used raltegravir. One patient started cART in the 2nd trimester, the others were on cART at conception.
The PANNA network is a European network of hospitals collecting pharmacokinetic curves of several antiretrovirals (ARVs) during pregnancy in a prospective study. Concentrations of ATV and RTV in plasma were analysed by use of a validated (ultra) high-performance liquid chromatography method
Crain
2011 		USA including Puerto Rico
2007 - 2009
cohort 		The multicenter Surveillance Monitoring for Antiretroviral Therapy Toxicities (SMARTT) protocol of the Pediatric HIV/AIDS Cohort Study (PHACS) (static and dynamic cohorts). Children born to HIV-infected women receiving Tenofovir-based regimens during pregnancy (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children born to HIV-infected women receiving non-Tenofovir-based regimens during pregnancy (unspecified regimens). 		during pregnancy (anytime or not specified) 299 / 1273
Information on maternal drug use during pregnancy was obtained by maternal self-report (shortly after delivery for the Dynamic Cohort, and at the entry visit for the Static Cohort).
Dadabhai
2019 		Malawi
2016 - 2017
retrospective cohort 		POISE (Pregnancy Outcomes and Infant Survival in the Era of Universal HAART in Africa) a prospective, observational study conducted at the main teaching hospital, the Queen Elizabeth Central Hospital (QECH), and at four major health centers. Pregnant HIV-infected women on Tenofovir, lamivudine and efavirenz. unexposed, disease free
Pregnant HIV-uninfected women. 		during pregnancy (anytime or not specified) 614 / 685
Information related to treatment is available in a “Health Passport” that women present at health facilities. Trained study nurses used study-specific structured questionnaires and case report forms to collect exposures.
Ejigu
2019 		Ethiopia
2010 - 2016
retrospective cohort 		A multicentre retrospective medical record review in three public hospitals and nine public health-care centres in Addis Ababa city, Ethiopia. Singleton pregnancies exposed to Tenofovir (TDF)-based highly active antiretroviral therapy (HAART) (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Singleton pregnancies exposed to Zidovudine (ZDV)-based highly active antiretroviral therapy (HAART) regimens (unspecified regimens). 		during pregnancy (anytime or not specified) 1004 / 379
Information on antiretroviral treatment (ART) exposure during pregnancy was extracted from the Antiretroviral Treatment and Follow-up Form (medical record review). The form is completed by healthcare providers as part of the routine care of HIV-infected individuals.
Favarato
2019 		The United Kingdom and Ireland.
2007 - 2015
prospective cohort 		The United Kingdom and Ireland’s National Study of HIV in Pregnancy and Childhood (NSHPC), a comprehensive, population-based surveillance study. Pregnant women exposed to Tenofovir-based regimens during pregnancy. (Addition of all ARV-regimens including Tenofovir). exposed to other treatment, sick
Pregnant women exposed to non-Tenofovir-based regimens during pregnancy. (Addition of all ARV-regimens non including Tenofovir). 		during pregnancy (anytime or not specified) 3115 / 3837
All pregnancies are notified prospectively by a named respondent in each maternity unitthrough an active, quarterly surveillance scheme.
Floridia
2013 		Italy
2001 - 2011
prospective cohort 		The Italian National Programme on Surveillance on Antiretroviral Treatment in Pregnancy. Pregnancies with first-trimester exposure to Tenofovir-based ART (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies unexposed to antiretroviral treatment during the first trimester. 		1st trimester 173 / 561
Treatment of HIV infection or prophylaxis for mother- to-child transmission were decided by the treating doctor. Laboratory and clinical data are collected from the hospital records of Obstetrics, Infectious Diseases, and Paediatrics departments, following the women’s consent.
Floridia
2018 		Italy
2001 - 2017
cohort 		The Italian National Program on Surveillance on Antiretroviral Treatment in Pregnancy. Pregnant women exposed to tenofovir–emtricitabine (TDF/FTC)-based regimens. exposed to other treatment, sick
Pregnant women exposed to Abacavir–lamivudine-based (ABC/3TC)-based regimens. 		during pregnancy (anytime or not specified) 661 / 252
The women and infants are followed during routine clinical care, and treatments are decided by the treating physician. Data were extracted from the general database.
Fowler
2016 		India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe.
2011 - 2014
randomized controlled trial 		The Promoting Maternal and Infant Survival Everywhere (PROMISE) trial. Pregnant HIV-infected women assigned to tenofovir-based ART (tenofovir, emtricitabine, and lopinavir–ritonavir). exposed to other treatment, sick
Pregnant HIV-infected women assigned to zidovudine-based ART (zidovudine, lamivudine, and lopinavir–ritonavir). 		2nd and/or 3rd trimester 406 / 410 For TDF-based-ART vs ZDV-based ART, we reported data available for the period 2 only (as made by the authors).
Pregnant women were randomly assigned to one of three regimens. Randomization was stratified according to HBV status and country.
Gibb
2012 		Uganda, Zimbabwe.
2004 - 2009
prospective cohort 		Substudy of the Development of AntiRetroviral Therapy in Africa (DART) open randomized trial. Infants with in utero exposure of tenofovir ≥90% days from the estimated start to end of pregnancy. (111 in subtudy: 94 TDF/zidovudine/lamivudine; 11 TDF/stavudine/lamivudine-based; 1 TDF/ lopinavir/ritonavir-based; 5 other TDF based). exposed to other treatment, sick
Infants without in utero exposure of tenofovir (62 in subtudy: 49 zidovudine/lamivudine-based; 2 stavudine/lamivudine-based; 3 lopinavir/ritonavir-based; 1 lamivudine/abacavir/nevirapine; 7 other non–TDF based). 		throughout pregnancy 251 / 115
Information on all pregnancies and ART taken by the mother throughout pregnancy and the infant at birth were collected within DART. High levels of adherence to ART were reported in DART using pharmacy refill, pill counts, and questionnaires (no randomisation to maternal ART regimens).
Greenup (Controls exposed to lamivudine)
2014 		Australia
2007 - ?
prospective cohort 		A multi-centre, prospective, opt-in observational study. Pregnancies exposed to Tenofovir for at least two weeks (after the 2nd trimester). exposed to other treatment, sick
Pregnancies exposed to Lamivudine for at least two weeks (after the 2nd trimester). 		2nd and/or 3rd trimester 58 / 52
Not specified.
Greenup (Controls unexposed, sick)
2014 		Australia
2007 - ?
prospective cohort 		A multi-centre, prospective, opt-in observational study. Pregnancies exposed to Tenofovir for at least two weeks (after the 2nd trimester). unexposed, sick
Pregnancies in mothers who chose not to take antiviral therapy. 		2nd and/or 3rd trimester 58 / 20
Not specified.
Heffron
2018 		Kenya and Uganda
2008 - 2016
prospective cohort 		Two longitudinal studies of tenofovir-based pre-exposure prophylaxis (PrEP) (the Partners Demonstration Project and the Partners PrEP Study). Pregnancies in women who choose to continue tenofovir-based pre-exposure prophylaxis (PrEP) during pregnancy. unexposed, sick
Pregnancies in women unexposed to pre-exposure prophylaxis (PrEP) during pregnancy (placebo arm). 		during pregnancy (anytime or not specified) 30 / 96
Participants using PrEP were issued electronic medication event monitoring (MEMS) bottle caps that recorded the date and time when every opening occurred. Archived plasma samples collected monthly from pregnant women dispensed PrEP were used for tenofovir quantification.
Jourdain a
2018 		Thailand
2013 - 2015
randomized controlled trial 		A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial conducted at 17 public hospitals. Participants randomly assigned to receive 300 mg of Tenofovir dministered once daily from 28 weeks of gestation to 2 months post partum. unexposed, sick
Participants randomly assigned to receive matching placebo dministered once daily from 28 weeks of gestation to 2 months post partum. 		3rd trimester 168 / 163
Participants were randomly assigned in a 1:1 ratio to receive treatment or placebo. The participants, the trial staff on site and at the coordination center, the investigators, and the laboratory personnel were unaware of the trial-group assignments.
Knapp
2012 		International
2002 - 2007
prospective cohort 		The International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) protocol P1025. Children exposed in utero to Tenofovir-based antiretroviral (unspecified regimens) in 1st trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children exposed in utero to non-Tenofovir-based antiretroviral (unspecified regimens). 		1st trimester, 2nd and/or 3rd trimester 138 / 876 Tenofovir-based antiretroviral: 97 exposures in 2nd/3rd trimester.
Not specified.
Kolgelier
2016 		Turkey
2010 - 2013
retrospective cohort 		Files of clinics of Adiyaman University Faculty of Medicine, Afyon Zubeyde Hanim Maternity Hospital, Konya Numune Hospital, Selcuk University Faculty of Medicine. Pregnant patients who began Tenofovir treatment during their pregnancy. exposed to other treatment, sick
Pregnant patients who began lamivudine treatment during their pregnancy. 		during pregnancy (anytime or not specified) 9 / 2
The files of patients were reviewed retrospectively and the following data were recorded: antiviral treatment received before pregnancy and, if so, the duration of the treatment; antiviral treatment started during pregnancy, the date it was started, and the antiviral used.
Lin
2018 		China
2013 - 2016
randomized controlled trial 		A double-blind randomized trial conducted in different hospitals located in northwest China. Pregnancies with Tenofovir (300 mg/day, oral) initiated at 24 weeks of gestation and continued to 4 weeks after delivery. unexposed, sick
Pregnancies that did not receive anti-viral treatment (routine nursing and prenatal care until the end of the study). 		3rd trimester 59 / 52 Abortions reported by authors occurred before treatment, thus there are not reported in Results.
The pregnant women were randomly divided into two groups then treatment was initiated. During the double-blind study, the participants did not know which type of intervention they accepted until the end of the intervention.
Liu (Controls exposed to LDT)
2019 		China
2010 - 2016
prospective cohort 		A prospective, multicentre study in 16 tertiary care hospitals (Shaanxi, China). Pregnant women who started on Tenofovir 300 mg daily from gestational weeks 24‐28. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women who started on Telbivudine 600 mg daily from gestational weeks 24‐28. (This is a subgroup of exposure among the whole exposed group considered in the study). 		3rd trimester 331 / 408
Based on patient‐physician mutual decision, the subjects were prescribed with antiviral drugs (treated groups) or underwent regular observation (the untreated group).
Liu (Controls unexposed, sick)
2019 		China
2010 - 2016
prospective cohort 		A prospective, multicentre study in 16 tertiary care hospitals (Shaanxi, China). Pregnant women who started on Tenofovir 300 mg daily from gestational weeks 24‐28. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnant women who refused to take medication during pregnancy. 		3rd trimester 331 / 154
Based on patient‐physician mutual decision, the subjects were prescribed with antiviral drugs (treated groups) or underwent regular observation (the untreated group).
Malaba
2017 		South Africa
2013 - 2015
prospective cohort 		A prospective cohort study conducted at a large, community-based public sector primary care facility in Cape Town, South Africa. Live births of HIV-infected pregnant women that received a first-line regimen of tenofovir/emtricitabine-based regimen (with efavirenz or nevirapine). unexposed, disease free
Live births of HIV-uninfected pregnant women. 		during pregnancy (anytime or not specified) 1276 / 278 In 1554 women, 82% were HIV-infected (n=1276), 92% (n=1173) of whom received a first-line regimen of tenofovir, emtricitabine and efavirenz or nevirapine. => HIV-infected women considered as exposed to tenofovir.
Initiation at the antenatal care (ANC) visit of under antiretroviral therapy (ART) at inclusion.
Mehta
2019 		South Africa
2013 - 2014
retrospective cohort 		A pregnancy exposure registry and birth defects surveillance (PER/BDS) initiated at Prince Mshiyeni Memorial Hospital (PMMH) in the KwaZulu-Natal province. Exposure to tenofovir-based regiments during the entire first trimester (96%TDF/emtricitabine (FTC)/EFV). unexposed, disease free
HIV-negative pregnancies and HIV-positive late initiation pregnancies (more than 15 weeks after LMP). 		1st trimester 336 / 7532 Control group: HIV-negative pregnancies and HIV-positive late initiation pregnancies (>15 weeks after LMP) => mainly HIV negative pregnancies. TDF exposures: addition of TDF/FTC/EFV, TDF/FTC/EFV and TDF/FTC/EFV (definitive and entire first trimester).
Five surveillance nurses surveyed the hospital’s maternity wards and labour ward registers to identify women who had recently delivered. The surveillance nurses notably collected information on medicine use.
Moodley (Controls exposed to other treatments)
2016 		South Africa
2011 - 2014
retrospective cohort 		A cross sectional study from maternity registers of a regional hospital in Durban, South Africa. Pregnant women receiving a fixed dose combination of triple ARVs [Tenofovir (TDF), Emtracitabine (FTC) and Efavirenz (EFV)]. exposed to other treatment, sick
Pregnant women receiving a dual ARV prophylaxis [Zidovudine from 14 weeks in pregnancy and single dose Nevirapine (NVP) in labour/delivery]. 		during pregnancy (anytime or not specified) 1666 / 974
Data abstracted from maternity registers of a regional hospital. The maternity register is routinely completed by the midwife immediately after a delivery, including ARV regimen.
Moodley (Controls unexposed, sick)
2016 		South Africa
2011 - 2014
retrospective cohort 		A cross sectional study from maternity registers of a regional hospital in Durban, South Africa. Pregnant women receiving a fixed dose combination of triple ARVs [Tenofovir (TDF), Emtracitabine (FTC) and Efavirenz (EFV)]. unexposed, sick
Pregnant women who had a reported CD4 count < 350 cells/mm3 in pregnancy and did not receive any ARV. 		during pregnancy (anytime or not specified) 1666 / 148
Data abstracted from maternity registers of a regional hospital. The maternity register is routinely completed by the midwife immediately after a delivery, including ARV regimen.
Mugo
2014 		Kenya and Uganda
2008 - 2013
randomized controlled trial 		The Partners PrEP Study, a phase 3, randomized, double-blind, placebo-controlled (9 sites in Kenya and Uganda). Pregnancies in women receiving daily oral tenofovir disoproxil fumarate (300 mg) (Addition of before and after July 2011). unexposed, sick
Pregnancies in women receiving placebo. 		early pregnancy 174 / 96 Study medication was discontinued in the event of pregnancy for the duration of pregnancy and breastfeeding. The study team estimated that the duration of study medication exposure in the event of pregnancy would be approximately 6 weeks or less.
At monthly follow-up visits for up to 36 months, participants received individualized adherence counseling and a month’s supply of study medication.
Pan
2016 		China
2012 - 2013
randomized controlled trial 		Trial with a multicenter, open-label, randomized, parallel-group design from academic tertiary care centers in five geographic regions of China. Pregnant women assigned to receive an oral dose of 300 mg of Tenofovir daily, starting from 30 to 32 weeks of gestation until postpartum week 4. unexposed, sick
Pregnant women assigned to receive usual care without antiviral therapy. 		late pregnancy 92 / 88
Using a randomization table, women were randomly assigned to control and TDF groups. Adherence to the TDF regimen was monitored by means of pill counts at each visit.
Phiri
2014 		USA
1994 - 2009
retrospective cohort (claims database) 		The Tennessee Medicaid Program (TennCare) linked to vital records and supplemented by in-depth medical chart reviews. Infant exposed in utero to tenofovir, i.e whose mother had at least 1 prescription dispensing from 30 days before the LMP through delivery. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Infant unexposed in utero to tenofovir in the first trimester (includes non-TDF ARV (25%) or no ARV (75%)). 		1st trimester 28 / 778 Total number of infants: 806, including 221 exposed to any ARV (including 28 exposed to Tenofovir-based ARV) and 585 unexposed to any ARV. Control group: 806-28=778 (including 585 unexposed to any ARV (75%) and 193 exposed to other ARVs).
Prescriptions for ARVs identified from the mothers’ Medicaid pharmacy claims.
Pintye
2015 		Kenya
June-Dec 2013
retrospective cohort 		Two cross-sectional surveys evaluating the national PMTCT program and maternal-child health (MCH). Mothers that used Tenofovir-containing regimens during pregnancy (mainly Tenofovir, lamivudine, and nevirapine (TDF/3TC/NVP) and tenofovir, lamivudine, and efavirenz (TDF/3TC/EFV)). exposed to other treatment, sick
Mothers that did not use Tenofovir-containing regimens during pregnancy (mainly zidovudine, lamivudine, and nevirapine (AZT/3TC/NVP) (78%)). 		during pregnancy (anytime or not specified) 89 / 188 Tenofovir, lamivudine, and nevirapine (TDF/3TC/NVP) and tenofovir, lamivudine, and efavirenz (TDF/3TC/EFV) were the most common regimens among mothers who used TDF-containing ART (65% and 26%, resp.).
At enrollment a nurse administered the study questionnaire. Maternal-child health (MCH) booklets confirmed clinical data self-reported on questionnaires. Data were abstracted from MCH booklets if mothers were not sure of ART regimen used during pregnancy.
Pintye
2017 		Kenya and Uganda
2008 - 2012
prospective cohort 		Longitudinal data of 2 HIV prevention studies (the Partners PrEP Study and the Partners Demonstration Project) conducted among HIV-serodiscordant couples from 9 sites in Kenya and Uganda. Pregnant women exposed to any Tenofovir (TDF)-containing 3-drug antiretroviral treatment (ART) during pregnancy (mainly Tenofovir/lamivudine-based regimens). exposed to other treatment, sick
Pregnant women exposed to non-Tenofovir (TDF)-containing 3-drug antiretroviral treatment (ART) during pregnancy (mainly Zidovudine/lamivudine-based regimens). 		at least 1st trimester, during pregnancy (anytime or not specified) 208 / 214 Exposed group: mainly Tenofovir/lamivudine-based regimens (n=205/208; 99%). Control group: mainly Zidovudine/lamivudine-based regimens (n=186/214; 87%).
TDF use was captured as part of information on maternal ART use during pregnancy, including the type of ART regimen and date of initiation self-reported by women and verified with clinical records or pill bottles when available.
Prieto (Controls exposed to other ARVs)
2014 		Spain
2000 - 2009
prospective cohort 		The Madrid Cohort of HIV-infected mother-infants pairs, a multicenter prospective observational study of HIV-infected mother and their infants. Pregnancies exposed to tenofovir in first or since second or third trimester (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnancies exposed to non-tenofovir-based regimens (unspecified regimens). 		1st trimester, 2nd and/or 3rd trimester 80 / 755
Women were visited during pregnancy, at delivery and at postpartum. At each visit, start and stop dates were recorded for each antiretroviral agent used.
Prieto (Controls unexposed, sick)
2014 		Spain
2000 - 2009
prospective cohort 		The Madrid Cohort of HIV-infected mother-infants pairs, a multicenter prospective observational study of HIV-infected mother and their infants. Pregnancies exposed to tenofovir in first or since second or third trimester (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed, sick
Pregnancies not exposed to antiretroviral treatment during pregnancy. 		1st trimester, 2nd and/or 3rd trimester 80 / 80
Women were visited during pregnancy, at delivery and at postpartum. At each visit, start and stop dates were recorded for each antiretroviral agent used.
Ransom
2013 		USA and Puerto Rico
2002 - 2011
prospective cohort 		The International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) protocol 1025, a prospective observational cohort study. Maternal use of a combination ARV regimen (at least triple ARV regimen) with Tenofovir. (Unspecified regimens). exposed to other treatment, sick
Maternal use of a combination ARV regimen (at least triple ARV regimen) without Tenofovir. (Unspecified regimens). 		2nd and/or 3rd trimester, at least 1st trimester, during pregnancy (anytime or not specified) 630 / 1395 Infants found to be HIV-infected were excluded. The publication of Rough 2018 updated data for Preterm birth. Thus data on preterm were not reported here.
Obstetrical history, substance use information, maternal antiretroviral use, and laboratory testing results were collected through medical chart abstraction or self-administered questionnaires.
Rice
2013 		USA including Puerto Rico
2007 - 2011
cohort 		The Surveillance Monitoring of ART Toxicities (SMARTT) study, a prospective cohort study conducted by the Pediatric HIV/AIDS Cohort Study (PHACS). (Dynamic and static cohort) Children with in utero Tenofovir-based regimens (unspecified regimens) exposure at any time during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children with in utero non-Tenofovir-combination antiretroviral (cARV) regimens (unspecified regimens) exposure at any time during pregnancy. 		during pregnancy (anytime or not specified) -9 / -9 Classified as 'cohort' because Static Cohort was a retrospective cohort and the Dynamic Cohort was a prospective cohort.
Maternal ARV history during pregnancy was collected through medical record review and from prior studies where PHACS had received permission to obtain participant-level data.
Rice
2018 		USA including Puerto Rico
2007 - 2014
cohort 		The Surveillance Monitoring of ART Toxicities (SMARTT) study, a prospective cohort study conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Pregnant women exposed to a Tenofovir-combination ARV (cARV) (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women exposed to a non-Tenofovir-combination ARV (cARV) or a triple nucleoside/nucleotide analog reverse transcriptase inhibitor (NRTI) regimen (unspecified regimens). 		during pregnancy (anytime or not specified) -9 / -9 Classified as 'cohort' because Static Cohort was a retrospective cohort and the Dynamic Cohort was a prospective cohort.
Maternal antiretroviral (ARV) history during pregnancy was collected through medical record review and from prior studies.
Rough
2018 		USA including Puerto Rico
2007-2016; 2002-2013
prospective cohort 		The Surveillance Monitoring for ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) and the P1025 study of the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network (dynamic cohort). Infants with in utero exposure to tenofovir, emtricitabine and any protease inhibitor (TDF–FTC–ATV/r or TDF–FTC–LPV/r). exposed to other treatment, sick
Infants with in utero exposure to zidovudine, lamivudine and any protease inhibitor (ZDV–3TC–based). 		during pregnancy (anytime or not specified) 960 / 1593 Supplemental Table S3 and S4.
Information on maternal antiretroviral exposure, including regimen start and stop dates, was abstracted from medical records.
Samadi Kochaksaraei
2016 		Canada,
2011 - 2014
prospective cohort 		A prospective study recruited from a tertiary referral centre. Pregnancies in Tenofovir-treated women with chronic hepatitis B (CHB). unexposed, sick
Pregnancies in untreated women with chronic hepatitis B (CHB). 		during pregnancy (anytime or not specified) 23 / 146 "Most women were seen in the 2nd trimester and at 3–6 months post-partum."
In the prenatal screening programme, all women are screened for HBV. Therapy with TDF 300 mg orally daily was recommended at ~28– 32 weeks gestation if HBV-DNA level was >7 log IU/mL.
Seidel
2020 		Germany
2008 - 2013
retrospective cohort 		Observational single-center study at the Charité University Medical Center, a tertiary care hospital offering specialized treatment for HIV-positive mothers and their children. HIV-pregnant women who received combination antiretroviral therapy (cART) with Tenofovir (unspecified regimens). exposed to other treatment, sick
Pregnant women who received combination antiretroviral therapy (cART) without Tenofovir (mainly with zidovudine). 		during pregnancy (anytime or not specified) 106 / 126
Maternal data on combination antiretroviral therapy (cART) regimen start and stop dates were obtained by medical chart data abstraction.
Seo
2018 		Korea
2011 - 2015
retrospective cohort 		Medical records of six tertiary hospitals of The Catholic University of Korea. Pregnant women with tenofovir administration once daily, starting from gestational week 28–34 until delivery. exposed to other treatment, sick
Pregnant women with telbivudine administration once daily, starting from gestational week 28–34 until delivery. 		3rd trimester 11 / 30
Gestational age at the initiation of antiviral therapy, the duration of antiviral treatment until delivery, and the types of antiviral agents were recorded from medical records.
Siberry
2012 		USA including Puerto Rico
2007 - 2010
cohort 		The Surveillance Monitoring for Antiretroviral Therapy Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network. Pregnant women receiving combination Tenofovir-based ART (unspecified regimens). exposed to other treatment, sick
Pregnant women receiving combination non-Tenofovir-based ART (unspecified regimens). 		during pregnancy (anytime or not specified) 449 / 1580 The publication of Rough 2018 updated data for Low birth weight. Thus data on Low birth weight were not reported here. Classified as 'cohort' because Static Cohort was a retrospective cohort and the Dynamic Cohort was a prospective cohort.
Maternal antiretroviral drug use early during pregnancy and prior to delivery were obtained by chart abstraction both overall and by trimester.
Sibiude
2014 		France
1994 - 2010
prospective cohort 		The French perinatal cohort (EPF) study (ANRS CO1/CO11). Children exposed in utero to Tenofovir-based ART (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children exposed to non–Tenofovir-based ART (unspecified regimens) . 		1st trimester, 2nd and/or 3rd trimester 823 / 12043 Exposed group: 823 first trimester TDF-based ART; 208 second/third trimester TDF- based ART (unspecified regimens). Two methods of classification for malformations: the higher OR are reported.
All ART combinations administered during pregnancy were recorded, with the dates when started and stopped.
Sibiude
2019 		France
2005 - 2014
prospective cohort 		The French Perinatal Cohort (EPF ANRS CO1) Children exposed in utero to Tenofovir-based ART (unspecified regimens) at conception. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children exposed to non–Tenofovir-based ART (unspecified regimens) at conception. 		during pregnancy (anytime or not specified) 1151 / -9 TDF-based ART: 1151 treated at conception and 277 started during pregnancy. Here we reported results for the group with more exposed women, i.e women treated at conception.
All ART combinations were recorded with dates at initiation and end.
The EPPICC study group
2019 		UK, Ireland, Belgium, Romania, Russia, Spain, Switzerland and Ukraine
2008 - 2014
cohort 		Seven observational studies across eight European countries. The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group. Pregnant women exposed to a combination of Tenofovir (with either lamivudine (3TC) or emtricitabine (FTC) and a third agent). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women exposed to a combination of Zidovudine (ZDV) - lamivudine (3TC) and a third agent. (This is a subgroup of exposure among the whole exposed group considered in the study). 		2nd and/or 3rd trimester 1122 / 5122 UK, Ireland and Ukraine : 89% of included pregnancies. ART was startedat median 22.9 gestation weeks (IQR 18.9–25.7) and received for median 15.7 weeks by delivery (IQR 12.3–19.6).
Not specified.
Torre
2016 		USA including Puerto Rico
? - 2013
prospective cohort 		The Surveillance Monitoring of ART Toxicities (SMARTT) cohort study (a protocol within the Pediatric HIV/AIDS Cohort Study [PHACS]). Pregnant women exposed to Tenofovir during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Not clearly specified (use exact adjusted logistic regression). 		1st trimester, during pregnancy (anytime or not specified) 602 / -9 The primary exposures of interest were in utero ARV exposure overall during pregnancy and within individual trimesters.
Maternal ARV data were retrospectively collected for the entire pregnancy through chart review or from prior studies.
Vigano
2011 		Not specified.
Not specified.
prospective cohort 		A multicentre observational cross-sectional cohort study performed in a cohort of seroreverters (SR). Children exposed in utero to protease-inhibitor-based HAART, including tenofovir (unspecified regimens). exposed to other treatment, sick
Children exposed in utero to protease-inhibitor-based HAART, not including tenofovir (unspecified regimens). 		during pregnancy (anytime or not specified) 33 / 35
Data regarding pattern and duration of HAART exposure during fetal life, antiretroviral prophylaxis at delivery and in the first weeks of life, and vitamin administration in the first 12 months of life were collected from clinical charts.
Wakano (Controls exposed to lamivudine)
2018 		Japan
2011 - 2015
prospective cohort 		A multicenter prospective study. Pregnant women treated with tenofovir (300 mg daily) initiated from 22 to 32 weeks. exposed to other treatment, sick
Pregnant women treated with lamivudine (100 mg daily) initiated from 28 to 32 weeks. 		2nd and/or 3rd trimester 2 / 3
To prevent mother-to-child transmission of HBV in subsequent pregnancies, the mothers were referred for antepartum antiviral therapy and treated if they consented.
Wakano (Controls unexposed, sick)
2018 		Japan
2011 - 2015
prospective cohort 		A multicenter prospective study. Pregnant women treated with tenofovir (300 mg daily) initiated from 22 to 32 weeks. unexposed, sick
Pregnant women that declined the antepartum antiviral therapy. 		2nd and/or 3rd trimester 2 / 3
To prevent mother-to-child transmission of HBV in subsequent pregnancies, the mothers were referred for antepartum antiviral therapy and treated if they consented.
Watts
2004 		International
1989 - 2003
prospective cohort 		The Antiretroviral Pregnancy Registry (APR). Pregnancies exposed to tenofovir-containing regimens (unspecified regimens). exposed to other treatment, sick
Pregnancies exposed to non-tenofovir-containing regimens (unspecified regimens). 		1st trimester, 2nd and/or 3rd trimester 64 / 3519 Control group: all exposed lived births (3583) excepted pregnancies exposed to tenofovir-containing regimens (19), i.e 3519.
Health care providers register exposed pregnant women before the pregnancy outcome is known. Shortly after delivery, the health care providers submit data on additional antiretroviral exposures in pregnancy.
Wilkinson
2013 		USA including Puerto Rico
2007 - 2009
cohort 		The Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study. Pregnant women receiving combination Tenofovir-based ART (unspecified regimens). This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children exposed in utero to non-tenofovir-based highly active antiretroviral therapy (HAART) (unspecified regimens). 		during pregnancy (anytime or not specified) -9 / -9 For tenofovir: the numbers of exposed and not exposed not provided. Classified as 'cohort' because Static Cohort was a retrospective cohort and the Dynamic Cohort was a prospective cohort.
Not specified.
Williams
2020 		USA including Puerto Rico
2007 - 2017
cohort 		The Surveillance Monitoring for ART Toxicities (SMARTT) study done by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Children exposed in utero to tenofovir-based regimens (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children exposed in utero to non-tenofovir-based regimens (unspecified regimens). 		1st trimester, during pregnancy (anytime or not specified) 1219 / 1764 "Microcephaly defined by Nellhaus criteria considered by authors as the primary outcome and results for microcephaly by SMARTT criteria included in the appendix (pp 7–8)."
At study entry, dates of prenatal antiretroviral use were obtained from medical charts and participant interview.
Williams
2015 		USA including Puerto Rico
2007-2012;1995-2008
cohort 		The Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study. Maternal use of Tenofovir-based ART (unspecified regimens) during the first trimester (<14 weeks gestation). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Maternal use of non-Tenofovir-based ART (unspecified regimens) during pregnancy. 		1st trimester 431 / 2086 Classified as 'cohort' because Static Cohort was a retrospective cohort and the Dynamic Cohort was a prospective cohort. '162 unique children with at least one major CA and 13 children with two or more conditional but no major anomalies'.
Information on ARV use during pregnancy was collected by medical chart abstraction.
Williams
2016 		USA and Puerto Rico
2007 - 2012
cohort 		The Surveillance Monitoring of ART Toxicities (SMARTT) Study established by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Children exposed in utero to Tenofovir-based regimens (unspecified regimens). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children unexposed in utero to the specific ARV drug class or drug being considered. 		1st trimester, during pregnancy (anytime or not specified) -9 / -9 Classified as 'cohort' because Static Cohort was a retrospective cohort and the Dynamic Cohort was a prospective cohort.
At study entry, dates of prenatal antiretroviral therapy use were obtained from medical charts and participant interview.
Zash
2016 		Botswana
2009 - 2014
retrospective cohort 		Database of the the 2 largest public maternity wards in Botswana, Princess Marina Hospital (PMH) in Gaborone, and Nyangabgwe Referral Hospital (NRH) in Francistown. Pregnant women who initiated Tenofovir/Emtricitabine/Efavirenz during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnant women who initiated any other antiretroviral (ARV) during pregnancy. 		during pregnancy (anytime or not specified) 1461 / 2172
Data were abstracted from maternal obstetric records (covering outpatient antenatal care and inpatient care during labor and delivery) including medications taken at the time of conception, and ARV start date, regimen, and any switch or discontinuation during pregnancy.
Zash (Controls exposed to other treatments)
2017 		Botswana
2014 - 2016
retrospective cohort 		Eight government maternity wards in Botswana. Births among HIV-infected women who started 3-drug Tenofovir-based regimens from conception and did not switch or stop ART in pregnancy. (Addition of TDF/FTC/EFV and TDF/FTC/NVP and TDF/FTC/LPV-R). exposed to other treatment, sick
Births among HIV-infected women who started 3-drug Zidovudine-Lamivudine-based regimens after conception and did not switch or stop ART in pregnancy. (Addition of ZDV-3TC-NVP and ZDV-3TC–LPV-R). 		during pregnancy (anytime or not specified) 3463 / 1532
Deidentified data were abstracted from obstetric cards (used throughout pregnancy).
Zash (Controls unexposed, disease free)
2017 		Botswana
2014 - 2016
retrospective cohort 		Eight government maternity wards in Botswana. Births among HIV-infected women who started 3-drug Tenofovir-based regimens from conception and did not switch or stop ART in pregnancy. (Addition of TDF/FTC/EFV and TDF/FTC/NVP and TDF/FTC/LPV-R). unexposed, disease free
Births among HIV unexposed with documentation of a negative maternal HIV test result during pregnancy. 		during pregnancy (anytime or not specified) 3463 / 34138 Authors studied ART exposure started before conception and ART exposure started after conception. Only results on ART exposure started after conception are reported here (higher number of pregnancies).
Deidentified data were abstracted from obstetric cards (used throughout pregnancy).
Zash (Controls unexposed, sick)
2017 		Botswana
2014 - 2016
retrospective cohort 		Eight government maternity wards in Botswana. Births among HIV-infected women who started 3-drug Tenofovir-based regimens from conception and did not switch or stop ART in pregnancy. (Addition of TDF/FTC/EFV and TDF/FTC/NVP and TDF/FTC/LPV-R). unexposed, sick
Births among HIV-infected women without antiretroviral therapy during pregnancy. 		during pregnancy (anytime or not specified) 3463 / 1059 Authors studied ART exposure started before conception and ART exposure started after conception. Only results on ART exposure started after conception are reported here (higher number of pregnancies).
Deidentified data were abstracted from obstetric cards (used throughout pregnancy).
Zeng (Controls exposed to telbivudine)
2019 		China
2013 - 2017
prospective cohort 		Not specified Pregnant patients who received tenofovir. exposed to other treatment, sick
Pregnant patients who received telbivudine. 		2nd and/or 3rd trimester 51 / 58
The patients were allocated to 3 groups according to their antiviral agents.
Zeng (Controls unexposed, sick)
2019 		China
2013 - 2017
prospective cohort 		Not specified Pregnant patients who received tenofovir. unexposed, sick
Pregnant patients who received no antiviral treatment. 		2nd and/or 3rd trimester 51 / 36
The patients were allocated to 3 groups according to their antiviral agents.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Garcia-Otero
2016 		Spain
2010 - 2014
case control 		A prospective cohort including pregnant women followed up in the Maternal–Fetal Medicine Department at BCNatal in Barcelona (Spain). Fetal cardiac hypertrophic phenotype (septal wall thickness > 4.5 mm that corresponds to the 95th centile reported in normal fetuses and the 75th centile of our cases) Fetal cardiac nonhypertrophic phenotype (septal wall thickness < 4.5 mm). Maternal epidemiological and obstetric parameters were collected by interview and review of medical records. The specific cART regimen during pregnancy was decided by the practitioner following local and international guidelines. Type and duration of ART before and during pregnancy were recorded. during pregnancy (anytime or not specified) -9 / -9 The fetal cardiac hypertrophic was the only parameter studied according to the kind of treatment. This analysis was only performed among the HIV group (as a case-control design).
Ultrasounds were performed by maternal– fetal medicine specialists skilled in fetal echocardiography who were blinded to the particular ART but not to the HIV status.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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