Tenofovir (all routes except local)

Major congenital malformations

R analysis
id Study   Lib. in paper Exposition period    Study type 
 Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S5630
R14041		 Mehta, 2019 Major congenital malformations 1st trimester retrospective cohort unexposed, disease free Adjustment: No Control group: Unexposed, disease free Exposed group: TDF/emtracitabine/efavirenz Indication: HIV 2.33 [0.71;7.69] C 3/336   29/7,532 32 336
ref
S5737
R14238		 Wakano (Controls exposed to lamivudine), 2018 Congenital anomalies (major) 2nd and/or 3rd trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Control group: Lamivudine Exposed group: TDF (only) Indication: CHB 1.67 [0.02;137.36] C
excluded (control group) 		0/2   0/3 0 2
ref
S5738
R14242		 Wakano (Controls unexposed, sick), 2018 Congenital anomalies (major) 2nd and/or 3rd trimester excluded prospective cohort unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 1.67 [0.02;137.36] C
excluded (exposition period) 		0/2   0/3 0 2
ref
S5206
R13509		 Bérard (Controls exposed to other ARV), 2017 Major congenital malformations 1st trimester population based cohort propective exposed to other treatment, sick excluded Adjustment: No Control group: non-TDF (mix or unspecified regimens) Exposed group: TDF (mix or unspecified regimens) Indication: HIV 2.76 [1.05;7.23] C
excluded (control group) 		9/53   10/145 19 53
ref
S5203
R13506		 Bérard (Controls unexposed, disease free), 2017 Major congenital malformations 1st trimester population based cohort propective unexposed, disease free excluded Adjustment: No Control group: Unexposed, disease free Exposed group: TDF (mix or unspecified regimens) Indication: HIV 2.18 [1.06;4.46] C
excluded (control group) 		9/53   18,388/214,042 18,397 53
ref
S5205
R13508		 Bérard (Controls unexposed, sick), 2017 Major congenital malformations 1st trimester population based cohort propective unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (mix or unspecified regimens) Indication: HIV 1.18 [0.51;2.71] C 9/53   25/169 34 53
ref
S5131
R13347		 Fowler, 2016 Major Congenital Anomalies 2nd and/or 3rd trimester excluded randomized controlled trial exposed to other treatment, sick Adjustment: Randomisation Control group: zidovudine/lamivudine/lopinavir–ritonavir Exposed group: TDF/emtricitabine/lopinavir–ritonavir Indication: HIV 0.34 [0.07;1.68] C
excluded (exposition period) 		2/320   6/328 8 320
ref
S5262
R13623		 Chen, 2015 Major congenital anomalies late pregnancy excluded prospective cohort unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 0.86 [0.02;44.08] C
excluded (exposition period) 		0/65   0/56 0 65
ref
S5130
R13338		 Williams, 2015 At least one major anomaly, or at least two conditional anomalies 1st trimester cohort exposed to other treatment, sick Adjustment: Yes Control group: non-TDF (mix or unspecified regimens) Exposed group: TDF (mix or unspecified regimens) Indication: HIV 1.14 [0.76;1.71] 32/431   137/2,086 169 431
ref
S5143
R13410		 Phiri, 2014 Major birth defects 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (mix or unspecified regimens) Indication: HIV 0.42 [0.02;6.99] C 0/28   32/778 32 28
ref
S5181
R13499		 Prieto (Controls exposed to other ARVs), 2014 Major birth defects 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: Yes Control group: non-TDF (mix or unspecified regimens) Exposed group: TDF (mix or unspecified regimens) Indication: HIV 1.01 [0.30;3.42]
excluded (control group) 		4/58   54/755 58 58
ref
S5180
R13497		 Prieto (Controls unexposed, sick), 2014 Major birth defects 1st trimester prospective cohort unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (mix or unspecified regimens) Indication: HIV 0.91 [0.25;3.40] C 4/58   6/80 10 58
ref
S5132
R13361		 Floridia, 2013 Major birth defects 1st trimester prospective cohort unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (mix or unspecified regimens) Indication: HIV 0.85 [0.31;2.31] 5/173   19/561 24 173
ref
S5122
R13295		 Gibb, 2012 Congenital abnormalities (extraction of majors) throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No Control group: zidovudine/lamivudine-based Exposed group: TDF/zidovudine/lamivudine Indication: HIV 0.76 [0.12;4.66] C 3/141   2/72 5 141
ref
S5115
R13259		 Brogly, 2010 At least one major or at least two conditional birth defects 1st trimester prospective cohort exposed to other treatment, sick Adjustment: Yes Control group: non-TDF (mix or unspecified regimens) Exposed group: TDF (mix or unspecified regimens) Indication: HIV 1.39 [0.45;4.34] 4/45   101/1,988 105 45
ref
S5326
R13811		 Watts, 2004 Birth defects (any major structural or chromosomal abnormality, or any cluster of 2 or more minor abnormalities) 1st trimester prospective cohort exposed to other treatment, sick Adjustment: No Control group: non-TDF (mix or unspecified regimens) Exposed group: TDF (mix or unspecified regimens) Indication: HIV 0.94 [0.06;15.82] C 0/19   38/1,372 38 19
ref
Total 9 studies 1.14 [0.85;1.54] 449 1,284
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

StudyTE95% CIn casesn exposedweightROBABCDEF Mehta, 2019Mehta, 2019 2.33[0.71; 7.69]323366%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Bérard (Controls unexposed, sick), 2017Bérard, 2017 1 1.18[0.51; 2.71]345313%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Williams, 2015Williams, 2015 1.14[0.76; 1.71]16943155%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Phiri, 2014Phiri, 2014 0.42[0.02; 6.99]32281%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Prieto (Controls unexposed, sick), 2014Prieto, 2014 2 0.91[0.25; 3.40]10585%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Floridia, 2013Floridia, 2013 0.85[0.31; 2.31]241739%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Gibb, 2012Gibb, 2012 0.76[0.12; 4.66]51413%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Brogly, 2010Brogly, 2010 1.39[0.45; 4.34]105457%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Watts, 2004Watts, 2004 0.94[0.06; 15.82]38191%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (9 studies) I2 = 0% 1.14[0.85; 1.54]4491,2840.25.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.14[0.85; 1.54]4491,2840%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Williams, 2015 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 Gibb, 2012 Brogly, 2010 Watts, 2004 9 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.33[0.71; 7.69]32336 -NAMehta, 2019 1 unexposed, sickunexposed, sick 0.97[0.55; 1.71]1003120%NABérard (Controls unexposed, sick), 2017 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 4 exposed to other treatment, sickexposed to other treatment, sick 1.14[0.79; 1.65]3176360%NAWilliams, 2015 Gibb, 2012 Brogly, 2010 Watts, 2004 4 Tags Adjustment   - No  - No 1.10[0.68; 1.79]1758080%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 Gibb, 2012 Watts, 2004 7   - Yes  - Yes 1.17[0.80; 1.71]2744760%NAWilliams, 2015 Brogly, 2010 2 Control group   - non-TDF (mix or unspecified regimens)  - non-TDF (mix or unspecified regimens) 1.16[0.80; 1.70]3124950%NAWilliams, 2015 Brogly, 2010 Watts, 2004 3   - Unexposed, disease free  - Unexposed, disease free 2.33[0.71; 7.69]32336 -NAMehta, 2019 1   - Unexposed, sick  - Unexposed, sick 0.97[0.55; 1.71]1003120%NABérard (Controls unexposed, sick), 2017 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 4   - zidovudine/lamivudine-based  - zidovudine/lamivudine-based 0.76[0.12; 4.66]5141 -NAGibb, 2012 1 Exposed group   - TDF (mix or unspecified regimens)  - TDF (mix or unspecified regimens) 1.10[0.80; 1.51]4128070%NABérard (Controls unexposed, sick), 2017 Williams, 2015 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 Brogly, 2010 Watts, 2004 7   - TDF/emtracitabine/efavirenz  - TDF/emtracitabine/efavirenz 2.33[0.71; 7.69]32336 -NAMehta, 2019 1   - TDF/zidovudine/lamivudine  - TDF/zidovudine/lamivudine 0.76[0.12; 4.66]5141 -NAGibb, 2012 1 Indication   - HIV  - HIV 1.14[0.85; 1.54]4491,2840%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Williams, 2015 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 Gibb, 2012 Brogly, 2010 Watts, 2004 9 All studiesAll studies 1.14[0.85; 1.54]4491,2840%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Williams, 2015 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 Gibb, 2012 Brogly, 2010 Watts, 2004 90.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.43.51.7310.000Mehta, 2019Bérard (Controls unexposed, sick), 2017Williams, 2015Phiri, 2014Prieto (Controls unexposed, sick), 2014Floridia, 2013Gibb, 2012Brogly, 2010Watts, 2004

Asymetry test p-value = 0.5599 (by Egger's regression)

slope=0.2185 (0.1685); intercept=-0.2247 (0.3672); t=0.6120; p=0.5599

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 5181, 5206, 5203, 5737

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.22[1.20; 4.10]18,4293890%NAMehta, 2019 Bérard (Controls unexposed, disease free), 2017 2 unexposed, sick controlsunexposed, sick controls 0.97[0.55; 1.71]1003120%NABérard (Controls unexposed, sick), 2017 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.26[0.90; 1.75]3947470%NABérard (Controls exposed to other ARV), 2017 Williams, 2015 Prieto (Controls exposed to other ARVs), 2014 Gibb, 2012 Brogly, 2010 Watts, 2004 60.510.01.0