Tenofovir (all routes except local)

All congenital malformations (majors, minors, majors and minors, or unspecified)

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.
S5175
R13494		 Liu (Controls exposed to LDT), 2019 Congenital malformation (NOS) 3rd trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Control group: telbivudine Exposed group: TDF (only) Indication: CHB 0.61 [0.05;6.74] C
excluded (control group) 		1/325   2/396 3 325
ref
S5174
R13487		 Liu (Controls unexposed, sick), 2019 Congenital malformation (NOS) 3rd trimester excluded prospective cohort unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 1.26 [0.05;31.04] C
excluded (exposition period) 		1/325   0/136 1 325
ref
S5630
R14202		 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
S5134
R13390		 Floridia, 2018 Birth defects during pregnancy (anytime or not specified) excluded cohort exposed to other treatment, sick Adjustment: No Control group: Abacavir/Lamivudine-based Exposed group: TDF/emtricitabine-based Indication: HIV 1.21 [0.58;2.51]
excluded (exposition period) 		31/552   10/213 41 552
ref
S5154
R13474		 Heffron, 2018 Any congenital anomalies during pregnancy (anytime or not specified) excluded prospective cohort unexposed, sick Adjustment: Yes Control group: Unexposed, sick Exposed group: TDF (mix or unspecified regimens) Indication: PrEP 0.22 [0.01;4.15] C
excluded (exposition period) 		0/25   5/65 5 25
ref
S5321
R13804		 Lin, 2018 Congenital malformations 3rd trimester excluded randomized controlled trial unexposed, sick Adjustment: Randomisation Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 0.90 [0.02;45.96] C
excluded (exposition period) 		0/58   0/52 0 58
ref
S5290
R13650		 Seo, 2018 Any congenital anomaly 3rd trimester excluded retrospective cohort exposed to other treatment, sick Adjustment: No Control group: telbivudine Exposed group: TDF (only) Indication: CHB 2.81 [0.05;150.78] C
excluded (exposition period) 		0/11   0/30 0 11
ref
S5737
R14237		 Wakano (Controls exposed to lamivudine), 2018 Congenital anomalies (major or minor) 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
R14241		 Wakano (Controls unexposed, sick), 2018 Congenital anomalies (major or minor) 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
R14196		 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
R14197		 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
R14198		 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
R14201		 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
S5259
R13613		 Pan, 2016 Birth defect or malformation late pregnancy excluded randomized controlled trial unexposed, sick Adjustment: Randomisation Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 1.87 [0.17;21.00] C
excluded (exposition period) 		2/95   1/88 3 95
ref
S5262
R13625		 Chen, 2015 Congenital anomalies (minors and majors) late pregnancy excluded prospective cohort unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 2.62 [0.10;65.68] C
excluded (exposition period) 		1/65   0/56 1 65
ref
S5130
R14207		 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
S5244
R13565		 Greenup (Controls exposed to lamivudine), 2014 Congenital abnormality (NOS) 2nd and/or 3rd trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Control group: Lamivudine Exposed group: TDF (only) Indication: CHB 0.45 [0.04;5.08] C
excluded (control group) 		1/58   2/53 3 58
ref
S5243
R13555		 Greenup (Controls unexposed, sick), 2014 Congenital abnormality (NOS) 2nd and/or 3rd trimester excluded prospective cohort unexposed, sick Adjustment: No Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 1.04 [0.04;26.49] C
excluded (exposition period) 		1/58   0/20 1 58
ref
S5265
R13636		 Mugo, 2014 Congenital anomalies early pregnancy randomized controlled trial unexposed, sick Adjustment: Randomisation Control group: Unexposed, sick Exposed group: TDF (only) Indication: PrEP 0.64 [0.19;2.17] C 6/119   5/65 11 119
ref
S5143
R14203		 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
R14204		 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
R14205		 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
S5128
R13324		 Sibiude, 2014 Overall birth defects (according to MACDP classification) 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 0.80 [0.59;1.08] 51/823   854/12,043 905 823
ref
S5132
R14200		 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
R13293		 Gibb, 2012 Congenital abnormalities throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No Control group: zidovudine/lamivudine-based Exposed group: TDF/zidovudine/lamivudine Indication: HIV 0.67 [0.15;3.08] C 4/141   3/72 7 141
ref
S5123
R13300		 Knapp, 2012 Congenital anomalies 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 1.69 [0.83;3.44] 11/138   45/876 56 138
ref
S5115
R14199		 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
R14206		 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 12 studies 0.99 [0.81;1.21] 1,423 2,364
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]323363%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]34536%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Williams, 2015Williams, 2015 1.14[0.76; 1.71]16943124%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Mugo, 2014Mugo, 2014 0.64[0.19; 2.17]111193%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]10582%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Sibiude, 2014Sibiude, 2014 0.80[0.59; 1.08]90582344%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Floridia, 2013Floridia, 2013 0.85[0.31; 2.31]241734%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Gibb, 2012Gibb, 2012 0.67[0.15; 3.08]71412%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Knapp, 2012Knapp, 2012 1.69[0.83; 3.44]561388%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Brogly, 2010Brogly, 2010 1.39[0.45; 4.34]105453%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 (12 studies) I2 = 0% 0.99[0.81; 1.21]1,4232,3640.25.01.0ROB: 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 1.00[0.82; 1.22]1,4122,2450%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Williams, 2015 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Sibiude, 2014 Floridia, 2013 Gibb, 2012 Knapp, 2012 Brogly, 2010 Watts, 2004 11 case control studiescase control studies 0 RCTRCT 0.64[0.19; 2.17]11119 -NAMugo, 2014 1 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 0.90[0.54; 1.51]1114310%NABérard (Controls unexposed, sick), 2017 Mugo, 2014 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 5 exposed to other treatment, sickexposed to other treatment, sick 0.98[0.78; 1.24]1,2801,5972%NAWilliams, 2015 Sibiude, 2014 Gibb, 2012 Knapp, 2012 Brogly, 2010 Watts, 2004 6 Tags Adjustment   - No  - No 1.08[0.67; 1.74]1778080%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 Gibb, 2012 Watts, 2004 7   - Randomisation  - Randomisation 0.64[0.19; 2.17]11119 -NAMugo, 2014 1   - Yes  - Yes 1.06[0.76; 1.47]1,2351,43739%NAWilliams, 2015 Sibiude, 2014 Knapp, 2012 Brogly, 2010 4 Control group   - non-TDF (mix or unspecified regimens)  - non-TDF (mix or unspecified regimens) 1.03[0.78; 1.36]1,2731,45618%NAWilliams, 2015 Sibiude, 2014 Knapp, 2012 Brogly, 2010 Watts, 2004 5   - Unexposed, disease free  - Unexposed, disease free 2.33[0.71; 7.69]32336 -NAMehta, 2019 1   - Unexposed, sick  - Unexposed, sick 0.90[0.54; 1.51]1114310%NABérard (Controls unexposed, sick), 2017 Mugo, 2014 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 5   - zidovudine/lamivudine-based  - zidovudine/lamivudine-based 0.67[0.15; 3.08]7141 -NAGibb, 2012 1 Exposed group   - TDF (mix or unspecified regimens)  - TDF (mix or unspecified regimens) 0.98[0.80; 1.21]1,3731,7680%NABérard (Controls unexposed, sick), 2017 Williams, 2015 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Sibiude, 2014 Floridia, 2013 Knapp, 2012 Brogly, 2010 Watts, 2004 9   - TDF (only)  - TDF (only) 0.64[0.19; 2.17]11119 -NAMugo, 2014 1   - TDF/emtracitabine/efavirenz  - TDF/emtracitabine/efavirenz 2.33[0.71; 7.69]32336 -NAMehta, 2019 1   - TDF/zidovudine/lamivudine  - TDF/zidovudine/lamivudine 0.67[0.15; 3.08]7141 -NAGibb, 2012 1 Indication   - HIV  - HIV 1.00[0.82; 1.22]1,4122,2450%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Williams, 2015 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Sibiude, 2014 Floridia, 2013 Gibb, 2012 Knapp, 2012 Brogly, 2010 Watts, 2004 11   - PrEP  - PrEP 0.64[0.19; 2.17]11119 -NAMugo, 2014 1 All studiesAll studies 0.99[0.81; 1.21]1,4232,3640%NAMehta, 2019 Bérard (Controls unexposed, sick), 2017 Williams, 2015 Mugo, 2014 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Sibiude, 2014 Floridia, 2013 Gibb, 2012 Knapp, 2012 Brogly, 2010 Watts, 2004 120.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.43.41.7310.000Mehta, 2019Bérard (Controls unexposed, sick), 2017Williams, 2015Mugo, 2014Phiri, 2014Prieto (Controls unexposed, sick), 2014Sibiude, 2014Floridia, 2013Gibb, 2012Knapp, 2012Brogly, 2010Watts, 2004

Asymetry test p-value = 0.5924 (by Egger's regression)

slope=-0.0837 (0.1573); intercept=0.2453 (0.4435); t=0.5530; p=0.5924

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 5244, 5181, 5206, 5203, 5737, 5175

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 0.90[0.54; 1.51]1114310%NABérard (Controls unexposed, sick), 2017 Mugo, 2014 Phiri, 2014 Prieto (Controls unexposed, sick), 2014 Floridia, 2013 5 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.12[0.83; 1.51]1,3571,70825%NABérard (Controls exposed to other ARV), 2017 Williams, 2015 Prieto (Controls exposed to other ARVs), 2014 Sibiude, 2014 Gibb, 2012 Knapp, 2012 Brogly, 2010 Watts, 2004 80.510.01.0