Tenofovir (all routes except local)

Late intrauterine deaths (> 22 weeks)

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.
S5276
R13643		 Favarato, 2019 Stillbirth (>24 weeks gestation) during pregnancy (anytime or not specified) 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 0.76 [0.45;1.29] C 23/3,115   37/3,837 60 3,115
ref
S5145
R13411		 Caniglia, 2018 Stillbirth (fetal death ≥24 weeks gestation) during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick Adjustment: Yes Control group: zidovudine/lamivudine/nevirapine Exposed group: TDF/emtracitabine/efavirenz Indication: HIV 0.34 [0.20;0.57] 25/1,108   42/637 67 1,108
ref
S5304
R13732		 Jourdain a, 2018 Stillbirth antepartum 3rd trimester randomized controlled trial unexposed, sick Adjustment: Randomisation Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 2.98 [0.12;73.74] C 1/162   0/160 1 162
ref
S5153
R13440		 Pintye, 2017 Pregnancy loss (> 20 weeks) at least 1st trimester prospective cohort exposed to other treatment, sick Adjustment: Yes Control group: zidovudine/lamivudine-based Exposed group: TDF/lamivudine-based Indication: PrEP 1.75 [0.41;7.82] 4/-   1/- 5 -
ref
S5258
R13594		 Zash (Controls exposed to other treatments), 2017 Stillbirth (> 24th weeks) during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick Adjustment: No Control group: zidovudine/lamivudine-based Exposed group: TDF (mix or unspecified regimens) Indication: HIV 0.44 [0.32;0.59] C 91/3,463   89/1,532 180 3,463
ref
S5131
R13345		 Fowler, 2016 Stillbirth (Intrauterine fetal death > 20 weeks) 2nd and/or 3rd trimester randomized controlled trial exposed to other treatment, sick Adjustment: Randomisation Control group: zidovudine/lamivudine/lopinavir–ritonavir Exposed group: TDF/emtricitabine/lopinavir–ritonavir Indication: HIV 3.09 [0.62;15.42] C 6/341   2/347 8 341
ref
S5136
R13395		 Moodley (Controls exposed to other treatments), 2016 Stillbirth during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick excluded Adjustment: No Control group: zidovudine/nevirapine Exposed group: TDF/emtracitabine/efavirenz Indication: HIV 1.28 [0.72;2.28] C
excluded (control group) 		37/1,666   17/974 54 1,666
ref
S5138
R13405		 Moodley (Controls unexposed, sick), 2016 Stillbirth during pregnancy (anytime or not specified) retrospective cohort unexposed, sick Adjustment: Yes Control group: Unexposed, sick Exposed group: TDF/emtracitabine/efavirenz Indication: HIV 0.18 [0.10;0.34] 37/1,666   20/148 57 1,666
ref
S5259
R13596		 Pan, 2016 Fetal loss or stillbirth late pregnancy randomized controlled trial unexposed, sick Adjustment: Randomisation Control group: Unexposed, sick Exposed group: TDF (only) Indication: CHB 3.13 [0.13;77.68] C 1/97   0/100 1 97
ref
S5140
R13447		 Zash, 2016 Stillbirths (> 30 gestational weeks) during pregnancy (anytime or not specified) retrospective cohort exposed to other treatment, sick Adjustment: Yes Control group: non-TDF (mix or unspecified regimens) Exposed group: TDF/emtracitabine/efavirenz Indication: HIV 0.60 [0.30;1.30] 18/1,054   70/2,172 88 1,054
ref
S5265
R13633		 Mugo, 2014 Pregnancy losses >20 weeks’ gestation early pregnancy randomized controlled trial unexposed, sick Adjustment: Randomisation Control group: Unexposed, sick Exposed group: TDF (only) Indication: PrEP 2.24 [0.25;20.29] C 4/174   1/96 5 174
ref
S5122
R13299		 Gibb, 2012 Stillbirths (> 22 weeks) throughout pregnancy prospective cohort exposed to other treatment, sick Adjustment: No Control group: zidovudine/lamivudine-based Exposed group: TDF/zidovudine/lamivudine Indication: HIV 2.40 [0.80;7.20] C 20/251   4/115 24 251
ref
Total 11 studies 0.70 [0.43;1.14] 496 11,431
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 Favarato, 2019Favarato, 2019 0.76[0.45; 1.29]603,11514%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Caniglia, 2018Caniglia, 2018 0.34[0.20; 0.57]671,10814%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Jourdain a, 2018Jourdain a, 2018 2.98[0.12; 73.74]11622%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Pintye, 2017Pintye, 2017 1.75[0.41; 7.82]5-7%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Zash (Controls exposed to other treatments), 2017Zash, 2017 1 0.44[0.32; 0.59]1803,46316%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Fowler, 2016Fowler, 2016 3.09[0.62; 15.42]83416%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Moodley (Controls unexposed, sick), 2016Moodley, 2016 2 0.18[0.10; 0.34]571,66613%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Pan, 2016Pan, 2016 3.13[0.13; 77.68]1972%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Zash, 2016Zash, 2016 0.60[0.30; 1.30]881,05412%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Mugo, 2014Mugo, 2014 2.24[0.25; 20.29]51744%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Gibb, 2012Gibb, 2012 2.40[0.80; 7.20]242519%ROB confusion: NAROB selection: NAROB classification: NAROB missing: NAROB mesure: NAROB reporting: NA Total (11 studies) I2 = 72% 0.70[0.43; 1.14]49611,4310.010.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls exposed to other treatments; 2: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 0.55[0.34; 0.90]48110,65777%NAFavarato, 2019 Caniglia, 2018 Pintye, 2017 Zash (Controls exposed to other treatments), 2017 Moodley (Controls unexposed, sick), 2016 Zash, 2016 Gibb, 2012 7 case control studiescase control studies 0 RCTRCT 2.83[0.92; 8.74]157740%NAJourdain a, 2018 Fowler, 2016 Pan, 2016 Mugo, 2014 4 Type of controls unexposed, sickunexposed, sick 0.97[0.15; 6.37]642,09969%NAJourdain a, 2018 Moodley (Controls unexposed, sick), 2016 Pan, 2016 Mugo, 2014 4 exposed to other treatment, sickexposed to other treatment, sick 0.74[0.45; 1.20]4329,33271%NAFavarato, 2019 Caniglia, 2018 Pintye, 2017 Zash (Controls exposed to other treatments), 2017 Fowler, 2016 Zash, 2016 Gibb, 2012 7 Tags Adjustment   - No  - No 0.79[0.37; 1.67]2646,82981%NAFavarato, 2019 Zash (Controls exposed to other treatments), 2017 Gibb, 2012 3   - Randomisation  - Randomisation 2.83[0.92; 8.74]157740%NAJourdain a, 2018 Fowler, 2016 Pan, 2016 Mugo, 2014 4   - Yes  - Yes 0.42[0.20; 0.85]2173,82873%NACaniglia, 2018 Pintye, 2017 Moodley (Controls unexposed, sick), 2016 Zash, 2016 4 Control group   - non-TDF (mix or unspecified regimens)  - non-TDF (mix or unspecified regimens) 0.70[0.46; 1.08]1484,1690%NAFavarato, 2019 Zash, 2016 2   - Unexposed, sick  - Unexposed, sick 0.97[0.15; 6.37]642,09969%NAJourdain a, 2018 Moodley (Controls unexposed, sick), 2016 Pan, 2016 Mugo, 2014 4   - zidovudine/lamivudine/lopinavir–rit ...  - zidovudine/lamivudine/lopinavir–ritonavir 3.09[0.62; 15.42]8341 -NAFowler, 2016 1   - zidovudine/lamivudine/nevirapine  - zidovudine/lamivudine/nevirapine 0.34[0.20; 0.57]671,108 -NACaniglia, 2018 1   - zidovudine/lamivudine-based  - zidovudine/lamivudine-based 1.10[0.30; 3.97]2093,71482%NAPintye, 2017 Zash (Controls exposed to other treatments), 2017 Gibb, 2012 3 Exposed group   - TDF (mix or unspecified regimens)  - TDF (mix or unspecified regimens) 0.55[0.32; 0.95]2406,57870%NAFavarato, 2019 Zash (Controls exposed to other treatments), 2017 2   - TDF (only)  - TDF (only) 2.60[0.53; 12.65]74330%NAJourdain a, 2018 Pan, 2016 Mugo, 2014 3   - TDF/emtracitabine/efavirenz  - TDF/emtracitabine/efavirenz 0.32[0.17; 0.61]2123,82868%NACaniglia, 2018 Moodley (Controls unexposed, sick), 2016 Zash, 2016 3   - TDF/emtricitabine/lopinavir–ritonavir  - TDF/emtricitabine/lopinavir–ritonavir 3.09[0.62; 15.42]8341 -NAFowler, 2016 1   - TDF/lamivudine-based  - TDF/lamivudine-based 1.75[0.40; 7.64]5- -NAPintye, 2017 1   - TDF/zidovudine/lamivudine  - TDF/zidovudine/lamivudine 2.40[0.80; 7.20]24251 -NAGibb, 2012 1 Indication   - CHB  - CHB 3.05[0.32; 29.55]22590%NAJourdain a, 2018 Pan, 2016 2   - HIV  - HIV 0.57[0.34; 0.96]48410,99879%NAFavarato, 2019 Caniglia, 2018 Zash (Controls exposed to other treatments), 2017 Fowler, 2016 Moodley (Controls unexposed, sick), 2016 Zash, 2016 Gibb, 2012 7   - PrEP  - PrEP 1.89[0.55; 6.43]101740%NAPintye, 2017 Mugo, 2014 2 All studiesAll studies 0.70[0.43; 1.14]49611,43172%NAFavarato, 2019 Caniglia, 2018 Jourdain a, 2018 Pintye, 2017 Zash (Controls exposed to other treatments), 2017 Fowler, 2016 Moodley (Controls unexposed, sick), 2016 Pan, 2016 Zash, 2016 Mugo, 2014 Gibb, 2012 110.010.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-3.93.51.9670.000Favarato, 2019Caniglia, 2018Jourdain a, 2018Pintye, 2017Zash (Controls exposed to other treatments), 2017Fowler, 2016Moodley (Controls unexposed, sick), 2016Pan, 2016Zash, 2016Mugo, 2014Gibb, 2012

Asymetry test p-value = 0.0424 (by Egger's regression)

slope=-1.2342 (0.2726); intercept=1.9079 (0.8076); t=2.3624; p=0.0424

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 5136

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed, sick controlsunexposed, sick controls 0.97[0.15; 6.37]642,09969%NAJourdain a, 2018 Moodley (Controls unexposed, sick), 2016 Pan, 2016 Mugo, 2014 4 exposed to other treatment, sick controlsexposed to other treatment, sick controls 0.82[0.51; 1.31]48610,99875%NAFavarato, 2019 Caniglia, 2018 Pintye, 2017 Zash (Controls exposed to other treatments), 2017 Fowler, 2016 Moodley (Controls exposed to other treatments), 2016 Zash, 2016 Gibb, 2012 80.510.01.0