Table 3 Description of the study population and summary results for studies included in the systematic review

Delicio et al. (2018) [34]

N = 801

Median age 28 years [13-46]

CD4 + median 444cell/ml [3–1915]

Caucasian ethnic 61%

PI = 603

NNRTI = 141

Before conception n = 217

Preterm birth

PI = 130/579 (22.5 [19.1–25.9])

NNRTI = 25/141 (17.7 [11.4–24.0])

1.27

[0.86–1.86]

LBW

PI = 135/591 (22.8 [19.5–26.2])

NNRTI = 28/142 (19.7 [13.2–26.3])

1.16

[0.81–1.67]

SGA

PI = 118/582 (20.3 [17.0–23.5])

NNRTI = 14/141 (9.9 [5.0–14.9])

2.04

[1.21–3.44]

Townsend et al

(2006) [35]

N = 3 147

Median age 29 years [16-44]

Median CD4 + ND

Caucasian ethnic 18.7%, African ethnic 73.6%

PI n = 205

NNRTI n = 291

First trimester n = 541, whose HAART n = 496

Congenital abnormalities

PI = 7/205 (3.4 [0.9–5.9])

NNRTI = 12/291(4.1[1.8–6.4])

0.83

[0.33–2.07]

Malaba et al. (2017) [36]

N = 1 494

Median age 29 years [26-34]

CD4 count (cell/µl) ≤ 350 43. > 350 54

PI = 33

NNRTI = 1245

Before conception n = 572

Preterm birth

PI = 10/29 (34.5 [17.2–51.8])

NNRTI = 217/961 (22.6 [19.9–25.2])

1.53

[0.91–2.56]

VPT

PI = 0/29 (0 [0–0])

NNRTI = 23/961 (2.4 [1.4–3.4])

0.68

[0.04–1.96]

LBW

PI = 5/29 (17.2 [3.5–31.0])

NNRTI = 139/961 (14.5 [12.2–16.7])

1.19

[0.53–2.69]

VLBW

PI = 0/29 (0 [0–0])

NNRTI = 20/961 (2.1 [1.2–3.0])

0.78

[0.05–12.63]

SGA

PI = 3/29 (10.3 [0.0–21.4])

NNRTI = 111/961 (11.6 [9.5–13.6])

0.90

[0.30–2.65]

Phiri et al. (2015) [37]

N = 3 228

Median age 26 years [14-43]

Caucasian ethnic 19%, African ethnic 81%

PI = 222

NNRTI = 78

ND

Preterm birth

PI = 41/222 (18.5 [13.4–23.6])

NNRTI = 14/78 (17.9 [9.4–26.5])

1.03

[0.59–1.78]

VPT

PI = 9/222 (4.1 [1.5–6.6])

NNRTI = 3/78 (3.8 [0.0–8.1])

1.05

[0.29–3.80]

LBW

PI = 43/222 (19.4 [14.2–24.6])

NNRTI = 25/78 (32.1 [21.7–42.4])

0.60

[0.40–0.92]

VLBW

PI = 6/222 (2.7 [0.6–4.8])

NNRTI = 1/78 (1.3 [0.0–3.8])

2.11

[0.26–17.24]

SGA

PI = 55/222 (24.8 [19.1–30.5])

NNRTI = 28/78 (35.9 [25.3–46.5])

0.69

[0.47–1.00]

Stillbirth

PI = 11/637 (1.7 [0.7–2.7])

NNRTI = 0/84 (0.0 [0.0–0.0])

3.06

[0.18–51.53]

Brogly et al. (2010) [38]

N = 2 202

Age < 20 years 6. 20–34 years 71. > 35 years 13

Non-Hispanic ethnic 67%, Hispanic ethnic 30%, Other ethnic 1%

PI = 353

NNRTI = 142

ND

Congenital abnormalities

PI = 23/353 (6.5 [3.9–9.1])

NNRTI = 8/142 (5.6 [1.8–9.4])

1.16

[0.53–2.52]

Prieto et al. (2014) [39]

N = 898

CD4 count at enrolment (cell/µl): > 500 30%, 200–500 28%, < 200 8%

Caucasian ethnic 72%, Sub-Saharan ethnic 16%, Latino American ethnic 11%, other ethnic 2%

PI = 476

NNRTI = 233

First trimester n = 329

Second/third trimester n = 488

Congenital abnormalities

PI = 31/476 (6.5 [4.3–8.7])

NNRTI = 14/233 (6.0 [3.0–9.1])

1.08

[0.59–2.00]

Floridia et al. (2013) [40]

N = 2 830

Median age 33 years [29-69]

Median CD4 + count (cell/mm³) 420 [295–575]

Caucasian ethnic 66%, African ethnic 29%, other ethnic 4%

PI = 349

NNRTI = 257

Before conception n = 1257

First trimester n = 1257

Congenital abnormalities

PI = 11/353 (3.1 [1.3–4.9])

NNRTI = 11/273 (4.0 51.7–6.4])

0.77

[0.34–1.76]

van der Merwe et al. (2011) [41]

N = 1 630

Mean age 30.3 years (sd 5.1)

Median CD4 + 154 cell/mm³ (101–195)

Ethnic group ND

PI n = 445

NNRTI n = 534

Before 28 weeks n = 533 (PI n = 155 and NNRTI n = 398)

After 28 weeks n = 427 (PI n = 290 and NNRTI n = 137)

Preterm birth

PI = 15/421 (3.6 [1.8–5.3]

NNRTI = 44/395 (11.1 [8.0–14.2])

0.32

[0.18- 0.57]

VPT^□

PI = 13/421 (3.1 [1.4–4.7])

NNRTI = 30/395 (7.6 [5.0–10.2])

0.41

[0.22–0.77]

LBW

PI = 64/419 (15.3 [11.8–18.7])

NNRTI = 92/376 (24.5 [20.1–28.8])

0.62

[0.47–0.83]

VLBW

PI = 7/419 (1.7 [0.4–2.9])

NNRTI = 3/376 (0.8 [0.0–1.7])

2.09 [0.55- 8.04]

SGA

PI = 147/403 (36.5 [31.8–41.2])

NNRTI = 57/309 (18.4 [14.1–22.8])

1.98

[1.51–2.58]

Watts et al

(2013) [18]

N = 2 218

Median age 27 years [23-32]

CD4 + (cell/mm³) < 200 13, 200–500 46

Caucasian ethnic 28%, African ethnic 65%, other ethnic 7%

PI n = 1319

NNRTI n = 160

ND

Preterm birth

PI = 255/1319 (19.3 [17.2–21.5])

NNRTI = 27/160 (16.9 [11.1–22.7])

1.15

[0.80–1.64]

SGA

PI = 99/1319 (7.5 [6.1- 8.9])

NNRTI = 11/160 (6.9 [3.0–10.8])

1.09

[0.60–1.99]

Zash et al

(2017) [42]

N = 47 027

Mean age 26.9 years (sd 6.5)

Median CD4 + (cell/mm³) 478 [363–600] for TDF-FTC-EFV group, 508 [388–685] for TDF-FTC-NVP group, 638 [492–735] for TDF-FTC-LPV-R group, 504 [408–625] for ZDV-3TC-NVP group, 609 [414–798] for ZDV-3TC-LPV-R group

Ethnic group ND

IP n = 398

INNTI n = 4597

Before conception n = 4812 (PI n = 398 and NNRTI n = 4597)

After conception n = 5780 (PI n = 406 and NNRTI n = 468)

Preterm birth

PI = 104/398 (26.1 [21.8–30.4])

NNRTI = 1012/4597 (22.0 [20.8–23.2])

1.19

[1.00–1.41]

VPT

PI = 27/398 (6.8 [4.3–9.3])

NNRTI = 220/4597 (4.8 [4.2–5.4])

1.42

[0.96–2.09]

SGA

PI = 98/398 (24.6 [20.4–28.9])

NNRTI = 993/4597 (21.6 [20.4–22.8])

1.14

[0.95–1.37]

VSGA

PI = 52/398 (13.1 [9.8–16.4])

NNRTI = 437/4597 (9.5 [8.7–10.4])

1.37

[1.05–1.80]

Stillbirth

PI = 16/398 (4.0 [2.1–5.9])

NNRTI = 164/4597 (3.6 [3.0–4.1])

1.13

[0.68–1.86]

Williams et al. (2015) [43]

N = 2580

Age ≥ 35 years 13

CD4 < 250cell/mm³ 14

Caucasian ethnic 27%, African ethnic 66%, other ethnic 1%

PI = 887

NNRTI = 214

First trimester n = 1219

Congenital abnormalities

PI = 75/887 (8.5 [6.6–10.3])

NNRTI = 13/214 (6.1 [2.9–9.3])

1.39

[0.79–2.46]

Schulte et al

(2007) [10]

N = 11 231

Median age ND

Median CD4 + ND

African ethnic 61.6%

PI n = 782

Non PI n = 1781

ND

Preterm birth

PI = 132/782 (16.9 [14.3–19.5])

Non PI = 329/1781 (18.5 [16.7–20.3])

0.91

[0.76- 1.10]

LBW

PI = 133/782 (17.0 [14.4–19.6])

Non PI = 330/1781 (18.5 [16.7–20.3])

0.92

[0.77–1.10]

Patel et al

(2005) [44]

N = 3 740

Median age 28 years [10-45]

Median CD4 + 420 cell/ml [0–2350]

Caucasian ethnic 72.2%, African ethnic 20.9%, other ethnic 6.8%

PI n = 273

NNRTI n = 195

First trimester n = 789 (PI n = 273 and NNRTI n = 195)

Second/third trimesters n = 1184

Congenital abnormalities

PI = 7/273 (2.6 [0.7–4.4])

NNRTI = 6/195 (3.1 [0.7–5.5])

0.83

[0.28–2.44]

Hu et al. (2019) [45]

N = 802

Mean age 29.8 years (sd 5)

Last CD4 count (cell/µl) < 350 23, ≥ 350 37

Asian ethnic 91%, other ethnic 9%

PI = 220

NNRTI = 146

ND

Preterm birth

PI = 34/220 (15.5 [10.7–20.2])

NNRTI = 23/146 (15.8 [9.8–21.7])

0.98

[0.60–1.60]

Grosch-Woerner et al. (2008) [46]

N = 190

Median age 28 years [17-41]

CD4 + (cell/mm³) < 200 12, 200–500 59

Caucasian ethnic 47%, African ethnic 36%, other ethnic 16%

PI n = 21

NNRTI n = 54

ND

Preterm birth^∆

PI = 13/21 (61.9 [41.1–82.7])

NNRTI = 16/54 (29.6 [17.5–41.8])

2.09

[1.23–3.55]

Congenital abnormalities

IP = 2/21 (9.5 [0.0–22.1])

INNTI = 1/54 (1.9 [0.0–5.4])

5.14

[0.49–53.76]

Cotter et al

(2006) [47]

N = 1 337

Age < 18 years 2.7, 18–34 years 79.1, > 34 years 14.0

CD4 + (cell/mm³) < 200 22.5, 200–499 58.3

Caucasian ethnic 4.3%, African ethnic 47.6%, Hispanic ethnic 13.2%, other ethnic 35%

PI n = 134

Non PI n = 373

Before 10 weeks n = 122 (PI n = 15 and non PI n = 107)

After 10 weeks n = 384 (PI n = 118 and NNRTI n = 266)

Preterm birth

PI = 49/134 (36.6 [28.4–44.7])

Non PI = 101/373 (27.1 [22.6–31.6])

1.35

[1.02- 1.78]

VPT

PI = 3/134 (2.2 [0.0–4.7])

Non PI = 17/373 (4.6 [2.4–6.7])

0.49

[0.15–1.65]

LBW

PI = 23/134 (17.2 [10.8–23.5])

Non PI = 59/373 (15.8 [12.1–19.5])

1.09

[0.70–1.68]

VLBW

PI = 3/134 (2.2 [0.0–4.7])

Non PI = 19/373 (5.1 [2.9–7.3])

0.44

[0.13–1.46]

Stillbirth

PI = 0/134 (0.0 [0.0- 0.0])

Non PI = 2/373 (0.5 [0.0–1.2])

0.55

[0.03–11.47]

Carceller et al

(2009) [48]

N = 206

Median age ND

Median CD4 + ND

Ethnic group ND

PI n = 176

Non PI n = 40

First trimester n = 78

Second trimester n = 92

Third trimester n = 33

Preterm birth

PI = 19/171 (11.1 [6.4–15.8])

Non PI = 2/28 (7.1 [0.0–16.7])

1.56

[0.38- 6.32]

SGA*

PI = 17/174 (9.8 [5.4–14.2])

Non PI = 3/29 (10.3 [0.0–21.4])

0.94

[0.30- 3.02]

Natureeba et al. (2014) [49]

N = 389

Mean age 29.5 ± 5.4

Median CD4 count (cell/mm3): for EFV group 374 [270–485], for LPV/r group 368 [282–506]

PI = 194

NNRTI = 195

Not mentioned

Prematurity

PI = 39/190 (20.5 [14.8–26.3])

NNRTI = 34/187 (18.2[12.7–23.7])

1.13

[0.75–1.71]

Low birth weight

PI = 39/181 (21.5 [15.6–27.5])

NNRTI = 33/178 (18.5[12.8–24.2])

1.16

[0.77–1.76]

Szyld et al

(2006) [50]

N = 803

Age < 20 years 6.3, 20–29 years 52.4, > 29 years 40.5

CD4 + (cell/mm³) < 200 12.9, 200–499 54.3

Ethnic group ND

PI n = 330

NNRTI n = 257

ND

Preterm birth

PI = 35/330 (10.6 [7.3–13.9])

NNRTI = 15/257 (5.8 [3.0–8.7])

1.82

[1.01- 3.25]

LBW

PI = 55/330 (16.7 [12.6–20.7])

NNRTI = 19/257 (7.4 [4.2–10.6])

2.25

[1.37–3.70]

Joao et al

(2010) [51]

N = 1 229

Age < 20 years 6.9, 20–29 years 54.8, > 29 years 38.3

CD4 + (cell/mm³) < 200 12.6, 200–499 54.6

Ethnic group ND

PI n = 511

NNRTI n = 305

First trimester n = 249

Second trimester n = 92

Third trimester n = 33

Congenital abnormalities

PI = 25/511 (4.9 [3.0–6.8]) NNRTI = 25/305 (8.2 [5.1–11.3])

0.60

[0.35–1.02]

EPPICC Study Group

(2019) [52]

N = 7193

Median age 29 years [25-33]

CD4 + count (cell/µl) < 200 14, 200–349 26, ≥ 350 59

Caucasian ethnic 59%, African ethnic 37%, other ethnic 3%

PI = 6492

NNRTI = 517

ND

Preterm birth

PI = 653/6492 (10.1 [9.3–10.8])

NNRTI = 51/517 (9.9 [7.3–12.4])

1.02

[0.78–1.34]

SGA

PI = 729/6399 (11.4 [10.6–12.2])

NNRTI = 39/510 (7.6 [5.3–10.0])

1.49

[1.09–2.03]

Snijdewind et al

(2018) [53]

N = 1 392

Median age 29.9 years [25.8–34.4]

Median CD4 + 520cell/µl [374–700]

Caucasian ethnic 20.7%, African ethnic 61.3%, other ethnic 18.0%

IP n = 928

INNTI n = 438

Before conception n = 550 (PI n = 269 and NNRTI n = 263)

After conception n = 842 (PI n = 659 and NNRTI n = 175)

Preterm birth

PI = 104/928 (11.2 [9.2–13.2])

NNRTI = 58/438 (13.2 [10.1–16.4])

0.85

[0.63–1.14]

VPT

PI = 23/928 (2.5 [1.5–3.5])

NNRTI = 15/438 (3.4 [1.7–5.1])

0.72

[0.38–1.37]

LBW

PI = 114/928 (12.3 [10.2–14.4])

NNRTI = 55/438 (12.6 [9.5–15.7])

0.98

[0.72–1.32]

VLBW

PI = 23/928 (2.5 [1.5–3.5])

NNRTI = 21/438 (4.8 [2.8–6.8])

0.52

[0.29- 0.92]

SGA

PI = 215/928 (23.2 [20.5–25.9])

NNRTI = 105/438 (24.0 [20.0–28.0])

0.97

[0.79–1.18]

Kreitchmann et al. (2014) [54]

N = 1 563

Mean age 28.2 years (sd 5.9)

CD4 + (cell/mm³) < 200 9.5, 200–499 40.1

Caucasian ethnic 58%, African ethnic 20.4%, other ethnic 21.6%

PI n = 907

Non PI n = 409

First trimester n = 367 (PI n = 192 and NNRTI n = 152)

Third trimester n = 1432 (PI n = 888 and NNRTI n = 410)

Combined outcome

PI = 310/907 (34.2 [31.1–37.3])

Non PI = 126/409 (30.8 [26.3–35.3])

1.11

[0.94–1.32]

Floridia et al. (2020) [55]

N = 794

Median age 32 years [28-36]

Median CD4 (count/mm³) 473 [328.5–664]

Caucasian ethnic 48%, African ethnic 46%, other ethnic 6%

PI = 623

NNRTI = 122

Before conception n = 794

Preterm birth

PI = 99/622 (15.9 [13.0–18.8])

NNRTI = 23/121 (19.0 [12-26] )

0.84

[0.56–1.26]

VPT

PI = 13/622 (2.1 [1.0–3.2])

NNRTI = 1/121 (0.8 [0.0–2.4])

2.53

[0.33–19.15]

LBW

PI = 113/597 (18.9 [15.8–22.1])

NNRTI = 24/124 (19.4 [12.4–26.3])

0.98

[0.66–1.45]

VLBW

PI = 16/597 (2.7 [1.4–4.0])

NNRTI = 4/124 (3.2 [0.1–6.3])

0.83

[0.28–2.44]

SGA

PI = 68/564 (12.1 [9.4–14.7])

NNRTI = 7/107 (6.5 [1.9–11.2])

1.84

[0.87–3.90]

Ejigu et al. (2019) [56]

N = 2412

Median age 29 years [26-32]

Median CD4 + (cell/mm³) 384 [256–534]

PI = 32

NNRTI = 1432

Before conception n = 826

Preterm birth

PI = 8/32 (25.0 [10-40] )

NNRTI = 255/1432 (17.8 [15.8–19.8])

1.40

[0.76–2.59]

LBW

PI = 4/32 (12.5 [1-24])

NNRTI = 298/1432 (20.8 [18.7–22.9])

0.60

[0.24–1.51]

SGA

PI = 8/32 (25.0 [10-40])

NNRTI = 481/1432 (33.6 [31.1–36.0])

0.74

[0.41–1.36]

Machado et al

(2008) [57]

N = 899

Median age 28.7 years for group who received antiretroviral combination before conception / 26.7 years for group who received antiretroviral combination after conception

Median CD4 + ND

Ethnic group ND

PI n = 213

NNRTI n = 100

Before conception n = 99

After conception n = 205

Preterm birth

PI = 30/213 (14.1 [9.4–18.8])

NNRTI = 11/100 (11.0 [4.9–17.1])

1.28

[0.67–2.45]

LBW

PI = 33/213 (15.5 [10.6–20.4])

NNRTI = 13/100 (13.0 [6.4–19.6])

1.19

[0.66–2.16]

Stringer et al. (2018) [58]

N = 359

Median age 29 years [26-33]

Median CD4 count (cell/mm³) 431 [304–608]

PI = 118

NNRTI = 127

Before conception n = 253

Preterm birth

PI = 45/118 (38.1 [29.4–46.9])

NNRTI = 36/127(28.3 [20.5–36.2])

1.35

[0.94–1.93]

Stillbirth

PI = 4/118 (3.4 [0.1–6.7])

NNRTI = 5/127 (3.9 [0.6–7.3])

0.86

[0.24–3.13]

Spontaneous abortion

PI = 27/118 (22.9 [15.3–30.5])

NNRTI = 23/127 (18.1 [11.4–24.8])

1.26

[0.77–2.08]

Patel et al

(2010) [59]

N = 1 196

Age 14–21 years 21, 22–25 years 24, 26–29 years 25, ≥ 30 years 30

CD4 + (cell/mm³) < 200 15, 200–499 55

Caucasian ethnic 11%, African ethnic 58%, Hispanic ethnic 30%

PI n = 558

Non PI n = 219

First trimester n = 153 (PI n = 117 and NNRTI n = 36)

Second trimester n = 507 (PI n = 363 and NNRTI n = 144)

Third trimester n = 117 (PI n = 78 and NNRTI n = 39)

Preterm birth

PI = 90/558 (16.1 [13.1–19.2])

NNRTI = 27/219 (12.3 [8.0–16.7]

1.31

[0.88–1.95]

VPT

PI = 12/558 (2.2 [0.9–3.4])

NNRTI = 1/219 (0.5 [0.0–1.3])

4.71

[0.62–36.00]

Favarato et al. (2018) [60]

N = 6073

Median age 33 years [29-36]

Median CD4 count (cell/mm³) 440 [311–596]

African ethnic 73%

PI = 4184

NNRTI = 1889

ND

Preterm birth

PI = 460/4184 (11.0 [10.0–11.9])

NNRTI = 169/1889 (8.9 [7.7–10.2])

1.13

[1.04–1.45]

^□VPT

PI = 157/4184 (3.8 [3.2–4.3])

NNRTI = 71/1889 (3.8 [2.9–4.6])

1.00

[0.76–1.31]

SGA

PI = 825/4184 (19.7 [18.5–20.9])

NNRTI = 338/1889 (17.9 [16.2–19.6])

1.10

[0.98–1.24]

VPT

PI = 3/179 (1.7 [0.0–3.6])

NNRTI = 3/177 (1.7 [0.0–3.6])

0.99

[0.20–4.83]

Combined outcome

PI = 34/184 (18.5 [12.9–24.1])

NNRTI = 32/183 (17.5 [12.0–23.0])

1.06

[0.68–1.64]

Aaron et al. (2012) [61]

N = 183

Mean age 28.0 (sd 6.2)

First CD4 > 200 73.2

African American ethnic 74.7%, all other ethnic 25.3%

PI = 117

NNRTI = 39

Before conception n = 46

During pregnancy n = 183

SGA

PI = 39/117 (33.3 [24.8–41.9])

NNRTI = 7/39 (17.9 [5.9–30.0])

1.86

[0.91–3.81]

VSGA

PI = 17/117 (14.5 [8.1–20.9])

NNRTI = 2/39 (5.1 [0.0–12.1])

2.83

[0.69–11.72]

Favarato et al. (2019) [62]

N = 10,434

Age < 28–36 years 73, > 36 years 27

CD4 + (cell/mm³) > 350 62, ≤ 350 32

Caucasian ethnic 19%, African ethnic 75%, Hispanic ethnic 3%, Asian ethnic 2%

PI = 4693

NNRTI = 2259

Before conception n = 5023

Stillbirth

PI = 41/4693 (0.9 [0.6–1.1])

NNRTI = 19/2259 (0.8 [0.5–1.2])

1.04

[0.60–1.79]

Bellón Cano et al

(2004) [63]

N = 124

Median age ND

CD4 + (cell/mm³) < 250 27, 250–500 51

Ethnic group ND

PI n = 72

NNRTI n = 52

ND

Preterm birth

PI = 13/74 (17.6 [8.9–26.2])

NNRTI = 5/52 (9.6 [1.6–17.6])

1.83

[0.69–4.81]

LBW

PI = 18/74 (24.3 [14.5–34.1])

NNRTI = 9/52 (17.3 [7.0–27.6])

1.41

[0.69–2.88]

VLBW

PI = 3/74 (4.1 [0.0 – 8.5])

NNRTI = 0/52 (0.0 [0.0 – 0.0])

4.95

[0.26–93.78]

Congenital abnormalities

PI = 4/74 (5.4 [0.3–10.6])

NNRTI = 4/52 (7.7 [0.4–14.9])

0.70

[0.18–2.68]