Table 2 Safety outcomes

Hoang et al., 2016 [31]

Self-reported fever without time limit

RCT

Tdap/TT

25.8 (18–36)

52

1

1.9

48

0

0.0

NR

NR

Munoz, 2014 [30]

Oral temperature of ≥38° Celsius during 7 days after Tdap vaccination

RCT

Tdap/placebo

30–32

33

1

3.0

15

0

0.0

NR

NR

Maertens et al., 2016 [15]

Fever

PCS

Tdap/no Tdap

28.6 (22–33)

57

1

1.8

42

0

0.0

NR

NR

Kharbanda et al., 2016 [39]

Medically attended fever during 3 days after Tdap vaccination

RCS

Tdap/no Tdap

81.8% ≥20

53,885

15

0.03

109,253

6

0.006

2.16 (1.65–2.83)^a

NR

Hoang et al., 2016 [31]

Stillbirth

RCT

Tdap/TT

25.8 (18–36)

52

0

0.0

51

1

2.0

NR

NR

Berenson et al., 2016 [33]

Stillbirth

RCS

Tdap/no Tdap

30.3 (1–40)

650

0

0.0

1109

1

0.1

NR

NR

Donegan et al., 2014 [36]

Intrauterine death after 24 WG within 14 days of vaccination

RCS

Tdap-IPV/no Tdap

31 (29–35)

13,371

5

0.0

13,371

7.2 (expected)

0.1

0.69 (0.23–1.62)

NR

Intrauterine death after 24 WG from vaccination to delivery

33 (30–36)

6185

12

0.2

18,523

42

0.3

0.85 (0.44–1.61)

NR

Morgan et al., 2015 [41]

Stillbirth

RCS

Tdap ≥32 WG/no Tdap

≥32

7152

25

0.3

226

1

0.4

0.79 (0.11–5.85)^b

NR

Shakib et al., 2013 [42]

Stillbirth

RCC

Tdap 3–280 days prepartal/no Tdap

87 (63%) 1st, 24 (17%) 2nd, 27 (20%) 3rd trimester

138

0

0.0

552

5

0.9%

0.36 (0.02–6.54)^b

NR

Morgan et al., 2015 [41]

Not defined

RCS

Tdap ≥32 WG/no Tdap

≥32 WG

7152

2

0.028

226

0

0

0.16 (0.01–3.31)^b

NR

Donegan et al., 2014 [36]

Neonatal death within 7 days of delivery

RCS

Tdap-IPV/no Tdap

33 (30–36)

6185

2

0.032

18,523

6

0.032

1.00 (0.20–4.95)

NR

Berenson et al., 2016 [33]

<  37 WG

RCS

Tdap/no Tdap

30.3 (1–40)

1109

58

5.2

650

59

9.1

0.77 (0.64–0.93)^a

0.68 (0.45–1.03)

Kharbanda et al., 2014 [38]

<  37 WG

RCS

Tdap in any WG/no Tdap

2.014 (7.7%) 1st, 10.936 (41.7%) 2nd, 13.280 (50.6%) 3rd trimester

26,229

1.527

6.3

97,265

7544

7.8

1.01 (0.95–1.06)

1.03 (0.97–1.09)

Tdap 27–36 WG/no Tdap

11,351

602

5.3

97,265

7544

7.8

0.88 (0.81–0.96)

0.88 (0.80–0.95)

Layton et al., 2017 [40]

Not defined; presumably < 37 WG

RCS

Tdap/no Tdap

< 27

25,037

2.593

10.4

871,177

66,968

7.7

1.37 (1.32–1.43)^a

NR

≥27

123,780

6.154

5.0

871,177

66,968

7.7

0.66 (0.64–0.68)^a

NR

Shakib et al., 2013 [42]

<  37 WG

RCC

Tdap 3–280 days antepartum/no Tdap

87 (63%) 1st, 24 (17%) 2nd, 27 (20%) 3rd trimester

134

8

6.0

505

38

7.5

0.78 (0.36–1.71)^b

NR

Munoz et al., 2014 [30]

<  37 WG

RCT

Tdap/placebo

30–32

33

3

9.1

15

1

6.7

1.50 (0.14–15.67)^b

NR

Griffin et al., 2018 [37]

Premature birth ICD-10-AM O60.1.3; birth < 37 WG

RCS

Tdap 28–38 WG/no Tdap

33. IQR: 30–35

8178

297

3.6

60,372

2829

4.7

0.74 (0.66–0.84)

0.72 (0.63–0.83)

Morgan et al., 2015 [41]

<  37 WG

RCS

Tdap at ≥32 WG/no Tdap

≥32

7152

427

5.9

226

27

11.9

0.47 (0.31–0.71)^b

NR

Hoang et al., 2016 [31]

Not defined

RCT

Tdap/ TT

25.8 (18–36)

52

0

0.0

51

1

2.0

NR

NR

DeSilva et al., 2017 [35]

< 34 WG

RCS

Tdap in any WG/no Tdap

51% 27–36

45,008

426

0.9

152,556

2711

1.8

0.59 (0.54–0.65)^a

NR

Halperin et al., 2018 [32]

MedDRA version 19.0 - definition

RCT

Tdap/Td

34.5 (32.6–35.6)

134

2

1.5

138

1

0.7

2.06 (0.19–22.45)

NR

Berenson et al., 2016 [33]

LBW: < 2500 g

RCS

Tdap/no Tdap

30.3 (1–40)

1109

61

5.5

650

59

9.1

NR

0.76 (0.51–1.14)

VLBW: <  1500 g

1109

2

1.1

650

12

0.3

NR

0.24 (0.05–1.20)

Griffin et al., 2018 [37]

Intrauterine growths retardation (ICD10-AM O36.5)

RCS

Tdap 28–38 WG/no Tdap

33. IQR: 30–35

8178

401

4.9

60,372

2916

4.8

0.94 (0.84–1.04)

0.92 (0.82–1.04)

Donegan et al., 2014 [36]

Intrauterine growths retardation/LBW < 2500 g

RCS

Tdap-IPV/no Tdap

33 (30–36)

6185

126

2.0

18,523

311

1.7

1.20 (0.98–1.48)

NR

Layton et al., 2017 [40]

Sepsis in the newborn during 30 days after birth

RCS

Tdap/no Tdap

< 27 WG

16,322

394

2.41

543,906

13,187

2.27

1.07 (0.97–1.18)

0.89 (0.81–0.99)^c 0.91 (0.81–1.02)^d

≥27 WG

80,217

1.774

1.84

543,906

13,187

2.27

0.81 (0.77–0.85)

0.83 (0.79–0.88)^c 0.89 (0.84–0.94)^d

Layton et al., 2017 [40]

Admission to newborn intensive care unit during 30 days after birth

RCS

Tdap/no Tdap

< 27 WG

16,322

1.458

8.93

543,906

42,904

7.39

1.22 (1.16. 1.29)

0.93 (0.88–0.98)^c 0.95 (0.89–.01)^d

≥27 WG

80,217

6996

7.25

543,906

42,904

7.39

0.98 (0.96–1.01)

0.97 (0.95–1.00)^c 1.00 (0.97–1.03)^d

Berenson et al., 2016 [33]

Not defined

RCS

Tdap/no Tdap

30.3 (1–40)

1109

103

9.3

650

86

13.2

NR

0.78 (0.56–1.08)

Griffin et al., 2018 [37]

Hypertension (ICD10-AM O13-O16)

RCS

Tdap in 28–38 WG/no Tdap

33. IQR: 30–35

8178

262

3.2

60.372

1484

2.5

1.20 (1.05–1.37)

1.02 (0.88–1.19)

Preeclampsia (ICD10-AM O14.09)

133

1.6

1007

2.5

0.91 (0.75–1.09)

0.85 (0.69–1.04)

Severe preeclampsia (ICD10-AM O14.1)

26

0.3

271

0.4

0.67 (0.45–1.00)

0.61 (0.39–0.94)

Layton et al., 2017 [40]

Preeclampsia/eclampsia (642.4x-642.8x)ICD-9 codes 624.xx during 7 days pre- and up to 30 days postpartum

RCS

Tdap/no Tdap

< 27

25,037

1.096

4.38

871,177

40,930

4.4

1.00 (0.94–1.06)

0.99 (0.93–1.05)^c 1.05 (0.99–1.12)^d

≥27

123,780

5.248

4.24

871,177

40,930

4.4

0.96 (0.94–0.99)

0.90 (0.87–0.93)^c 0.96 (0.94–0.99)^d

Kharbanda et al., 2014 [38]

Gestational hypertension (ICD642.3x). Hypertension in pregnancy (ICD642.9) Preeclampsia or eclampsia (ICD642.4x-642.8x); onset ≥20 WG

RCS

Tdap< 20 WG/no Tdap

2.014 (7.7%) 1st, 10.936 (41.7%) 2nd, 13.280 (50.6%) 3rd trimester

6083

497

8.2

97,265

7736

8.0

1.03 (0.94–1.12)

1.09 (0.99–1.20)

Donegan et al., 2014 [36]

Not defined; clinical diagnoses during pregnancy from primary care general practice databases

RCS

Tdap-IPV/no Tdap

33 (30–36)

6185

22

0.4

18,523

54

0.3

1.22 (0.74–2.01)

NR

Halperin et al., 2018 [32]

Preeclampsia (MedDRA version 19.0- definition)

RCT

Tdap/Td

34.5 (32.6–35.6)

134

1

0.7

138

2

1.4

0.51 (0.05–5.61)

NR

Maertens et al., 2016 [15]

Preeclampsia

PCS

Tdap/no Tdap

28.6 (22–33)

57

4

7.0

41

1

2.4

1.40 (0.88–2.25)^a

NR

Hypertension

57

2

3.5

41

1

2.4

1.15 (0.51–2.61)^a

NR

Preeclampsia or hypertension

57

6

10.5

41

2

4.9

1.32 (0.85–2.05)^a

NR

Hoang et al., 2016 [31]

Not defined. Not reported in results section

RCT

Tdap/TT

25.8 (18–36)

52

0

0.0

48

0

0.0

NR

NR

Munoz et al., 2014 [30]

Not defined

RCT

Tdap/placebo

30–32

33

1

3.0

15

2

13.3

0.2 (0.02–2.44)^b

NR

Berenson et al., 2016 [33]

Ten most commonly encountered birth defects reported by the Centers for Disease Control and Prevention

RCS

Tdap/no Tdap

30.3 (1–40)

1109

18

1.6

650

15

2.3

NR

0.80 (0.38–1.67)

DeSilva et al., 2016 [34]

Diagnostic codes for any structural birth defect, diagnosed during first YOL

RCS

Tdap/no Tdap

any WG

41,654

2816

6.8

282,809

17,422

6.2

1.09 (1.05–1.14)

0.98 (0.94–1.03)

27–36 (50%)

20,568

1435

7.0

120,097

8367

7.0

1.00 (0.95–1.06)

1.02 (0.96–1.08)

Diagnostic codes for selected major structural birth defects: such as spina bifida (741.0x and 741.9x); encephalocele, etc., diagnosed during first YOL

any WG

41,654

717

1.7

282,809

4521

1.6

1.08 (1.00–1.17)

1.06 (0.98–1.16)

27–36 (50%)

20,568

356

1.7

120,097

1920

1.60

1.08 (0.97–1.21)

1.09 (0.97–1.23)

Diagnostic codes for microcephaly, diagnosed during first YOL

any WG

41,654

38

0.09

282,809

348

0.12

0.74 (0.53–1.04)

0.86 (0.60–1.24)

27–36 WG (50%)

20,568

21

0.10

120,097

146

0.12

0.84 (0.53–1.33)

1.01 (0.63–1.61)

Maertens et al., 2016 [15]

Not defined

RCS

Tdap/no Tdap

28.6 (22–33)

57

0

0.0

42

0

NR

NR

Morgan et al., 2015 [41]

Major malformations

RCS

Tdap ≥32 WG/no Tdap

≥32 WG

7152

84

1.2

226

3

1.3

0.88 (0.28–2.82)^b

NR

Berenson et al., 2016 [33]

Physician’s diagnosis in medical file AND fever ≥38 °C AND ≥1 of the following symptoms: uterine tenderness, malodorous vaginal discharge or maternal leucocytosis

RCS

Tdap in any WG/no Tdap

30.3 (1–40)

1.109

39

3.5

650

14

2.2

NR

1.53 (0.80–2.90)

Kharbanda et al., 2014 [38]

ICD-9 code 658.41 as diagnosis during stay in birth clinic

RCS

Tdap in any WG/no Tdap

2014 (7.7%) 1st, 10,936 (41.7%) 2nd 13,280 (50.6%) 3rd trimester

26,229

1596

6.1

97,265

5329

5.5

1.11 (1.05–1.17)

1.19 (1.13–1.26)

Tdap during 27–36 WG/no Tdap

11,351

637

5.6

97,265

5329

5.5

1.02 (0.95–1.11)

1.11 (1.03–1.21)

Layton et al., 2017 [40]

ICD-9762.7. 658.4. 658.4x coded for mother or newborn during stay in birth clinic

RCS

Tdap/no Tdap

< 27

25,037

984

3.93

871,177

25,149

2.7

1.45 (1.37–1.55)

1.23 (1.16–1.31)^c 1.19 (1.11–1.28)^d

≥27

123,780

4529

3.66

871,177

25,149

2.7

1.35 (1.31–1.40)

1.14 (1.10–1.18)^c 1.11 (1.07–1.15)^d

DeSilva et al., 2017 [35]

ICD-9 code 658.41 from maternal medical file during stay in birth clinic

RCS

Tdap at any WG/no Tdap

51% 27–36

45,008

2.883

6.4

152,556

7970

5.2

NR

1.23 (1.17–1.28)

Tdap during 27–36 WG/no Tdap

22,772

1430

6.3

133,882

7109

5.3

NR

1.20 (1.14–1.28)

Griffin et al., 2018 [37]

ICD-10-AM O41.1

RCS

Tdap during 28–38 WG/no Tdap

33. IQR: 30–35

8178

26

0.3

60,372

198

0.3

0.89 (0.59–1.34)

1.10 (0.70–1.75)

Morgan et al., 2015 [41]

Not defined. Extracted from data base with information on pregnancy, birth and newborn

RCS

Tdap ≥32 WG/no Tdap

≥32

7152

421

5.9

226

9

4.0

1.51 (0.77–2.96)^b

NR