Table 1.
Characteristics and results of the reviewed studies
| Author, year [references] | Study design [setting/data source] | Recruitment/study dates | Inclusion (exclusion) criteria | Interventions (number of participants) | Methods | Results |
|---|---|---|---|---|---|---|
| Retrospective database reviews | ||||||
| Berenson et al. [50] | Chart review [EMR of PW delivering at the University of Texas Medical Branch at Galveston, Galveston County, USA] | Nov 2012–Jun 2014 | PW—singleton birth at ≥ 27 GW and adequate prenatal care |
Tdap (n = 1109)a Tdap 27–36 GW (n = 835)a No Tdap (n = 650)a |
Database analysis of PW |
Maternal adverse events and adverse fetal outcomes pre-delivery: No significant differences in frequency of individual or combined maternal outcomesb for Tdap vs. no Tdap; including chorioamnionitis (aOR = 1.53 [95% CI 0.80–2.90]; p = 0.19) Adverse birth and neonatal outcomes: No significant differences in frequency of individual or combined neonatal outcomesc for Tdap vs. no Tdap Defectsc were rare and frequency not significantly different for Tdap vs. no Tdap For infants admitted to NICU, number of days in the unit (p = 0.001) and frequency of admission for preterm birth (p = 0.03) or anemia (p = 0.03) lower for Tdap vs. no Tdap |
| Moro et al. [44] | Database review [VAERS database, USA vs. older published safety data] |
Oct 2011–Jun 2015 (database) (vs. Jan 2005–Jun 2010 [published data]) |
Tdap PW with reported AEs following Tdap |
Tdap at 0–13 GW (8.7%), 14–27 GW (12.0%) or ≥ 28 GW (79.2%); following ACIP recommendations for Tdap in PW (n = 392)a Tdap (Adacel, Sanofi Pasteur [59.7%], Boostrix, GSK [33.2%], unknown [7.1%]) (vs. Tdap in first [77%], second [19%] or third trimester [4%] before recommendations [n = 132]a) |
Database analysis of PW reporting AEs (vs. published safety data) |
Reactogenicity: Most frequently: ISRs (11.9%), systemic reactions (e.g., fever, chills; 4.3%), musculoskeletal and connective tissue disorders (3.6%), and immune system disorders (e.g., allergic reactions; 3.6%) Maternal adverse events and adverse fetal outcomes pre-delivery: Most frequently: oligohydramnios (3.1%), stillbirth (2.8%), and preterm delivery (2.8%), spontaneous abortion (1.0%) Adverse birth and neonatal outcomes: Death (n = 1), major birth defect (n = 4; 1.0%) Other: Proportion of stillbirths (2.8% vs. 1.5%) and ISRs (11.9% vs. 4.5%) increased and spontaneous abortions decreased (16.7% vs. 1.0%) after vs. before ACIP recommendations |
| Kharbanda et al. [42] | Cohort database review [Claims, administrative and EHR data from 7 VSD sites in the USAf and EHR-linked vaccine registries] | Delivery Jan 2007–Nov 2013 | PW with live birth (gestational trophoblastic disease, ectopic pregnancy, abortion, stillbirth, or unknown pregnancy outcome) |
Tdap during pregnancy (any trimester) (n = 53,885) Tdap ≥ 20 GW (n = 44,063) No Tdap (n = 109,253) |
Database analysis |
Reactogenicity: Rate of any eventd 0–3 days (ARR = 1.19 [95% CI 0.81–1.73]) or any neurological evente 0–42 days (ARR = 0.98 [95% CI 0.70–1.37]) similar after Tdap vs. no Tdap (all events rate < 0.1%) Rate of medical visits for fever within 3 days increased with Tdap vs. no Tdap (ARR = 5.4 [95% CI 2.1–13.9]) Maternal adverse events: Rate of proteinuria (ARR = 0.81 [95% CI 0.6–1.05]) or VTE (ARR = 0.65 [95% CI 0.40–1.05]) similar after Tdap vs. no Tdap (rate for both < 0.1%) Rate of gestational diabetes (ARR = 0.96 [95% CI 0.89–1.03]), thrombocytopenia (ARR = 0.85 [95% CI 0.73–0.98]), VTE (ARR = 0.58 [95% CI 0.35–0.97]), cardiac events (ARR = 0.90 [95% CI 0.70–1.15]) not increased by Tdap ≥ 20 GW vs. no Tdap |
| Sukumaran et al. [46] | Cohort database review [Claims, administrative and EHR data from 7 VSD sites in the USAf and EHR-linked vaccine registries] | Delivery Jan 2007–Nov 2013 | Tdap PW, aged 14–49 y, with prior tetanus-containing vaccine data, singleton livebirth (live or non-Tdap tetanus-containing vaccine during pregnancy, trophoblastic disease, abortion, stillbirth, or ectopic pregnancy) |
Tdap during pregnancy with < 2 y prior tetanus-containing vaccine (n = 4812) Tdap during pregnancy with 2–5 y prior tetanus-containing vaccine (n = 9999) Tdap during pregnancy with > 5 y prior tetanus-containing vaccine (n = 14,344) |
Database analysis |
Reactogenicity: Acute fever 0–3 days after Tdap: 0–3.5/10,000 PW in each group; 0–7 days after Tdap: 1.0–6.2/10,000 PW in each group Allergic reaction 0–3 days after Tdap: 1.0–2.1/10,000 PW; 0–7 days after Tdap: 3.5–4.2/10,000 PW Local reaction 0–3 days after Tdap: 4.2–11.2/10,000 PW; 0–7 days after Tdap: 12.5–17.0/10,000 PW Fever, allergic reactions, or local reactions not significantly different in PW who received tetanus-containing vaccine < 2 y vs. > 5 y or 2–5 y vs. > 5 y No reports of anaphylaxis, Arthus reactions, or Guillain–Barré syndrome Maternal adverse events, adverse fetal outcomes pre-delivery, birth and neonatal outcomes: Preterm delivery (≈ 6.5%), low birth weight (≈ 5%), SGA (≈ 9%) not significantly different in infants of PW who received tetanus-containing vaccine < 2 y vs. > 5 y or 2–5 y vs. > 5 y Other: Most PW who had received a tetanus-containing vaccine < 2 y (94%) or 2–5 y (85%) previously had received Tdap vs. only 17% of the > 5 y group |
| Sukumaran et al. [45] | Cohort database review [Claims, administrative and EHR data from 7 VSD sites in the USAf and EHR-linked vaccine registries] | Jan 2007–Nov 2013 | PW aged 14–49 y, singleton livebirth, Tdap and influenza vaccine during pregnancy (any live vaccines in pregnancy, multiple gestations, trophoblastic disease, abortion, stillbirth, or ectopic pregnancy, > 1 tetanus vaccine or similar influenza vaccine in pregnancy) |
Tdap 20–37 GW + influenza vaccine concomitantly during pregnancy (any trimester) (n = 8464) Tdap 20–37 GW + influenza vaccine sequentially during pregnancy (any trimester) (n = 28,380) |
Database analysis |
Reactogenicity: Frequency of medically attended fever (< 4.5/10,000) and any acute reaction (< 25.5/10,000) (0–3 days and 0 –7 days) did not differ between PW receiving Tdap and influenza vaccines concomitantly vs. sequentially (p > 0.3) There were no cases of Arthus reaction or Guillain–Barré Syndrome There was no interaction between acute AEs and GW at Tdap vaccination Maternal adverse events, adverse fetal outcomes pre-delivery, birth and neonatal outcomes (N = 4554 vs. 4440): Preterm delivery (≈ 7%), low birth weight (≈ 6%), SGA (≈ 10%) not significantly different in infants of PW who received Tdap and influenza vaccine concomitantly vs. sequentially (p > 0.3) There was no interaction between adverse birth outcomes and GW at Tdap vaccination |
| Datwani et al. [51] | Database review [VAERS database, USA] | Jul 1990–Feb 2014 | PW with chorioamnionitis | Any vaccine during pregnancy (including Tdap) (n = 31) | Database analysis |
Maternal adverse events and adverse fetal outcomes pre-delivery: Chorioamnionitis: Vaccines most frequently documented in reports of chorioamnionitis were inactivated vaccines (90%), most commonly 2009 H1N1 inactivated influenza (32%), quadrivalent human papillomavirus (29%), and Tdap (26%) In 58% of reports, PW had ≥ 1 risk factor for chorioamnionitis Additional adverse outcomes specified but association with specific vaccine not reported Adverse birth and neonatal outcomes: Adverse outcomes specified but association with specific vaccine not reported |
| Wang et al. [57] | Registry review [Sanofi Pasteur Adacel Pregnancy Registry] | Jun 2005–Jan 2011 | PW receiving Adacel during or < 30 days before pregnancy |
Tdap (Adacel, Sanofi Pasteur) (n = 539)a: Phase IV studies (n = 49) Prospective reports (n = 480) Retrospective reports (n = 10) |
Database analysis |
Maternal events: Phase IV studies: 10% non-serious AEs, 20% SAEs, 69% no AEs Prospective reports: 7% non-serious AEs, 6% SAEs, 55% no AEs, 33% NR Retrospective reports: 20% SAEs, 80% no AEs Maternal adverse events, adverse fetal outcomes pre-delivery, birth and neonatal outcomes: Phase IV studies: 86% term delivery, 4% preterm delivery, 4% elective abortion, 2% spontaneous abortion, and 4% lost to follow-up 43 infants with no congenital anomaly, 1 with right-side hydronephrosis Prospective reports: 19% term delivery, 2% preterm delivery, < 1% very preterm delivery with no congenital abnormality, < 1% elective abortion, 3% spontaneous abortion, 26% lost to follow-up, 50% awaiting pregnancy outcome Retrospective reports: 80% term delivery, 20% spontaneous abortion 7 infants no congenital abnormality, 1 infant with patent foramen ovale and peripheral pulmonic stenosis Other: Data raise no concerns for maternal or infant health following Tdap during pregnancy |
| Morgan et al. [55] | Cohort database review [EPIC electronic medical charting system at Parkland hospital and affiliated clinics, Texas, USA] | Jun 2013–Jul 2014 | PW |
Tdap ≥ 32 GW (n = 7152) No Tdap (n = 226) Prior Tdap (< 5 y) + Tdap ≥ 32 GW (n = 1229) Tdap ≥ 32 GW (single dose) (n = 4159) |
Database analysis |
Maternal adverse events and adverse fetal outcomes pre-delivery: Frequency of stillbirths and chorioamnionitis for Tdap vs. no Tdap not significantly different Preterm birth rates increased with no Tdap vs. Tdap (AOR = 1.88 [95% CI 1.25–2.84]) Adverse birth and neonatal outcomes: Frequency of major malformations, 5-min Apgar score < 4, cord blood pH ≤ 7, and neonatal requirement for ventilation, intraventricular hemorrhage, sepsis, and death for Tdap vs. no Tdap not significantly different Frequency of SGA (10% vs. 15%, p = 0.03) and length of neonatal hospitalization (3.9 says vs. 4.7 days, p < 0.001) lower for Tdap vs. no Tdap Delivery and neonatal outcomesg not significant different between women who received multiple doses of Tdap vs. those who received a single dose |
| Donegan et al. [53] | Cohort database review [Clinical Practice Research Datalink data from > 650 primary care practices in the UK] | Oct 2012–Mar 2013 | PW |
Any pertussis-containing vaccine 30–36 GW (n = 6185) No vaccine (HC) (n = 18,523) |
Database analysis + comparison with published national data |
Maternal adverse events and adverse fetal outcomes pre-delivery: Frequency of stillbirth, preeclampsia, eclampsia, placenta previa, cesarean section, premature labor (without delivery), postpartum hemorrhage not significantly different between Tdap and no Tdap Observed stillbirth rate in 17,560 vaccinated PW vs. expected stillbirth rate in published national statistics data ratio: 0.69 (95% CI 0.23–1.62) Adverse birth and neonatal outcomes: Intrauterine growth retardation/low birth weight/weight < 2500 g and neonatal death (within 7 days) not significantly different between Tdap and no Tdap |
| Kharbanda et al. [54] | Cohort database review [Administrative and EHR data from 2 Kaiser Permanente VSD sites (Northern and Southern California), USA] | Delivery Jan 2010–Nov 2012 | PW aged 14–49 y, singleton livebirth (≥ 1 live vaccine during pregnancy; Tdap, ≤ 7 days after estimated pregnancy start or ≤ 7 days before delivery) |
Tdap (Adacel in majority) during pregnancy (n = 26,229)a Second + third trimester (92%) No Tdap (n = 97,265)a Tdap before pregnancy (46%) |
Database analysis |
Maternal adverse events and adverse fetal outcomes pre-delivery: Chorioamnionitis: 6.1% vs. 5.5% for Tdap vs. no Tdap; ARR = 1.19 (95% CI 1.13–1.26; p < 0.001) Tdap at 27–36 GW vs. no Tdap ARR = 1.11 (95% CI 1.03–1.21; p = 0.009) Hypertensive disorder of pregnancy: 8.2% vs. 8.0% for Tdap < 20 GW vs. no Tdap; ARR = 1.09 (95% CI 0.99–1.20) Preterm delivery (< 37 GW): Tdap at any time during pregnancy not associated with increased risk of preterm delivery (ARR = 1.03 [95% CI 0.97–1.09) Tdap at 27–36 GW vs. no Tdap ARR = 0.88 (95% CI 0.80–0.95; p = 0.002) Adverse birth and neonatal outcomes: Tdap at any time during pregnancy not associated with increased risk of SGA (ARR = 1.00 [95% CI 0.96–1.06) Tdap at 27–36 GW vs. no Tdap ARR = 1.03 (95% CI 0.96–1.10) |
| Shakib et al. [56] | Cohort database review [EHR of Intermountain Healthcare Enterprise Data Warehouse, USA] | May 2005–Aug 2009 | PW |
Tdap during pregnancy (n = 138) First trimester (63%), second trimester (17%), third trimester (20%) No Tdap (n = 552) |
Database analysis |
Maternal adverse events and adverse fetal outcomes pre-delivery: Spontaneous or elective abortion: 2.9% vs. 8.9% for Tdap vs. no Tdap Stillbirth: 0 vs. 0.9% for Tdap vs. no Tdap Preterm live birth (< 37 GW): 6.0% vs. 7.5% for Tdap vs. no Tdap No significant differences between Tdap and no Tdap Adverse birth and neonatal outcomes: No increased risk of congenital abnormalities or additional health problems in the first year of life for infants of Tdap PW vs. no Tdap PW |
| Zheteyeva et al. [47] | Database review [VAERS database, USA] | Jan 2005–Jun 2010 | PW who received Tdap during pregnancy with or without adverse events |
Tdap (Adacel, Sanofi Pasteur [72%], Boostrix, GSK [15.2%], unknown [12.9%]) during pregnancy (any trimester)a (n = 132) First trimester (77%) |
Database analysis |
Reactogenicity: ISRs in 4.5% of reports Maternal adverse events and adverse fetal outcomes pre-delivery: Most frequently reported: spontaneous abortion (16.7%) at 5–16 GW, 9–61 days after Tdap Stillbirth in 2 reports and preterm delivery in 3 reports Adverse birth and neonatal outcomes: Isolated adverse infant outcomes in 4.5% of reports; major birth defect reported in 1 infant (gastroschisis) Other: No unusual pattern of adverse maternal, birth or neonatal outcomes reported |
| Layton et al. [43] | Database review [Truven MarketScan® Commercial Claims and Encounters insurance claims database] | 2010–2014 | PW with singleton livebirth or stillbirth born > 26 GW + infants |
Tdap ≥ 27 GW (n = 123,780)a Tdap < 27GW (n = 25,037)a Tdap ≤ 7 days postpartum (n = 59,040)a No Tdap (n = 871,117)a Matched newborns (n = 677,075)a |
Database analysis |
Reactogenicity: Uncommon; most frequently local pain (24.22 per 10,000 PW); appeared least common with Tdap ≥ 27 GW Fever reported in 6.2 per 10,000 PW Maternal adverse events and adverse fetal outcomes pre-delivery: Placental abruption, premature rupture of membranes, caesarian section, preeclampsia/eclampsia generally similar between Tdap ≥ 27 GW vs. no Tdap in PW Chorioamnionitis: IPTW-weighted risks: 2.8%–3.6% Tdap ≥ 27 GW vs. no Tdap: RR = 1.11 (95% CI 1.07–1.15) Tdap < 27 GW vs. no Tdap: RR = 1.19 (95% CI 1.11–1.28) Postpartum hemorrhage: IPTW-weighted risks: 2.3%–3.1% Tdap ≥ 27 GW vs. no Tdap: RR = 1.23 (95% CI 1.18–1.28) Tdap < 27 GW vs. no Tdap: RR = 1.34 (95% CI 1.25–1.44) Adverse birth and neonatal outcomes: No increased risk of adverse neonatal outcomes with Tdap at ≥ 27 GW or < 27 GW vs. no Tdap |
| De Silva et al. [52] | Database review [Administrative and EHR data from 7 VSD sites in California, Colorado, Minnesota, Oregon, Washington and Wisconsin, USA] | Jan 2010–Sep 2013 | PW with singleton livebirth, ≥ 1 outpatient visit during pregnancy, (Tdap < 8 days after pregnancy start or < 8 days before delivery, live vaccine) |
Tdap during pregnancy (n = 45,008)a Tdap 27–36 GW (n = 22,772)a No Tdap (n = 152,556)a |
Database analysis |
Maternal adverse events and adverse fetal outcomes pre-delivery: Chorioamnionitis: Tdap vs. no Tdap in PW: 6.4% vs. 5.2%; ARR = 1.23 (95% CI 1.17–1.28) Tdap 27–36 GW vs. no Tdap in PW: 6.3% vs. 5.3%; ARR = 1.20 (95% CI 1.14–1.28) Adverse birth and neonatal outcomes: Transient tachypnea of newborn, neonatal sepsis, neonatal pneumonia, respiratory distress syndrome, newborn convulsions, or the composite of any of these outcomes similar between Tdap vs. no Tdap in PW and Tdap 27–36 GW vs. no Tdap in PW |
| Becerra-Culqui et al. [59] | Cohort database review [Kaiser Permanente Southern California hospitals, USA] | Delivery Jan 2011–Dec 2014 | PW with natural conception and singleton livebirth at 22–45 GW |
Tdap (Adacel, Sanofi Pasteur) during pregnancy (interquartile range 26–33 GW) (n = 39,077) No Tdap (n = 42,916) |
Database analysis with 1.2–6.5 y of follow-up data |
Adverse birth and neonatal outcomes: Autism spectrum disorder: incidence rate of 3.78/1000 person-y in children of vaccinated PW vs. 4.05/1000 person-y in children of unvaccinated PW; aHR 0.85 (95% CI: 0.77–0.95) |
| Griffin et al. [48] | Cohort database review [National Health Index (NHI) Database including all pregnant women in New Zealand] | 2013 | PW with live or stillbirth ≥ 20 GW in 2013 (birthweight < 400 g, missing maternal or gestational age, live births < 28 GW, not eligible for Tdap at 28–38 GW in 2013) |
Tdap 28–38 GW (Boostrix, GSK) (n = 8178)a No Tdap (n = 60,372)a |
Database analysis |
Maternal adverse events and adverse fetal outcomes pre-delivery: Gestational hypertension, preeclampsia, intrauterine growth retardation, postpartum hemorrhage, gestational diabetes mellitus, chorioamnionitis, placental abruption, premature rupture of membranes, fetal distress, maternal fever before or after labor, anemia during pregnancy and purpura, maternal neurologic disorders similar between Tdap vs. no Tdap (aHR = 0.85–1.10 across outcomes) Tdap associated with reduced risk of pre-eclampsia with severe features (aHR = 0.61; 95% CI 0.39–0.94), preterm labor (0.32; 0.17–0.62) and delivery (0.72; 0.63–0.83), antenatal bleeding (0.61; 0.49–0.78) Tdap associated with increased risk of hospitalization for lactation disorders (1.63, 1.15–2.33) Chorioamnionitis: Tdap vs. no Tdap: aHR = 1.10 (95% CI 0.70–1.75) Postpartum hemorrhage: Tdap vs. no Tdap: aHR = 1.05 (95% CI 0.96–1.15) One maternal death (no Tdap group); insufficient cases of eclampsia and stillbirth in Tdap group for analysis |
| Sukumaran et al. [60] | Case–control database review [VSD data from Kaiser Permanente Northern California, Southern California, Colorado and Northwest, and Marshfield Clinic Research Foundation hospitals, USA] | Delivery Jan 2004–June 2014 |
PW enrolled at a VSD site with ≥ 1 prenatal care visit; their infants enrolled until age 6 mo or death (live vaccine during pregnancy, multiple gestation, birth at < 34 GW, infant with major birth defects or death during delivery) Matched controls for outcomes of interest |
25,222 cases of hospitalized infants, 25,222 matched controls; 157 infants died, 157 matched controls Tdap and/or influenza vaccine No Tdap and/or influenza vaccine |
Conditional logistic regression analysis to estimate odds of maternal vaccination in matched cases and controls |
Risk of hospitalization: aOR for Tdap: 0.94 (95% CI 0.88–1.01; p = 0.09) aOR for Tdap or influenza vaccine: 0.97 (95% CI 0.90–1.05; p = 0.44) Risk of death: aOR for Tdap: 0.44 (95% CI 0.17–1.13; p = 0.09) aOR for Tdap or influenza vaccine: 0.32 (95% CI 0.08–1.24; p = 0.10) |
| Prospective studies | ||||||
| Munoz et al. [13] | Randomized, double-blind, placebo-controlled [NIH VTEU sites in the USA (n = 3: Houston, Durham, Seattle)] | Oct 2008–May 2012 |
PW aged 18–45 y Non-PW age-matched to PW (previous Tdap or any tetanus-containing vaccine within the prior 2 y, high risk for obstetric complications) |
PW: Tdap (Adacel, Sanofi Pasteur) at 30–32 GW Infants: DTaP-IPV-Hib (Pentacel) at 2, 4, 6, 12 mo (33 PW and infants) PW: Placebo (Tdap [Adacel] postpartum) Infants: DTaP-IPV-Hib (Pentacel) at 2, 4, 6, 12 mo (15 PW and infants) Non-PW: Tdap (Adacel) (n = 32) |
AE monitoring in clinical trial (infants for up to 13 mo) |
Reactogenicity: Frequency of any ISR after Tdap was not different for PW (78.8% [95% CI 61.1–91.0]), postpartum women (80.0% [95% CI 51.9–95.7]) and nonpregnant women (78.1% [95% CI 60.0–90.7]) (p > 0.99) but was lower after placebo (PW: 20.0% [95% CI 4.3–48.1]; postpartum women: 18.2% [95% CI 7.0–35.5]); usually mild and resolved within 72 h Most frequently: local pain (> 70% per group; p = 0.94); swelling and erythema infrequent (< 13% per group; p > 0.3) Frequency of any systemic symptom after Tdap was not significantly different for PW (36.4% [95% CI 20.4–54.9]), postpartum women (73.3% [95% CI 44.9–92.2]) or in nonpregnant women (53.1% (95% CI 34.7–70.9%]) (p = 0.055); usually mild and self-limiting Frequency of fever after Tdap was higher in postpartum women (26.7% [95% CI 7.8–55.1]) than PW (3.0% [95% CI 0.1–15.8]) or nonpregnant women (9.4% [95% CI 2.0–25.0]) (p = 0.04) but was similar in postpartum women receiving Tdap vs. placebo (15.2% [95% CI 5.1–31.9]; p = 0.43) and in Tdap PW and Tdap nonpregnant women (p = 0.36) Frequencies of headache, myalgia, and malaise not significantly different between groups (p ≥ 0.35); headache was most frequent (33.3% and 46.7% for PW and postpartum women, respectively) Maternal adverse events and adverse fetal outcomes pre-delivery: None attributed to Tdap Birth and neonatal outcomes: All live born, mostly at term and by vaginal delivery No significant differences in gestational ages, birth weights, Apgar scores, neonatal examinations, complications, growth or development |
| Regan et al. [39] | Cohort [Telephone survey of PW receiving Tdap and/or TIV in Western Australia, Australia] | Apr 2015–Jun 2015 | PW |
Tdap (Adacel, Sanofi Pasteur [76.9%], Boostrix, GSK [23%], unknown [0.1%]) second/third trimester (n = 1257) TIV any trimester (no Tdap) (n = 1584) Tdap third trimester + TIV any trimester (n = 1506) |
Telephone survey of PW receiving Tdap and/or TIV |
Reactogenicity: Frequency of any reaction, fever, rigors, fatigue, vomiting, malaise, myalgia, or medically attended events similar in PW receiving Tdap, TIV, or Tdap + TIV (p > 0.1) Frequency of ISRs (Tdap: 7.1%, TIV: 3.2%, Tdap + TIV: 5.4%; p < 0.001 for Tdap vs. TIV, p = 0.002 for Tdap + TIV vs. TIV), rash (0.9%, 0.3%, 0.3%; p = 0.03, 1.00), headache (2.8%, 4.3%, 3.9%; p = 0.03, 0.58), and congestion (2.9%, 4.3%, 3.1%, p = 0.04, 0.07) significantly different for Tdap vs. TIV Any maternal AE after Tdap in 2015 more frequent in PW who had also received Tdap in 2011–2012 (13/70; 18.6%) than those who had not (291/2693; 10.8%; p = 0.04; OR = 1.88 [95% CI 1.02–3.48])h Adverse birth and neonatal outcomes: All women who had delivered at follow-up had a healthy infant |
| Hoang et al. [36] | Randomized, controlled [Ha Nam province (3 villages), Northern Vietnam] | Delivery Feb 2013–Oct 2013 | PW |
PW: Tdap (Adacel, Sanofi Pasteur, Canada) 18–36 GW (n = 52) Infants: DTaP-IPV-Hib-HepB (Infanrix hexa, GSK) at age 2, 3, 4 mo Tetanus vaccine (IVAC, Vietnam) (n = 51) Infants: DTaP-IPV-Hib-HepB (Infanrix hexa, GSK) at age 2, 3, 4 mo |
AE monitoring in clinical trial |
Reactogenicity: 23 PW experienced ≥ 1 solicited AE after Tdap (mean duration, 1.3 days) and 22 PW experienced ≥ 1 solicited AE after tetanus vaccine (mean duration, 1.2 days) Most common adverse events were stiffness, swelling and injection site itching Serious AEs reported with Tdap: fever (n = 1) and fatigue (n = 1) Maternal adverse events and adverse fetal outcomes pre-delivery: Premature contractions > 1 mo after Tdap (n = 2) or tetanus vaccine (n = 1) Adverse birth and neonatal outcomes: No AEs related to vaccination reported |
| Maertens et al. [37] | Controlled cohort [Five hospitals in Antwerp, Belgium] | Feb 2012–Sep 2014 | PW with healthy livebirths, no pertussis-containing vaccine for ≥ 10 y |
Tdap (Boostrix, GSK) mean 28.6 GW (PW: 57, infants (Infanrix hexa, GSK): 55) No Tdap (PW: 42, infants: 26) |
AE monitoring in clinical trial |
Reactogenicity: Adverse events, mostly mild and self-limiting, reported by 46 PW after Tdap Most frequent AEs were injection site stiffness (N = 42) and minor injection site swelling; fever reported in 1 PW after Tdap (1.75%) Maternal adverse events and adverse fetal outcomes pre-delivery: Of the 11 serious AEsi in PW receiving Tdap, none related to Tdap Three SAE reported in PW not receiving Tdap Adverse birth and neonatal outcomes: Serious AEs requiring infant hospitalization reported after Tdap (n = 7) and no Tdap (n = 1)j No congenital disorders detected |
| Petousis-Harris et al. [38] | Observational, cohort [Primary care and antenatal centers in North Island (3 District Health Boards) or South Island (Canterbury) of New Zealand] |
North Island: Jan 2014–Jun 2014 South Island: Sep 2012–Jun 2014 |
PW with ≥ 1 ultrasound during pregnancy, adequate prenatal care, ± TIV | Tdap (Boostrix, GSK) at 28–38 GW (n = 793)k | Active AE monitoring for up to 4 weeks after vaccination |
Reactogenicity: Most frequent ISR was pain (mild-moderate: 78.9%, severe: 2.6%); swelling (7.6%) and erythema (5.8%) uncommon and resolved in < 48 h in ≈ 50% of cases Systemic events were fever (2.1%), headache/dizziness (3.9%), nausea/vomiting (2.8%), fatigue (8.4%) and myalgia/arthralgia (3.0%) Maternal adverse events and adverse fetal outcomes pre-delivery: SAEs in 31 PW (3.9%), 23 resulting in hospitalization (obstetric bleeding [4], hypertension [2], infection [4], tachycardia [1], preterm labor [9], exacerbation of pre-existing condition [2], preeclampsia [1]) Adverse birth and neonatal outcomes: Two perinatal deaths (congenital abnormality [1], unexplained [1]) |
| Walls et al. [58] | Observational, cohort [Canterbury region of New Zealand] | Sep 2012–Nov 2014 | PW with ≥ 1 ultrasound during early pregnancy, adequate prenatal care, ± TIV (fetus with congenital/severe structural/chromosomal abnormalities during prenatal screening) | Tdap (Boostrix, GSK) 28–38 GW (403 PW + 408 infants: 345 followed for 12 mo, 63 followed for 6–12 mo)a | Maternal reports and healthcare provider information prospectively collected |
Birth and neonatal outcomes: 94% delivered at term; 6% delivered pre-term (< 37 GW) Isolated medically significant events in 10 infants (2.5%); 1 stillborn (reason unknown despite postmortem) No evidence of increase in any adverse neonatal/infant outcome vs. baseline population rates |
| Villarreal Pérez et al. [40] | Randomized, double-blind, parallel group, placebo-controlled [12 outpatient health centers of the Nuevo Leon Health Services, Mexico] | Sep 2011–Aug 2014 | PW aged 18–38 y, low obstetric risk, normal anatomical ultrasound in second trimester(psychiatric or severe physical disease, drug or tobacco use, history of severe reactions to any vaccine or febrile illness in the 72 h prior to vaccination, immunization against tetanus and/or pertussis < 2 y previously) |
Tdap at 30–32 GW (90 PW + infants) Placebo (81 PW + infants) |
AE monitoring in clinical trial |
Reactogenicity: Uncommon, AEs reported in 41% of PW with Tdap and 31% with placebo in first 24 h; most frequently local reactions that had resolved by 48 h Most common within 24 h: mild local pain; similar with Tdap vs. placebo (22% vs. 21%) |
| Fortner et al. [34] | Observational, cohort [Two CDC-funded CISA centers (Vanderbilt University Medical Center, Duke University Health System), USA] | Jul 2014–Jul 2015 |
PW aged 18–45 y with singleton pregnancy and Tdap vaccination at 20–33 GW Controls: non-PW aged 18–45 y |
Tdap (Adacel or Boostrix) 20–33 GW (374 PW) Tdap (Adacel or Boostrix) (225 non-PW) |
Active AE monitoring for up to 4 weeks after vaccination |
Reactogenicity: Local symptoms in PW vs. non-PW: moderate/severe pain (17.9% vs. 11.1%), tenderness (19.0% vs. 16.9%), swelling/induration (5.6% vs. 5.8%), erythema (5.6% vs. 5.3%); each event severe in < 2% of PW and < 3.5% of non-PW Moderate/severe pain was more common in PW than non-PW Systemic symptoms in PW vs. non-PW: moderate/severe fever (0.5% vs. 2.2%), feverishness (3.2% vs. 4.0%), malaise (10.4% vs. 4.9%), body aches/myalgias (7.8% vs. 5.3%), headaches (7.2% vs. 8.9%); each event severe in < 1% of PW and < 2.5% of non-PW No woman required medical care for any reaction Moderate/severe and severe local and systemic reactions not affected by previous Tdap vaccination |
| Halperin et al. [35] | Randomized, single-blind, parallel group, Td-controlled [Centers in Canada (Halifax, Montreal, Ottawa, Calgary, Edmonton, Vancouver)] | Nov 2007–Jun 2011 and Mar 2012–Apr 2014 | Healthy PW aged 18–45 y at ≥ 30 GW, with low risk for complications (history of significant medical disorder, receipt of high-dose systemic corticosteroids or, in previous 5 y, pertussis or previous Td/Tdap or, within 3 mo, blood products or immunoglobulin, except rhesus immunoglobulin or, within 2 weeks, any vaccine, except influenza, or sensitivity to any component of Td or Tdap) |
Tdap (Adacel, Sanofi Pasteur) ≥ 30 GW (n = 135) Td ≥ 30 GW (n = 138) |
AE monitoring for 8 days after vaccination; infant developmental testing (Bayley-III Scales of Infant and Toddler Development) at age 18 mo |
Reactogenicity: Injection site pain in > 80% of both groups; predominantly mild Erythema, swelling in about 10%–20% of both groups; predominantly mild Muscle aches, fatigue, headache in 16.9%–34.4% of both groups; predominantly mild Events less common with Tdap vs. Td: mild fatigue (13.3% vs. 23.4%; p = 0.041), mild muscle aches (4.4% vs. 20.4%; p < 0.001) Events more common with Tdap vs. Td: severe muscle aches (4.4% vs. 0%; p = 0.014) Maternal adverse events and adverse fetal outcomes pre-delivery: No serious AEs in PW considered related to Tdap or Td except: gestational hypertension (n = 1 Tdap) and hemolysis, elevated liver enzymes, low platelet count syndrome + preeclampsia + premature delivery (n = 1 Td)—possibly related Adverse birth and neonatal outcomes: No differences in rates of congenital abnormalities or neonatal complications between infants of Tdap and Td PW No serious AEs in infants considered related to Tdap or Td No developmental differences between infants of Tdap and Td PW (3% abnormal findings in each group) |
| Wanlapakorn et al. [41] | Randomized, controlled [King Chulalongkorn Memorial Hospital, Bangkok, Thailand] | Apr 2015–Sep 2016 | Healthy PW aged 18–45 y, with low risk for complications; infants born after 36 GW and weighing 2500 g | PW: Tdap (Boostrix, GSK) 26–36 GW (n = 370) | Active AE monitoring for 7 days after vaccination; passive AE monitoring thereafter |
Reactogenicity: No AEs reported in the first 30 min after vaccination Most frequently local pain (76.2%; mild: 62.4%, moderate: 13.8%) then low-grade fever (5.1%), swelling (4.1%; mild: 4.1%), erythema (1.4%, mild: 1.4%) Not affected by receipt of previous tetanus-containing vaccine Maternal adverse events and adverse fetal outcomes pre-delivery: No serious AEs in PW considered related to Tdap Gestational diabetes (2.7%) or hypertension (1.4%), premature delivery (6.7%) and other serious AEs not more frequent than reported among all deliveries in hospital (N = 4636) Not affected by receipt of previous tetanus-containing vaccine Chorioamnionitis: 0.5% Adverse birth and neonatal outcomes: No serious AEs (including deaths, congenital defects and birth asphyxia) in infants considered related to Tdap Not affected by maternal receipt of previous tetanus-containing vaccine |
ACIP Advisory Committee on Immunization Practices, AE adverse event, ARR adjusted rate ratio/relative risk, aHR adjusted hazard ratio, aOR adjusted odds ratio, CI confidence interval, CDC Centers for Disease Control and Prevention, CISA Clinical Immunization Safety Assessment, CNS central nervous system, EHR electronic health record, EMR electronic medical records, GW gestational weeks, HC historical control, IPTW inverse-probability of treatment weights, ISR injection site reaction, mo month(s), NICU neonatal intensive care unit, NIH VTEU National Institute of Health Vaccine Treatment Evaluation Unit, NR not reported, OR odds ratio, PW pregnant women, RR relative risk, SAE serious adverse events, SGA small for gestational age, TIV trivalent influenza vaccine, VSD Vaccine Safety Datalink, VAERS Vaccine Adverse Event Reporting System, WA Western Australia, y year(s)
aPW could have also received other vaccines, including any of influenza, hepatitis A, hepatitis B, meningococcal, and pneumococcal vaccine
bMaternal outcomes included chorioamnionitis, postpartum endometritis, preterm premature rupture of membranes, preterm delivery (delivery < 37 GW), and a composite endpoint including these outcomes. Mode of delivery and need for induction were also considered
cNeonatal outcomes included low birth weight, very low birth weight, small for gestational age, Apgar score < 8 at 5 min of life, admission to NICU, and birth defects. Birth defects included spina bifida, transposition of great arteries, atrioventricular septal defect, cleft palate, cleft lip, and diaphragmatic hemia (all 0–2% frequency per group); Tetralogy of Fallot, rectal and large intestinal atresia/stenosis, reduction deformity of upper limbs, and gastroschisis not observed
dAny event included allergic reaction, fever, malaise, seizure, altered mental status, or local or other reaction
eAny neurological event included autonomic disorders, cranial nerve disorders, CNS degeneration/demyelinating conditions, peripheral neuropathy, Guillain–Barré syndrome, meningoencephalitides, movement disorders, paralytic syndromes, and spinocerebellar disease
fKaiser Permanente Northern California, Southern California, Colorado and Northwest (Oregon and Washington), Marshfield Clinic (Wisconsin), Group Health Cooperative (Washington), and HealthPartners (Minnesota)
gDelivery and neonatal outcomes included gestational age at delivery, stillbirth and major malformation rate, neonatal care admission, ventilation requirements, and incidence of neonatal death
hWomen were considered to have received a previous dose of Tdap only if record of a vaccination during the area’s 2011–2012 parental pertussis vaccination program could be located on the program database
iSAEs included preeclampsia, premature contractions, hypertension, oligohydramnios, and placenta previa
jThe 8 SAE requiring infant hospitalization for at least 1 h were premature delivery, fever at birth, hypoglycemia at birth, pneumonia at birth, infection at the age of 1 months, infection at the age of 5 months, febrile seizures at the age of 2 months, and extreme vomiting at the age of 5 months (n = 1 for all)
kTIV administered with Tdap in 27.5%