Abstract
Background
Available evidence indicates that seasonal inactivated influenza vaccination during pregnancy protects both the mother and her newborn and is safe. Nevertheless, ongoing safety assessments are important in sustaining vaccine uptake. Few studies have explored safety in relation to major congenital malformations (MCMs), particularly in the first trimester when most organogenesis occurs.
Methods
Anonymized UK primary care data (the Clinical Practice Research Datalink), including a recently developed Pregnancy Register, were used to identify live-born singletons delivered between 2010 and 2016. Maternal influenza vaccination was determined using primary care records and stratified by trimester. Ascertainment of MCMs from infant primary care records was maximized by linkage to hospitalization data and death certificates. The relationship between vaccination and MCMs recorded in the year after delivery and in early childhood was then assessed using multivariable Cox regression.
Results
A total of 78 150 live-birth pregnancies were identified: 6872 (8.8%) were vaccinated in the first trimester, 11 678 (14.9%) in the second, and 12 931 (16.5%) in the third. Overall, 5707 live births resulted in an infant with an MCM recorded in the year after delivery and the adjusted hazard ratio when comparing first-trimester vaccination to no vaccination was 1.06 (99% CI, .94–1.19; P = .2). Results were similar for second- and third-trimester vaccination and for analyses considering MCMs recorded beyond the first birthday.
Conclusions
In this large, population-based historical cohort study there was no evidence to suggest that seasonal influenza vaccine was associated with MCMs when given in the first trimester or subsequently in pregnancy.
Keywords: pregnancy, influenza vaccine, safety, congenital malformations
In this UK-based historical cohort study, there was no evidence to suggest that seasonal influenza vaccine was associated with major malformations when given in the first trimester or subsequently in pregnancy.
Influenza vaccination during pregnancy provides protection from influenza-related complications in mothers and newborn infants but women are often concerned about their infant’s safety [1–6]. Postlicensure studies, most of which only examined the 2009/2010 pandemic influenza vaccine, have not demonstrated an association between maternal influenza vaccination and major congenital malformations (MCMs) (pooled odds ratio, 1.03; 95% confidence interval [CI], .7–1.6; P = .38; n = 20 studies) [7–11].
A small number of studies have examined seasonal influenza vaccines (SIVs) using data from the United States or Canada and have not found evidence of an increased risk of MCMs [12–16]. However, all but one [16] were limited by low numbers of vaccinations in the first trimester, the critical period of organogenesis when the risk of MCMs is highest [12–15]. Furthermore, although MCMs continue to be diagnosed and recorded into early childhood [17–19], most studies ended follow-up of infants shortly after delivery [13–15].
We examined the association between SIV and MCMs in a different setting using a large UK cohort. Analyses were stratified by trimester of vaccination and the ascertainment of MCMs was maximized through long-term follow-up of infants and the use of linked primary care, hospitalization, and mortality datasets.
METHODS
Data Sources
This study utilized the Clinical Practice Research Datalink (CPRD), the CPRD/London School of Hygiene and Tropical Medicine (LSHTM) Pregnancy Register, hospital admissions data from the Hospital Episode Statistics database (HES), Office for National Statistics (ONS) death certificate data, deprivation quintiles linked to household postcodes, and data on influenza activity from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre.
The CPRD contains anonymized, electronic primary care records for 7% of the UK population registered at a general practice. It includes diagnoses and procedures recorded using the Read codes (version 2) hierarchical clinical coding system [20, 21], vaccination records, and prescriptions [22]. The CPRD has been shown to be broadly representative of the UK population and diagnostic validity is high [22, 23].
The Pregnancy Register lists all pregnancies identified in the CPRD for women aged 11–49 years [24]. It includes pregnancy outcomes and estimates of pregnancy timings derived from all available pregnancy data in CPRD including estimated delivery dates, last menstrual period dates, ultrasound dating scans, and prematurity records. The first, second, and third trimesters are defined as the pregnancy start through week 13, week 14 through 26, and week 27 through the pregnancy end, respectively. Live-birth deliveries are linked to records of infants registered at the same practice as their mother. Validation of the Pregnancy Register against linked electronic maternity records in HES has indicated overall good agreement, suggesting most pregnancies are well captured in the register [24].
Patient data in CPRD can be linked to the HES and ONS data for 75% of English practices [22]. Linked HES data include information on diagnoses and procedures, recorded using the International Classification of Diseases, 10th revision (ICD-10), and the Classification of Surgical Operations and Procedures (OPCS-4), respectively. The ONS death certificate data include primary and contributory causes of death recorded using ICD-10. Deprivation quintiles are derived from the 2015 Index of Multiple Deprivation (IMD) for Lower Super Output Areas [25].
Weekly general practice consultation rates for influenza-like illness from the RCGP were used to identify periods of influenza circulation above baseline levels for each season. The validity of these data has been confirmed through microbiological surveillance [26].
This study received approval from the Independent Scientific Advisory Committee of the Medicines & Healthcare Products Regulatory Agency (reference 17_040RA); the approved protocol was made available to the reviewers. Approval was also received from LSHTM’s ethics committee (reference 13720).
Study Design
This historical cohort study compared live-birth pregnancies in women who received SIV, stratified by trimester of vaccination, with those who were unvaccinated. The primary outcome was the presence of any MCMs among infants in the year after delivery. Secondary outcomes examined any MCMs, major limb malformations, and congenital heart defects recorded after delivery and anytime in the study period between 1 September 2010 and 31 March 2016 (the latest date for which all linked data were available).
Study Population
Pregnancies resulting in a live-born singleton during the study period were identified from the Pregnancy Register. Pregnant women had to be registered at an up-to-standard practice (a quality standard set by CPRD to indicate continuous recording of data within the practice) [22] for at least 6 months before the start of pregnancy to enable the ascertainment of preconception exposures. Live-born infants had to be eligible for HES and ONS linkage. Finally, pregnancies were required to overlap with a period of influenza vaccine availability (1 September to 31 March, annually) by at least 1 week.
Identifying Vaccinations
In the United Kingdom, pregnant women are offered SIV in any trimester [27]. The earliest vaccination record in each influenza season was identified in CPRD from immunization records, prescriptions, or Read codes, and used to determine the trimester of vaccination. Pregnancies were excluded if the timing or nature of vaccination was uncertain (eg, if there was a possibility that SIV was received outside of the practice at an unknown time or a possibility that pandemic vaccine was received) (Figure 1).
Figure 1.
Derivation of pregnancies used in analyses. aAt least 1 week of the pregnancy had to occur when influenza vaccine was available. All infants had to be eligible for linkage to HES and ONS data. bPandemic vaccine was available alongside SIV in 2009/2010 and 2010/2011. Pregnant women could be offered the pandemic vaccine in 2010/2011 or in 2009/2010 if their pregnancy ended after 1 September 2010 but started in the prior influenza season. Pregnant women who received pandemic vaccine or an unspecified influenza vaccine in 2009/2010 or 2010/2011 were excluded. cToxoplasmosis, rubella, cytomegalovirus, herpes, parvovirus, varicella-zoster, syphillis, HIV. dChromosomal anomalies, heritable conditions, or malformations due to a known teratogen. eAmong pregnancies for which linkage to the infant record was available, 720 had unknown maternal ethnicity, 403 had unknown maternal smoking status, and 449 had an uncertain maternal clinical risk group status. Abbreviations: HES, Hospital Episode Statistics database, HIV, human immunodeficiency virus; ONS, Office for National Statistics; SIV, seasonal influenza vaccine.
Identifying Major Congenital Malformations
Code lists for MCMs were developed with a consultant neonatologist (S. T. K.), following EUROCAT guidelines (see Supplementary Material; code lists are available at https://datacompass.lshtm.ac.uk/1629/) [28]. Major congenital malformations were then ascertained from infant records in CPRD, HES data for diagnoses and procedures, and ONS. Pregnancies were excluded if there was an antenatal or infant record indicating a chromosomal or heritable anomaly, a malformation due to a known teratogen (eg, fetal alcohol syndrome), or a congenital infection associated with malformations. Infants were followed up from delivery for 1 year or until the end of the study period. Follow-up ended earlier if they died, left the practice, or the practice stopped collecting data for CPRD.
Potential Confounders
We considered a priori confounders to be maternal age and ethnicity, geographical region (due to variation in vaccine uptake and MCM ascertainment), and influenza season. Other potential confounders included the following: household deprivation quintile (IMD), number of children in the household, maternal smoking, hazardous drinking, extreme body mass index (BMI) of less than 18 kg/m2 or 35 kg/m2 or higher, belonging to another clinical risk group for which vaccination was recommended during the study period [27], non–pregnancy-related chronic hypertension, exposure to teratogenic drugs or live vaccines, and number of weeks the first trimester overlapped with influenza activity above baseline levels (see Supplementary Table 1 for details of how these were derived).
Statistical Analyses
Baseline pregnancy characteristics were described by vaccination status. Logistic regression was used initially to model the univariable relationship between vaccination and MCMs recorded in the year after delivery and assess confounding. After a priori confounders, remaining potential confounders were added individually to the logistic regression model and assessed for a 5% or greater change in the odds ratios between first-trimester vaccination or vaccination anytime and MCMs. Multicollinearity was monitored between IMD, ethnicity, and region and between the number of children in the household and maternal age. Finally, random-effects models were used to assess clustering by mother and practice. Once confounders had been identified using logistic regression models, all final analyses were conducted using Cox proportional hazards models to account for improved ascertainment of the outcome among infants with longer follow-up time. Results were compared with those from logistic regression. To account for multiple analyses, 99% CIs were calculated. All models were complete case analyses. We estimated we had more than 90% power to detect a risk ratio of 1.2 in primary analyses.
Three sensitivity analyses were conducted. First, we included pregnancies in women who received SIV in the 4 weeks prior to their start to account for any imprecision in the estimated pregnancy start dates. Second, we included MCMs recorded in HES or ONS after follow-up in CPRD had ended because the infant left the practice or the practice ended data collection. In the main analyses, pregnancies of women with unknown BMI or a BMI between 18 and 34 kg/m2 were combined in a single category as they had comparable associations with MCMs. The third sensitivity analysis excluded pregnancies of women with unknown BMI. STATA version 14.2 (StataCorp) was used for all analyses.
RESULTS
Characteristics of the Eligible Study Cohort
We identified 103 742 potentially eligible pregnancies resulting in live-born singletons during the study period. After exclusions were applied, the final cohort included 78 150 pregnancies among 71 124 women (Figure 1). Most pregnancies were in white women (85.5%) aged 25–34 (58.9%) years (Table 1).
Table 1.
Characteristics of Eligible Pregnancies Included in Analyses, by Vaccination Status
| No. of Pregnancies (%) (N = 78 150) | No. of Pregnancies Unvaccinated (%) (n = 46 669) | No. of Pregnancies Vaccinated in Trimester 1 (%) (n = 6872) | No. of Pregnancies Vaccinated Anytime (%) (n = 31 481) | |
|---|---|---|---|---|
| Maternal age (years) | ||||
| <18 | 719 (0.9) | 458 (63.7) | 33 (4.6) | 261 (36.3) |
| 18–24 | 13 243 (17) | 8451 (63.8) | 982 (7.4) | 4792 (36.2) |
| 25–34 | 46 030 (58.9) | 27 138 (59) | 4150 (9) | 18 892 (41) |
| ≥35 | 18 158 (23.2) | 10 622 (58.5) | 1707 (9.4) | 7536 (41.5) |
| Maternal ethnicity | ||||
| White | 66 849 (85.5) | 39 618 (59.3) | 5939 (8.9) | 27 231 (40.7) |
| South Asian | 5501 (7) | 3272 (59.5) | 507 (9.2) | 2229 (40.5) |
| Black | 2881 (3.7) | 1953 (67.8) | 196 (6.8) | 928 (32.2) |
| Other | 1850 (2.4) | 1171 (63.3) | 146 (7.9) | 679 (36.7) |
| Mixed | 1069 (1.4) | 655 (61.3) | 84 (7.9) | 414 (38.7) |
| Maternal IMD statusa | ||||
| 1 = least deprived | 15 847 (20.3) | 8730 (55.1) | 1579 (10) | 7117 (44.9) |
| 2 | 14 905 (19.1) | 8569 (57.5) | 1345 (9) | 6336 (42.5) |
| 3 | 15 144 (19.4) | 8880 (58.6) | 1406 (9.3) | 6264 (41.4) |
| 4 | 16 064 (20.6) | 10 015 (62.3) | 1304 (8.1) | 6049 (37.7) |
| 5 = most deprived | 16 190 (20.7) | 10 475 (64.7) | 1238 (7.7) | 5715 (35.3) |
| Region | ||||
| London | 12 922 (16.5) | 8295 (64.2) | 991 (7.7) | 4627 (35.8) |
| North East | 1811 (2.3) | 1203 (66.4) | 113 (6.2) | 608 (33.6) |
| North West | 11 636 (14.9) | 6771 (58.2) | 1133 (9.7) | 4865 (41.8) |
| Yorkshire and The Humber | 1453 (1.9) | 922 (63.5) | 123 (8.5) | 531 (36.6) |
| East Midlands | 780 (1) | 549 (70.4) | 45 (5.8) | 231 (29.6) |
| West Midlands | 8545 (10.9) | 4561 (53.4) | 997 (11.7) | 3984 (46.6) |
| East of England | 7862 (10.1) | 4463 (56.8) | 741 (9.4) | 3399 (43.2) |
| South West | 9974 (12.8) | 5936 (59.5) | 777 (7.8) | 4038 (40.5) |
| South Central | 11 670 (14.9) | 6710 (57.5) | 1157 (9.9) | 4960 (42.5) |
| South East Coast | 11 497 (14.7) | 7259 (63.1) | 795 (6.9) | 4238 (36.9) |
| Mother was part of a clinical risk groupb | ||||
| No | 73 804 (94.4) | 44 513 (60.3) | 6230 (8.4) | 29 291 (39.7) |
| Yes | 4346 (5.6) | 2156 (49.6) | 642 (14.8) | 2190 (50.4) |
| Maternal smoking status | ||||
| Nonsmoker | 41 081 (52.6) | 23 922 (58.2) | 3729 (9.1) | 17 159 (41.8) |
| Current smoker | 17 687 (22.6) | 11 630 (65.8) | 1278 (7.2) | 6057 (34.3) |
| Ex-smoker | 19 382 (24.8) | 11 117 (57.4) | 1865 (9.6) | 8265 (42.6) |
| Maternal hazardous drinking | ||||
| No | 77 502 (99.2) | 46 308 (59.8) | 6811 (8.8) | 31 194 (40.3) |
| Yes | 648 (0.8) | 361 (55.7) | 61 (9.4) | 287 (44.3) |
| Extreme maternal BMI | ||||
| No | 71 335 (91.3) | 42 560 (59.7) | 6235 (8.7) | 28 775 (40.3) |
| Underweight (<18 kg/m2) | 1656 (2.1) | 1042 (62.9) | 147 (8.9) | 614 (37.1) |
| Obese (≥35 kg/m2) | 5159 (6.6) | 3067 (59.5) | 490 (9.5) | 2092 (40.6) |
| Maternal chronic hypertension (nonpregnancy related) | ||||
| No | 77 097 (98.7) | 46 074 (59.8) | 6760 (8.8) | 31 023 (40.2) |
| Yes | 1053 (1.4) | 595 (56.5) | 112 (10.6) | 458 (43.5) |
| Maternal exposure to teratogenic medication(s)c or live vaccinesd | ||||
| No | 73 370 (93.9) | 43 928 (59.9) | 6386 (8.7) | 29 442 (40.1) |
| Yes | 4780 (6.1) | 2741 (57.3) | 486 (10.2) | 2039 (42.7) |
| Influenza season | ||||
| 2009/2010 | 5234 (6.7) | 5171 (98.8) | 0 (0) | 63 (1.2) |
| 2010/2011 | 13 040 (16.7) | 10 135 (77.7) | 425 (3.3) | 2905 (22.3) |
| 2011/2012 | 18 468 (23.6) | 11 254 (60.9) | 1607 (8.7) | 7214 (39.1) |
| 2012/2013 | 15 910 (20.4) | 7833 (49.2) | 2067 (13) | 8077 (50.8) |
| 2013/2014 | 13 383 (17.1) | 6906 (51.6) | 1503 (11.2) | 6477 (48.4) |
| 2014/2015 | 9987 (12.8) | 4715 (47.2) | 1251 (12.5) | 5272 (52.8) |
| 2015/2016 | 2128 (2.7) | 655 (30.8) | 19 (0.9) | 1473 (69.2) |
| No. of weeks the first trimester overlapped with influenza activity above baseline levels | ||||
| None | 63 145 (80.8) | 35 467 (56.2) | 4813 (7.6) | 27 678 (43.8) |
| 0–2 | 6556 (8.4) | 4649 (70.9) | 1091 (16.6) | 1907 (29.1) |
| 2–4 | 1668 (2.1) | 1200 (71.9) | 154 (9.2) | 468 (28.1) |
| 4–6 | 2059 (2.6) | 1525 (74.1) | 260 (12.6) | 534 (25.9) |
| 6–8 | 2954 (3.8) | 2377 (80.5) | 346 (11.7) | 577 (19.5) |
| 8–10 | 703 (0.9) | 541 (77) | 88 (12.5) | 162 (23) |
| 10–12 | 1065 (1.4) | 910 (85.5) | 120 (11.3) | 155 (14.6) |
| No. of children in the maternal household | ||||
| None | 27 868 (35.7) | 15 211 (54.6) | 2833 (10.2) | 12 657 (45.4) |
| 1–2 | 42 911 (54.9) | 26 419 (61.6) | 3565 (8.3) | 16 492 (38.4) |
| ≥3 | 7371 (9.4) | 5039 (68.4) | 474 (6.4) | 2332 (31.6) |
Abbreviations: BMI, body mass index; IMD, Index of Multiple Deprivation.
aFor 46 (0.06%) pregnancies, maternal household IMD was unavailable and practice-level IMD was used.
bChronic respiratory, heart, kidney, liver or neurological disease; diabetes; immunosuppression due to disease or treatment; asplenia or dysfunction of the spleen.
cExposure from 6 months before pregnancy start until the end of the first trimester.
dExposure from 3 months before pregnancy start until the end of the first trimester.
Vaccine uptake was 40.3% (n = 31 481): 8.8% (n = 6872) in the first trimester, 14.9% (n = 11 678) in the second trimester, and 16.5% (n = 12 931) in the third trimester. Vaccination in the first trimester or anytime in pregnancy was less likely if the woman was young, of Black ethnicity, living in a more deprived area, not part of a clinical risk group for which vaccination was recommended [27], unexposed to teratogenic medications and/or live vaccines, a current smoker, or part of a household with children (Table 1, Supplementary Table 2). Vaccination also varied by region and influenza season.
Of the 78 150 pregnancies, 7.3% (n = 5707) resulted in an infant with an MCM recorded in the year after delivery, while 7.7% (n = 6029) had an MCM recorded after delivery and anytime in the study period. Most MCMs were recorded early in life, with 51% recorded at delivery and 87.2% in the following 3 months (Supplementary Figure 1). Most infants had at least 1 year of follow-up (73.5%) and almost half had at least 2 years of follow-up (48.9%) (Supplementary Table 3).
Primary Analyses
The univariable Cox regression analysis suggested an increased rate of MCMs recorded in the year after delivery among those vaccinated anytime in pregnancy compared with those never vaccinated (hazard ratio [HR], 1.10; 99% CI, 1.03–1.18; P < .001). Results were similar for first-trimester and second-trimester vaccination (Table 2). However, all associations were eliminated following adjustment for a priori confounders: maternal age, ethnicity, region, and influenza season (Table 2). The most important of these appeared to be region and season; HRs remained similar upon the addition of age and ethnicity (Supplementary Tables 4 and 5). Both region and season were associated with age and ethnicity (χ 2, P < .001), suggesting that adjustment for the former likely resulted in partial adjustment for the latter.
Table 2.
Examining the Association Between Vaccination and Major Congenital Malformations
| Time of Vaccination During Pregnancy (No. of Pregnancies) | No. MCMs/Person-years (Rate per 100 Person-years) | HR, Unadjusted (99% CI) | P | HR, Adjusted for A Priori Confounders (99% CI) | P | HR, Adjusted for All Potential Confounders (99% CI) | P |
|---|---|---|---|---|---|---|---|
| Models including MCMs ascertained in the year after delivery (N = 5707 MCMs) | |||||||
| Never (46 669) | 3289/38 898 (8.5) | 1.00 | 1.00 | 1.00 | |||
| Any trimester (31 481) | 2418/24 827 (9.7) | 1.10 (1.03–1.18) | <.001 | 1.03 (.96–1.11) | .33 | 1.02 (.94–1.10) | .54 |
| Trimester 1 (6872) | 565/5560 (10.2) | 1.17 (1.04–1.32) | <.001 | 1.08 (.96–1.22) | .11 | 1.06 (.94–1.19) | .23 |
| Trimester 2 (11 678) | 902/9153 (9.9) | 1.11 (1.01–1.22) | .006 | 1.03 (.93–1.14) | .45 | 1.02 (.92–1.13) | .63 |
| Trimester 3 (12 931) | 951/10 115 (9.4) | 1.05 (.96–1.16) | .17 | 1.00 (.91–1.10) | >.99 | .99 (.90–1.10) | .86 |
| Models including MCMs ascertained after delivery and anytime in the study period (N = 6029 MCMs) | |||||||
| Never (46 669) | 3505/102 311 (3.4) | 1.00 | 1.00 | 1.00 | |||
| Any trimester (31 481) | 2524/54 389 (4.6) | 1.09 (1.02–1.17) | .001 | 1.03 (.96–1.10) | .36 | 1.02 (.94–1.09) | .56 |
| Trimester 1 (6872) | 594/11 648 (5.1) | 1.18 (1.05–1.32) | <.001 | 1.09 (.97–1.22) | .07 | 1.07 (.95–1.20) | .16 |
| Trimester 2 (11 678) | 941/20 203 (4.7) | 1.10 (1.00–1.21) | .008 | 1.03 (.93–1.13) | .48 | 1.02 (.92–1.13) | .65 |
| Trimester 3 (12 931) | 989/22 539 (4.4) | 1.04 (.95–1.14) | .27 | .99 (.90–1.09) | .85 | .99 (.90–1.09) | .73 |
A priori confounders were maternal age, maternal ethnicity, region, and influenza season. Other potential confounders included the number of weeks the first trimester overlapped with a period of influenza activity above baseline levels as well as the following maternal factors: IMD, number of children in the household, smoking status, hazardous drinking, extreme BMI, clinical risk group, chronic hypertension, and exposure to teratogenic drugs and/or live vaccines.
Abbreviations: BMI, body mass index; CI, confidence interval; HR, hazard ratio; IMD, Index of Multiple Deprivation; MCM, major congenital malformation.
Of the remaining potential confounders, only maternal IMD and number of children in the household were associated with both vaccination and MCMs in univariable analyses (Supplementary Tables 2 and 6). However, upon addition to the model, neither these nor any others altered HRs by 5% or more (Supplementary Tables 4 and 5). Fully adjusted models showed no evidence of an association between vaccination anytime (HR, 1.02; 99% CI, .94–1.10; P = .54), vaccination in the first trimester (HR, 1.06; 99% CI, .94–1.19; P = .23), or vaccination in the second trimester (HR, 1.02; 99% CI, .92–1.13; P = .63) and MCMs recorded in the year after delivery (Table 2). The logistic regression models used to investigate confounding gave very similar results to our final Cox regression models (Supplementary Tables 4 and 5).
Secondary Analyses
Results from analyses in which follow-up was extended to include any MCMs ascertained from delivery until the end of the study period were almost identical (Table 2). In models examining MCM subgroups, there was evidence of an increased rate of limb malformations following first-trimester vaccination (HR, 1.20; 99% CI, 1.00–1.44; P = .01) (Table 3). Adjusting for a priori or all potential confounders removed this association (HR, 1.03; 99% CI, .86–1.25; P = .66). Results were similar for other trimesters. For congenital heart defects, no association was seen with vaccination in any model.
Table 3.
Examining the Association Between Vaccination, Major Limb Malformations, and Congenital Heart Defects
| Time of Vaccination During Pregnancy (No. of Pregnancies) | No. of MCMs/Person-years (Rate per 100 Person-years) | HR, Unadjusted (99% CI) | P | HR, Adjusted for A Priori Confounders (99% CI) | P | HR, Adjusted for All Potential Confounders (99% CI) | P |
|---|---|---|---|---|---|---|---|
| Models including limb malformations ascertained after delivery and anytime in the study period (N = 2425 limb malformations) | |||||||
| Never (46 669) | 1350/107 080 (1.3) | 1.00 | 1.00 | 1.00 | |||
| Any trimester (31 481) | 1075/56 940 (1.9) | 1.20 (1.08–1.33) | <.001 | 1.10 (.99–1.23) | .03 | 1.07 (.96–1.21) | .11 |
| Trimester 1 (6872) | 235/12 259 (1.9) | 1.20 (1.00–1.44) | .01 | 1.07 (.89–1.29) | .34 | 1.03 (.86–1.25) | .66 |
| Trimester 2 (11 678) | 405/21 145 (1.9) | 1.22 (1.06–1.41) | <.001 | 1.11 (.96–1.29) | .07 | 1.09 (.93–1.27) | .17 |
| Trimester 3 (12 931) | 435/23 536 (1.9) | 1.18 (1.02–1.36) | .003 | 1.11 (.96–1.28) | .07 | 1.09 (.94–1.26) | .14 |
| Models including congenital heart defects ascertained after delivery and anytime in the study period (N = 789 heart defects) | |||||||
| Never (46 669) | 479/109 133 (0.4) | 1.00 | 1.00 | 1.00 | |||
| Any trimester (31 481) | 310/58 303 (0.5) | .99 (.82–1.20) | .90 | .96 (.79–1.17) | .58 | .93 (.76–1.15) | .39 |
| Trimester 1 (6872) | 67/12 568 (0.5) | .97 (.69–1.36) | .82 | .93 (.66–1.31) | .58 | .91 (.64–1.29) | .49 |
| Trimester 2 (11 678) | 129/21 621 (0.6) | 1.12 (.87–1.44) | .26 | 1.08 (.83–1.41) | .45 | 1.04 (.79–1.37) | .68 |
| Trimester 3 (12 931) | 114/24 114 (0.5) | .89 (.68–1.16) | .25 | .87 (.66–1.14) | .18 | .85 (.65–1.13) | .14 |
A priori confounders were maternal age, maternal ethnicity, region, and influenza season. Other potential confounders included the number of weeks the first trimester overlapped with a period of influenza activity above baseline levels as well as the following maternal factors: IMD, number of children in the household, smoking status, hazardous drinking, extreme BMI, clinical risk group, chronic hypertension, and exposure to teratogenic drugs and/or live vaccines.
Abbreviations: BMI, body mass index; CI, confidence interval; HR, hazard ratio; IMD, Index of Multiple Deprivation; MCM, major congenital malformation.
Sensitivity Analyses
Sensitivity analyses that included 216 additional pregnancies for which vaccination occurred 4 weeks prior to their estimated start, or allowed for follow-up in HES and ONS data to continue after follow-up in CPRD had ended, or excluded 8093 pregnancies of women with unknown BMI did not differ substantially from the main analyses (Table 4).
Table 4.
Examining the Association Between First-Trimester Vaccination and Major Congenital Malformations in Sensitivity Analyses
| Models | HR, Unadjusted (99% CI) | P | HR, Adjusted for A Priori Confounders (99% CI) | P | HR, Adjusted for All Potential Confounders (99% CI) | P |
|---|---|---|---|---|---|---|
| Models including MCMs diagnosed in the year after delivery | ||||||
| Main model | 1.17 (1.04–1.32) | <.001 | 1.08 (.96–1.22) | .11 | 1.06 (.94–1.19) | .23 |
| Including pregnancies vaccinated in the 4 weeks prior to the starta | 1.19 (1.06–1.33) | <.001 | 1.09 (.97–1.23) | .06 | 1.07 (.95–1.21) | .14 |
| Including diagnoses made beyond truncation of follow-up in CPRDb | 1.17 (1.04–1.32) | <.001 | 1.08 (.96–1.22) | .11 | 1.06 (.94–1.19) | .23 |
| Excluding pregnancies with unknown BMIc | 1.18 (1.05–1.33) | <.001 | 1.09 (.96–1.23) | .09 | 1.07 (.94–1.21) | .19 |
| Models including MCMs diagnosed after delivery and anytime in the study period | ||||||
| Main model | 1.18 (1.05–1.32) | <.001 | 1.09 (.97–1.22) | .07 | 1.07 (.95–1.20) | .16 |
| Including pregnancies vaccinated in the 4 weeks prior to the starta | 1.19 (1.07–1.33) | <.001 | 1.10 (.98–1.24) | .03 | 1.08 (.96–1.21) | .09 |
| Including diagnoses made beyond truncation of follow-up in CPRDd | 1.17 (1.05–1.31) | <.001 | 1.09 (.97–1.22) | .06 | 1.07 (.95–1.20) | .14 |
| Excluding pregnancies with unknown BMIc | 1.18 (1.05–1.33) | <.001 | 1.09 (.96–1.23) | .08 | 1.07 (.95–1.21) | .16 |
A priori confounders were maternal age, maternal ethnicity, region, and influenza season. Other potential confounders included the number of weeks the first trimester overlapped with a period of influenza activity above baseline levels as well as the following maternal factors: IMD, number of children in the household, smoking status, hazardous drinking, extreme BMI, clinical risk group, chronic hypertension, and exposure to teratogenic drugs and/or live vaccines.
Abbreviations: BMI, body mass index; CI, confidence interval; CPRD, Clinical Practice Research Datalink; HES, Hospital Episode Statistics database; HR, hazard ratio; IMD, Index of Multiple Deprivation; MCM, major congenital malformation; ONS, Office for National Statistics death certificate data.
aThis model included an additional 216 pregnancies with a vaccination in the 4 weeks before the pregnancy start.
bThere were 22 infants with an MCM recorded in HES or ONS after follow-up in the CPRD had ended.
cThis model excluded 8093 pregnancies that belonged to women with unknown BMI.
dThere were 110 infants with an MCM recorded in HES or ONS after follow-up in the CPRD had ended.
DISCUSSION
This UK-based historical cohort study examined the association between SIV during pregnancy and MCMs in live-born infants, between the 2010/2011 and 2015/2016 influenza seasons. Based on 6872 pregnancies vaccinated in the first trimester, there was no evidence for an association with MCMs recorded in the year after delivery (adjusted HR, 1.06; 99% CI, .94–1.19; P = .2). No evidence of an association was seen in analyses assessing subsequent trimesters or pregnancy overall or analyses including MCMs recorded after delivery and anytime in the study period. Analyses of major limb and congenital heart defects adjusted for confounding also showed no evidence for an association with first-trimester or later vaccination.
Strengths
Reviews examining the safety of influenza vaccination with respect to MCMs have highlighted the limited number of studies examining first-trimester vaccination with SIV. Among the few such studies, further limitations such as the low number of pregnant women vaccinated in the first trimester and short follow-up time of infants have prompted calls for further safety evidence [7, 8, 10, 11].
The utilization of the Pregnancy Register, which includes information on trimester dates, allowed for the identification of a large number of pregnant women vaccinated in the first trimester. Follow-up in most studies has been limited to the immediate period around delivery [13–15]. While a few studies have attempted follow-up for the year after delivery [12, 16], extending follow-up beyond 1 year has been shown to still increase the prevalence of recorded MCMs in CPRD [18, 19, 29]. The majority of infants in our cohort had at least 1 year of follow-up and almost half had at least 2 years of follow-up. The value of longer follow-up is demonstrated by the fact that 12.8% of MCMs in our cohort were identified after 3 months and 5.3% after 1 year.
A further strength of this study was the linkage of CPRD data to HES and ONS to maximize MCM ascertainment. Previous research suggests that reliance on sole data sources can lead to significant underascertainment of conditions [30]. This may be particularly true for MCMs, many of which are likely to be identified in hospital and communicated in letters not available to researchers in the electronic primary care record unless encoded, which may be incomplete or delayed. Linkage to ONS further serves to ascertain those cases that may have been detected following the infant’s death. For completeness, we also examined MCM recordings made in HES or ONS after follow-up in CPRD had ended, but this made minimal difference.
Limitations
While our study had a number of strengths, there were also limitations. Coding algorithms to identify MCMs were developed in accordance with EUROCAT guidelines and with a consultant neonatologist. The few studies that have assessed the positive-predictive value of MCMs recorded in CPRD have found this to be good overall (78–86%), with results for congenital heart defects being above 90% [31–34]. However, validation of diagnoses in HES has not been undertaken.
The estimate of gestation at the time of vaccination is based on the Pregnancy Register’s use of a wide range of information recorded in primary care, which is thought to give rise to increased accuracy. However, any imprecision in the estimated pregnancy start date could result in misclassification of the timing of vaccination during pregnancy. Sensitivity analyses including pregnant women who received SIV in the 4 weeks prior to their pregnancy start went some way in addressing this and did not reveal evidence for an association with MCMs. In addition to the above, while general practitioners are required to document vaccinations received outside of the surgery and the maternal influenza vaccination program was delivered almost entirely through general practices over the study period, misclassification of vaccination could potentially occur if women were vaccinated elsewhere and practitioners were not notified [35].
We adjusted for a number of potential confounders but were not always able to determine maternal smoking, hazardous drinking, or BMI at the start of pregnancy and sometimes had to rely on the most proximate record. Although in our main analyses women with unknown BMI were categorized as not having any evidence of extreme BMI, our sensitivity analyses excluding these pregnancies yielded similar results. We cannot discount the possibility of residual confounding from other risk factors for MCMs that may also be associated with vaccine uptake in pregnancy and that are likely to be poorly recorded in the CPRD, such as religion [36].
This study only examined live-birth pregnancies with linked infant records, excluding 10.6% of pregnancies because they lacked linkage. There are many reasons for nonlinkage, including the general practice ending data contributions to CPRD or the mothers moving away. It is possible that severe malformations resulting in the death or prolonged hospitalization of neonates could also prevent linkage, but it seems unlikely that this incomplete ascertainment would depend on maternal vaccination status. This study also did not explore any potential role of malformations on the causal pathway between vaccination and pregnancy losses. However, studies thus far have found no evidence for an association between vaccination and such outcomes [10, 37, 38].
Comparison With Other Studies
Our results are consistent with those from other studies that have examined SIV receipt during pregnancy and have shown no association with MCMs; this includes analyses of first-trimester vaccination for which point estimates from other studies ranged between 0.67 and 1.91, with CIs including the null [12, 13, 15, 16]. Reassuringly, our point estimates for MCMs following first-trimester vaccination are in line with those from the largest study to date, which examined SIV receipt between 2004 and 2013 in the United States (adjusted prevalence ratio, 1.02; 95% CI, .94–1.10; P = .55) [16]. Ours is the next largest study and provides further evidence on the safety of SIV during pregnancy in another setting and for subsequent years using a recently developed Pregnancy Register that considers all available data in the CPRD to estimate gestation at the time of vaccination as well as maximizing ascertainment of MCMs through long-term follow-up in linked data.
The lack of an association between first-trimester vaccination and congenital heart defects in our study was consistent with results from 2 other studies, including the large US study [13, 16]. While other studies have examined limb malformations and have not found any association with vaccination, they have grouped these with defects in other organ systems or examined a limited selection of particular diagnoses such as talipes equinovarus (clubfoot) [13, 16]. This study assessed all major limb malformations as a stand-alone subgroup and confirmed the lack of association with SIV.
CONCLUSIONS
The findings from this large cohort study, in which the majority of infants were followed up for at least 1 year, provide further evidence on the safety profile of influenza vaccination in pregnancy. There was no evidence for an association between first-trimester vaccination and MCMs, limb malformations, or congenital heart defects after controlling for confounding. This study shows ongoing monitoring of the safety of first-trimester vaccination is possible using CPRD and could usefully include additional MCM subgroups when sufficient numbers become available.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Author contributions. Study concept and design: all authors. Acquisition of data: S. L. T., C. M., M. P., P. M., J. L. W., and N. J. A. Analysis and interpretation of data: M. P., S. L. T., P. M., C. M., H. I. M., J. L. W., and N. J. A. Drafting of the manuscript: M. P., P. M., C. M., and H. I. M. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: M. P., S. L. T., C. M., J. L. W., and N. J. A. Obtained funding: S. L. T., and P. M. and M. P. had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the analyses.
Disclaimer. The views expressed are those of the authors and not necessarily those of the National Institute for Health Research (NIHR) or the Department of Health and Social Care. The funding agency was not involved in the study design, data collection, data management, analysis or interpretation. There was no involvement of the funding agency in the preparation, review or approval of the manuscript for submission for publication.
Financial support. This work was supported by the National Institute for Health Research Health Protection Research Unit in Immunisation at the London School of Hygiene and Tropical Medicine in partnership with Public Health England (grant number EPIDZD03). P. M. reports grants from the Medical Research Council and Biotechnology and Biological Sciences Research Council, and grants and travel costs from the World Health Organization Global Advisory Committee on Vaccine Safety, outside the submitted work.
Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
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