Over 700 000 women in the third trimester of pregnancy were to be offered vaccination in the UK over the first year. Given relatively high background rates for several adverse outcomes during pregnancy, particularly stillbirth, it was inevitable that such events would occur in temporal association with vaccination, regardless of causality. The key challenges were to quickly identify any evidence of risks attributable to the vaccine so that any required action could be taken and, in the absence of such evidence, to provide robust safety data to support public health.

In 2011-12, the UK saw the largest pertussis outbreak for over a decade, with 14 deaths in 2012 in infants born before the start of the pregnancy vaccination campaign who were too young to be vaccinated themselves. The pertussis vaccination in pregnancy programme was an important public health intervention aimed at reducing morbidity and mortality in infants.

Strengths and limitations of the study

Given the high uptake of the vaccine,21 the size of the database, and that vaccination was almost exclusively in primary care we were able to quickly identify a large number of vaccinated pregnant women with rapid data on outcomes. To comprehensively monitor the safety profile of the vaccination in pregnancy, optimise the use of all the available data, and overcome some of the limitations of observational studies conducted with GP data, we took several different approaches to the analysis. By comparing post-vaccination event rates from the CPRD with background data from external sources where available, we were able to consider the impact of any changes in GP recording practices. The different approaches taken to the study design add weight to the findings, with the analysis on short term risk using as much of the data as possible to maximise power, while the analyses looking at total risk after vaccination were designed to reduce confounding by accounting for changes in risk with gestational and maternal age.

We analysed data amassed six months after the start of the vaccination programme. Given that this study was designed to monitor the safety profile of the pertussis vaccine in pregnancy on a continuous basis we made no a priori calculations on the power of the study. Our results showed no significantly increased risks, and, indeed, confidence intervals are such that in general we can exclude twofold risks. The analysis presented, however, cannot rule out smaller increases in risk, and the short study period limits the possibility of examining longer term adverse events. The vaccination programme remains ongoing, and the MHRA continues to monitor the safety of the vaccine in pregnancy with the aim of identifying any smaller increases in the risk of adverse events related to pregnancy as well as longer term safety.

There is, of course, the potential for unmeasured confounding. Given the nature of this study, designed as it was to be analysed as soon as data became available to provide rapid safety data, we did not fully adjust for potential confounders. In particular, smoking, alcohol and drug use, parity, socioeconomic status, and some drug treatments are known to be associated with the risk of adverse events in pregnancy and were not adjusted for in this study. We did, however, account for two of the potentially most important confounders: maternal and gestational age.

It is possible that women choosing not to be vaccinated have inherently different risks because of unmeasured confounders such as concomitant drug treatment, medical and obstetric history, smoking, and body mass index. The sensitivity analysis including all women with a pregnancy outcome during the campaign, regardless of vaccination status, however, found no significant increases in the risk of any of the predefined adverse events related to pregnancy before and after the introduction of the vaccination campaign, suggesting that unmeasured confounding has not masked any safety signals here, assuming there have been no significant changes in the characteristics of the pregnant population.

Despite the use of constraints on the follow-up time required for patients to be eligible for analysis to try to allow for recording delay, there is still the possibility of missing event data in the CPRD. In particular, data on events in women presenting to hospital might not be recorded, meaning that we are underestimating the rate of adverse events. The severity of the events, and the fact that women experiencing them would subsequently be monitored by their GP, however, means that missing data should be minimal, though this is still a limitation of general practice electronic medical records data in general. In addition, we would not expect the level of missing data to have changed significantly within the study period so internal comparisons of event rates would remain valid. The sensitivity and specificity of the mother-child link is unknown, meaning that we could be missing some data on the child record, but again we would not expect the linkage to be substantially different between the vaccinated and historical unvaccinated cohorts.

Given that the recommendation was for vaccination in the third trimester of pregnancy, the risk of congenital malformations was not prespecified as an adverse event of interest. However, this is continuously monitored through routine pharmacovigilance, and no signal of an increased risk has been raised. It should also be noted that no safety concerns were raised for any adverse event related to pregnancy through spontaneous suspected adverse reaction reports through the UK Yellow Card scheme (www.mhra.gov.uk/yellowcard).

We did not evaluate the effectiveness of the vaccine or the impact of the immunisation campaign on control of pertussis. Public Health England has in place a programme to evaluate these outcomes, which are important factors to balance against the evidence of safety. A further limitation of the study is that we could not evaluate factors such as optimal timing of vaccination or persistence of maternal antibody, which could influence the best timing of booster doses in future pregnancies, or the potential for transplacental antibody to interfere with the infant response to the primary immunisation schedule. These are important aspects relevant to the overall safety and effectiveness of the immunisation campaign and require further research.