Safety of five years of pertussis vaccination in pregnancy in England: a cohort study

Date of ISAC Approval: 
Lay Summary: 
Whooping cough (‘pertussis’) can cause serious illness, particularly in young babies. Since October 2012, pregnant women in the UK have been offered pertussis vaccine. This was introduced in response to an increase in cases of whooping cough, which particularly affected babies under 3 months old. Vaccination in pregnancy aims to protect infants against whooping cough, from vaccine antibody transferral from mother to the unborn child. Pertussis vaccination for pregnant women is a recent change, and it is important to monitor the safety of this new programme. Safety studies globally have included nearly 150 000 vaccinated women in total. The results have been reassuring and consistent, however, some questions remain which we will look at in this study. First we will assess whether there may be a small increased risk of infection of the fluid in the womb (‘chorioamnionitis’) or bleeding after birth (‘postpartum haemorrhage’), next we will look at safety using longer term follow-up of babies for birth defects, and finally we will look at any effects of changes to the vaccine brand and recommended stage of pregnancy that the vaccine is given. To do this study we will compare pregnant women who were vaccinated to pregnant women who were not vaccinated. We will look at death of the mother, stillbirth or death of a baby soon after birth, premature birth, chorioamnionitis, postpartum haemorrhage and major birth defects. This study will inform vaccine safety monitoring by Public Health England and the Medicines and Healthcare products Regulatory Agency.
Technical Summary: 
Pertussis vaccination in pregnancy was introduced in the UK in October 2012, in response to a national outbreak with the highest incidence, hospitalisation and death in infants under 3 months old. A recent systematic review identified 16 international safety studies, including 150 000 women. Results are generally reassuring, but there are research gaps. Some (but not all) previous studies found a signal for an association of vaccination with postpartum haemorrhage and with chorioamnionitis (but not its expected consequence of preterm delivery) and length of follow up has been insufficient for ascertainment of congenital malformations diagnosed after birth. Using a cohort study design, this study will examine whether there is any association between vaccination in pregnancy and adverse maternal, foetal or infant outcomes which are severe (stillbirth, maternal death, neonatal death) or for which specific research gaps have been identified (chorioamnionitis, preterm delivery, postpartum haemorrhage, major congenital malformations) during the first 5 years of the programme. The LSHTM/CPRD Pregnancy Register will be used to identify pregnant women eligible for vaccination. The main analysis will compare adverse outcomes among women vaccinated in pregnancy to concurrent eligible but unvaccinated pregnant controls. Multivariable Cox regression models will be used to adjust for confounding by gestational age for analyses of stillbirth, maternal death, preterm delivery, and to adjust for length of follow up for analysis of congenital malformations. Multivariable logistic regression models will be used for analyses of neonatal mortality, postpartum haemorrhage and chorioamnionitis. A secondary analysis will examine whether the two different vaccines used during the programme, or vaccination earlier in pregnancy are associated with adverse outcomes. A sensitivity analysis will compare rates of stillbirth, maternal death and neonatal death among women vaccinated in pregnancy to historical controls (matched on maternal age and gestation) using conditional Poisson regression, to update an earlier MHRA analysis.
Health Outcomes to be Measured: 
Primary: Stillbirth; maternal death; neonatal death Secondary: chorioamnionitis; preterm delivery; post partum haemorrhage; major congenital malformations.

Dr Helen McDonald - Chief Investigator - Imperial College Healthcare NHS Trust
Miss Caroline Minassian - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Dr Christopher Rentsch - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Dr Gayatri Amirthalingam - Collaborator - Public Health England
Ms Helen Campbell - Collaborator - Public Health England
Dr Helen McDonald - Corresponding Applicant - Imperial College Healthcare NHS Trust
Dr Julia Stowe - Collaborator - Public Health England
Katherine Donegan - Collaborator - MHRA
Maria Peppa - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)
Professor Nick Andrews - Collaborator - Public Health England
Dr Philip Bryan - Collaborator - MHRA
Professor Punam Mangtani - Collaborator - London School of Hygiene & Tropical Medicine (LSHTM)

HES Admitted;Mother Baby Link;ONS;Patient IMD;Practice IMD (Standard);Practice IMD (Standard);Pregnancy Register