Facilitating safety evaluation in maternal immunization trials: a retrospective cohort study to assess pregnancy outcomes and events of interest in low-risk pregnancies in England

Abstract

Background Maternal characteristics like medical history and health-related risk factors can influence the incidence of pregnancy outcomes and pregnancy-related events of interest (EIs). Data on the incidence of these endpoints in low-risk pregnant women are needed for appropriate external safety comparisons in maternal immunization trials. To address this need, this study estimated the incidence proportions of pregnancy outcomes and pregnancy-related EIs in different pregnancy cohorts (including low-risk pregnancies) in England, contained in the Clinical Practice Research Datalink (CPRD) Pregnancy Register linked to Hospital Episode Statistics (HES) between 2005 and 2017. Methods The incidence proportions of 7 pregnancy outcomes and 15 EIs were calculated for: (1) all pregnancies (AP) represented in the CPRD Pregnancy Register linked to HES (AP cohort; N = 298 155), (2) all pregnancies with a gestational age (GA) ≥ 24 weeks (AP24+ cohort; N = 208 328), and (3) low-risk pregnancies (LR cohort; N = 137 932) with a GA ≥ 24 weeks and no diagnosis of predefined high-risk medical conditions until 24 weeks GA. Results Miscarriage was the most common adverse pregnancy outcome in the AP cohort (1 379.5 per 10 000 pregnancies) but could not be assessed in the other cohorts because these only included pregnancies with a GA ≥ 24 weeks, and miscarriages with GA ≥ 24 weeks were reclassified as stillbirths. Preterm delivery (< 37 weeks GA) was the most common adverse pregnancy outcome in the AP24+ and LR cohorts (742.9 and 680.0 per 10 000 pregnancies, respectively). Focusing on the cohorts with a GA ≥ 24 weeks, the most common pregnancy-related EIs in the AP24+ and LR cohorts were fetal/perinatal distress or asphyxia (1 824.3 and 1 833.0 per 10 000 pregnancies), vaginal/intrauterine hemorrhage (799.2 and 729.0 per 10 000 pregnancies), and labor protraction/arrest disorders (752.4 and 774.5 per 10 000 pregnancies). Conclusions This study generated incidence proportions of pregnancy outcomes and pregnancy-related EIs from the CPRD for different pregnancy cohorts, including low-risk pregnancies. The reported incidence proportions of pregnancy outcomes and pregnancy-related EIs are largely consistent with external estimates. These results may facilitate the interpretation of safety data from maternal immunization trials and the safety monitoring of maternal vaccines. They may also be of interest for any intervention studied in populations of pregnant women.

Adverse infant outcomes following low-risk pregnancies in England: a retrospective cohort study

“…18_144RA) and has been made available to the journal reviewers. Detailed methods are presented in the accompanying paper describing pregnancy outcomes and pregnancy-related events of interest from the same study [ 10 ]. An overview of the key elements of the study design and methodology are presented here.…”

“…Pregnancies associated with multiple births (e.g., twins, triplets) and with an unknown outcome were excluded. Exclusion criteria are reported in detail in the accompanying paper [ 10 ].

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“…As described previously [ 10 ], three maternal cohorts were defined. The All Pregnancies cohort (AP cohort), including all eligible pregnancies, the All Pregnancies ≥ 24 weeks GA cohort (AP24 + cohort), including all pregnancies fulfilling the aforementioned criteria and excluding those with a GA record that did not reach 24 0/7 weeks (calculated using the variable in the Pregnancy Register: “gestdays” < 168 days) and a Low-Risk cohort (LR cohort), including pregnancies from the AP24 + cohort without diagnosis of select high-risk medical conditions or procedures in the woman’s medical history (including all available medical history prior to the start of pregnancy through 24 0/7 weeks GA) as detailed in the accompanying paper [ 10 ].…”

“…As described previously [ 10 ], three maternal cohorts were defined. The All Pregnancies cohort (AP cohort), including all eligible pregnancies, the All Pregnancies ≥ 24 weeks GA cohort (AP24 + cohort), including all pregnancies fulfilling the aforementioned criteria and excluding those with a GA record that did not reach 24 0/7 weeks (calculated using the variable in the Pregnancy Register: “gestdays” < 168 days) and a Low-Risk cohort (LR cohort), including pregnancies from the AP24 + cohort without diagnosis of select high-risk medical conditions or procedures in the woman’s medical history (including all available medical history prior to the start of pregnancy through 24 0/7 weeks GA) as detailed in the accompanying paper [ 10 ]. While the optimal window for administering a vaccine during pregnancy to maximize antibody transfer to the fetus has not been determined, the GA cut-off of 24 weeks reflects the cut-off chosen in previous group B streptococcus maternal immunization trials [ 16 – 18 ] and falls within the window during which maternal pertussis immunization is recommended in several countries [ 19 ].…”

“…The study also aimed to estimate the incidence proportions of pregnancy outcomes and pregnancy-related events of interest; these results are presented in an accompanying paper [ 10 ]. A plain language summary is provided in Fig.…”