Comparison of Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications in a Multinational, Population-Based Cohort

Key Points Question What is the association between ondansetron exposure during pregnancy and the risk of adverse fetal outcomes? Findings In this meta-analysis of cohort studies of 456 963 pregnancies in 3 countries, treatment with ondansetron was not significantly associated with increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with other antiemetics. Meaning These findings suggest that ondansetron use during pregnancy is not associated with an increased risk of adverse fetal outcomes compared with the use of other antiemetics.


EAPPENDIX 2: IDENTIFICATION OF OUTCOME EVENTS
The table below provides information on the eligible windows during pregnancy and exposure in which events were counted in the analyses of primary and secondary outcomes. Note: the term COHORTENTRY_GA was the gestational age (GA) in days when a study or comparator drug is first initiated, and OUTCOME_GA was gestational age on the date the outcome event occurred. These terms were not used in the manuscript text.

Termination of Pregnancy for Fetal Anomaly (TOPFA, included with induced abortions in the analysis)
TOPFFA included a code for induced abortion, co-occurring with one (or more) of the following during the same care episode (i.e., hospitalization or service date) as the induced abortion code: 2. We extract all hospitalizations with any diagnosis code of a congenital malformation (based on codes in the table below) and admission date. For records with ICD-9, we checked each diagnosis variable individually, and selected the record if the code was included in Column 'B' but not in Column 'C'. For example, if the diagnosis code was 743.
x, but not 743.6 or 743.8, then we included the malformation. If the code was 743.6 we excluded the malformation. We repeated this process using Columns 'D' and 'E'. Congenital malformations were excluded if they were on our list of excluded malformations defined in the following two tables. Regarding the CPRD, we included pregnancies identified in the CPRD pregnancy register, which uses a validated algorithm (https://pubmed.ncbi.nlm.nih.gov/31197928/) to identify pregnancies from the general practitioner records. This register includes a unique identifier for the mother and pregnancy, the date of delivery, the estimated gestational age, and the pregnancy outcome. We used the 'Gold' version of the CPRD, as a pregnancy register is not yet available for CPRD AURUM. CPRD primary care records (including the pregnancy register) were linked to hospitalization data (acute patient care and maternity) from Hospital Episode Statistics (HES) and Office for National Statistics (ONS) vital statistics data, with inclusion restricted to linkable patients. Pregnancy outcomes were defined using the outcome variable in the CPRD pregnancy register. Congenital malformations were defined using diagnoses recorded in maternal and offspring CPRD and HES records, with the offspring identified using the Mother-Baby linkage. Comorbidities were defined using Read codes in CPRD primary care data and ICD-10 codes from HES, and prescription drug information was assessed using product codes and BNF codes recorded in general practitioner prescription records. ONS vital statistics data were used to supplement CPRD and HES data to define censoring.
For the CPRD analysis of congenital malformations, we used the CPRD Mother-Baby link to identify the offspring records in the CPRD. The Mother-Baby Link was created using a cartesian join of mothers to babies using the general practitioner practice identification number and the practice-specific family number, with inclusion restricted to records whose delivery date and estimated birth date are within 60 days.
For the main analysis, exposure was assessed as follows: Once a woman was exposed to ondansetron or a comparator antiemetic, she was considered exposed until the end of the follow-up (end of pregnancy).
Once a woman started contributing person-time to the comparator antiemetic category, she could only subsequently switch her exposure status to ondansetron. If a woman tried another antiemetic after ondansetron, her exposure status remained defined as ondansetron-exposed.
A woman could not contribute person-time to two different exposure categories at the same time.
In rare instances where a woman started NVP pharmacotherapy simultaneously with ondansetron and a comparator antiemetic, she was assigned to the ondansetron-exposed category.
The table below provides information on the eligible windows during pregnancy during which exposure was assessed. Note: the term COHORTENTRYDT denotes the first day of pregnancy. This variable name was not used in the manuscript text. In order to enter cohort, exposed to a study and or comparator drug ≥COHORTENTRYDT, until, but not including, the outcome date (Sensitivity analysis of exposure between 4 and 10 weeks: In order to enter cohort, exposed to a study and or comparator drug ≥COHORTENTRYDT + 27 days, until the earliest of COHORTENTRYDT + 69 days or up to and including the day before the outcome; but NOT exposed to a study and or comparator drug ≥COHORTENTRYDT and < COHORTENTRYDT + 27) Secondary Outcomes Stillbirth In order to enter cohort, exposed to a study and or comparator drug ≥COHORTENTRYDT, until outcome date, until, but not including, the outcome date (Sensitivity analysis: In order to enter cohort, exposed to a study and or comparator drug ≥COHORTENTRYDT + 27 days, until the earliest of COHORTENTRYDT + 69 days, or up to and including the day before the outcome; but NOT exposed to a study and or comparator drug ≥COHORTENTRYDT and < COHORTENTRYDT + 27) Spontaneous Abortion In order to enter cohort, exposed to a study and or comparator drug ≥COHORTENTRYDT, until the earliest of COHORTENTRYDT + 140 days, or up to and including the day before the outcome (Sensitivity analysis: In order to enter cohort, exposed to a study and or comparator drug ≥COHORTENTRYDT + 27 days, until the earliest of COHORTENTRYDT + 69 days, or up to and including the day before the outcome; but NOT exposed to a study and or comparator drug ≥COHORTENTRYDT and < COHORTENTRYDT + 27) Major Congenital Malformation In order to enter cohort, exposed to a study and or comparator drug COHORTENTRYDT to COHORTENTRYDT + 83 days, inclusive. (Sensitivity analysis: In order to enter cohort, exposed to a study and or comparator drug ≥COHORTENTRYDT + 27 days, until COHORTENTRYDT + 69 days, inclusive)