- Medication and Pregnancy KB

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Anderka, 2012	case control	Histories of NVP and treatments obtained from a standardized computer- assisted telephone interview with the mother. Data were collected by month for the first trimester and by trimester for the second and third trimesters.	Case infants (over 30 different birth defects) are identified prenatally, at birth or during the first year of life from surveillance systems (10 participating states). 9 sites also collected fetal deaths at 20 GW or greater and 8 sites collected diagnosed and electively terminated.	Potential confounders for the adjusted analyses were selected a priori: maternal age, race-ethnicity, education, parity, smoking in the month before conception through the first trimester, plurality, previous miscarriage, infant sex, use of folic acid, body mass index (BMI), study site, and year of expected date of delivery.
Andersen, 2013	population based cohort retrospective	National Prescription Register	National Hospital Register	Authors reported an adjusted OR but the potential confounders considered are not mentioned.
Bérard, 2019	population based cohort propective	The Quebec Prescription Drug Insurance Plan administered by the Régie de l’assurance maladie du Quebec (RAMQ)	MCMs were identified in the Régie de l’assurance maladie du Quebec (RAMQ) and MedEcho databases and defined according to ICD-9 and ICD-10 codes	Adjustment for diagnosis of NVP during pregnancy, demographic characteristics, exposure to folic acid, maternal comorbidities, use of health services in the year before.
Clements, 2015	case control	The Partners HealthCare EHR includes medication data.	The Partners HealthCare EHR includes sociodemographic data, billing codes, laboratory results, problem lists, vital signs, procedure reports and narrative notes from hospitals which are part of the Partners HealthCare system, and affiliated outpatient clinics.	Model 1 is adjusted/matched for gender, race, birth year, insurance type, maternal age and median income tertile. Model 2 is adjusted for variables in model 1 and past history of maternal depression.
Colvin, 2013	retrospective cohort (claims database)	The Australian Pharmaceutical Benefits Scheme (PBS)	Hospital Morbidity Data System (HMDS), the Midwives’ Notification System (MNS), the Registry of Births and Deaths, and the WA Birth Defects Registry (now called the WA Register of Developmental Anomalies (WARDA))	For preterm birth and threatened preterm labour, the odds ratios were adjusted for previous preterm birth, smoking during pregnancy, socio-economic index (SEIFA), parity, multiple birth, private insurance, and maternal age as these are known potential confounders. The risk of a postpartum haemorrhage was adjusted for Caesarean delivery, private insurance, and multiple birth.
Danielsson, 2014	population based cohort retrospective	Two sources were used for the identification of women who used ondansetron in early pregnancy: one was the midwife interviews at the first antenatal care visit of the pregnant woman (usually during weeks 10-12) and we also used the Swedish Prescription Register (dor the period 2006–2012).	Three sources: diagnoses given by the attending pediatrician in Medical Birth Register, Birth Defect Register (previously called the Register of Congenital Malformations), and discharge diagnoses from hospitalizations	Adjustment was made for year of birth, maternal age, parity, smoking in early pregnancy, and body mass index.
Einarson (Control exposed to other antiemetics), 2004	prospective cohort	Exposure (ondansetron and any concurrent anti-emetic or other medication) assessed by mother interviews: interviewers completed a standardised intake form that was used by both centres.	The women were contacted 4–6 months after delivery to obtain outcome data using a standardised follow up form. Then, the interviewer sent a letter to the caller’s physician asking for verification of the information obtained from the mother concerning the baby’s health.	None. There were no significant differences in the maternal characteristics be- tween the exposed and comparison groups, their ages were similar and very few smoked cigarettes or drank alcohol during pregnancy.
Einarson (Unexposed control), 2004	prospective cohort	Exposure (ondansetron and any concurrent anti-emetic or other medication) assessed by mother interviews: interviewers completed a standardised intake form that was used by both centres.	The women were contacted 4–6 months after delivery to obtain outcome data using a standardised follow up form. Then, the interviewer sent a letter to the caller’s physician asking for verification of the information obtained from the mother concerning the baby’s health.	None. There were no significant differences in the maternal characteristics be- tween the exposed and comparison groups, their ages were similar and very few smoked cigarettes or drank alcohol during pregnancy.
Fejzo, 2015	case control	Participants were asked to submit their medical records and complete an online survey regarding treatment.	Participants were asked to submit their medical records and complete an online survey regarding outcomes. A follow-up survey was administered on the diagnosis of childhood emotional, behavioral, and learning disorders.	Cases and controls were well-matched for mean maternal age, spontaneous labor, delivery method, and use of assisted reproduction. Children of cases and controls were well-matched for gender and age, with the average age between 8 and 9 years old.
Fejzo (Mainly exposed to other treatements, sick), 2016	retrospective cohort	Participants were asked to complete an online survey regarding detailed information on symptoms, treatments, including ondansetron. The majority of participants joined the study and began the survey during their pregnancies.	Participants were asked to complete an online survey regarding detailed information on symptoms and outcomes, including birth defects. The participants were automatically prompted to complete the survey on fetal outcome following their due date.	None
Fejzo (Unexposed control, disease free), 2016	retrospective cohort	Participants were asked to complete an online survey regarding detailed information on symptoms, treatments, including ondansetron. The majority of participants joined the study and began the survey during their pregnancies.	Participants were asked to complete an online survey regarding detailed information on symptoms and outcomes, including birth defects. The participants were automatically prompted to complete the survey on fetal outcome following their due date.	None
Huybrechts, 2019	retrospective cohort (claims database)	Prescriptions filled on an outpatient basis. (As described previously in Huybrechts, 2018)	The presence of congenital malformations was defined using algorithms based on inpatient or outpatient diagnoses and procedure codes in the maternal (first month after delivery) or infant (first 3 months after date of birth) record.	Propensity score (PS) fine stratification was used for confound- ing adjustment (50 strata based on the PS distribution in the exposed).
Huybrechts (Control exposed to other treatment), 2018	retrospective cohort (claims database)	Prescriptions filled on an outpatient basis.	The presence of congenital malformations was defined using algorithms based on inpatient or outpatient diagnoses and procedure codes in the maternal (first month after delivery) or infant (first 3 months after date of birth) record.	Several adjusted analyses considering some or all potential confounders (or proxies) including treatment indication (nausea and vomiting during pregnancy, hyperemesis gravidarum) and associated conditions (weight loss, dehydration, ...), calendar year, state of residence, age, race, multiple gestation, maternal conditions, concomitant medications, and general markers of the burden of illness.
Huybrechts (Unexposed control), 2018	retrospective cohort (claims database)	Prescriptions filled on an outpatient basis.	The presence of congenital malformations was defined using algorithms based on inpatient or outpatient diagnoses and procedure codes in the maternal (first month after delivery) or infant (first 3 months after date of birth) record.	Several adjusted analyses considering some or all potential confounders (or proxies) including treatment indication (nausea and vomiting during pregnancy, hyperemesis gravidarum) and associated conditions (weight loss, dehydration, ...), calendar year, state of residence, age, race, multiple gestation, maternal conditions, concomitant medications, and general markers of the burden of illness.
Kerr, 2018	case control	Within 6 months of delivery, trained Birth Defects Study (BDS) nurse- interviewers contacted mothers to complete a roughly 1-hr computer-assisted telephone interview, including medications during pregnancy.	Cases and controls were ascertained at participating hospitals or birth defect registries in the same areas.	Adjusted models included maternal age, race/ethnicity, education, study center, and study year (aORs were calculated when there were five or more exposed cases).
Lemon, 2019	retrospective cohort (claims database)	Extracted from both the inpatient electronic medical record for treatment administered within the hospital and through insurance claims for outpatient prescriptions.	The Magee Obstetric, Medical, and Infant (MOMI) Database, a registry of all deliveries at the hospital linked with claims from UPMC Health Plan and to the inpatient (hospitalization) and outpatient (clinic visit) electronic medical records.	Adjusted for nausea/vomiting/hyperemesis/gastrointestinal infection, encounters, insurance type, maternal age, race, years of education, marital status, pre-gravid BMI, parity, history of intrauterine death, drug use, arrhythmia, chronic hypertension, collagen vascular disease, diabetes (any), maternal structural heart disease, nuchal measurement, smoking and patient of Magee-resident clinic.
Lind, 2013	case control	The National Birth Defects Prevention Study uses computer-assisted telephone interviews to collect information from women 6 weeks to 24 months after their estimated date of delivery on exposures (notably prescription or over-the-counter medications).	Cases are identified through population-based birth defects surveillance from each states. A clinical geneticist classifies eligible cases of hypospadias. Controls are selected randomly from vital records or birth logs to represent the population from which the birth defects cases were ascertained.	Adjusted for maternal age, race/ethnicity, education, pre-pregnancy Body mass index, previous live births, sub-fertility, study site, and year of due date.
Marciniak, 2015	randomized controlled trial	Patients were randomly assigned to two groups: one group received 8 mg of intravenous ondansetron and the other group received 10 ml of isotonic sodium chloride (placebo group).	Apgar scores determined by staff after caesarean section.	No adjustment. Randomisation.
Oofuvong, 2018	randomized controlled trial	Before spinal anesthesia was performed, the 4 mL clear solution containing the allocated treatment was administered intravenously five min before spinal anesthesia.	The incidence of hypotension maternal complications during the intraoperative period and in the post- anesthetic care unit and neonatal complications were reported by investigators.	Post-hoc analysis was performed for multiple comparisons between groups when the overall differences were significant.
Ozdemirci, 2014	retrospective cohort	The patients in ondansetron group treated with 8 mg ondansetron once a day intravenously. The patients in chlorpromazine group treated with 12.5 mg chlorpromazine twice a day intravenously.	Pregnancy outcome including still- birth, low birth weight, congenital anomaly, pregnancy com- plications (preterm birth, pregnancy induced hypertension) were evaluated. (NOS)	None
Parker, BDS study, 2018	case control	Among women with nausea and vomiting of pregnancy, both studies used standardized interviews to capture treatments with prescription and nonprescription medications, herbal products, and supplements.	Case and control participants were identified by review of discharge records or registry data at participating hospitals or birth defect registries.	Controls matched on the areas.
Parker, NBDPS study, 2018	case control	Among women with nausea and vomiting of pregnancy, both studies used standardized interviews to capture treatments with prescription and nonprescription medications, herbal products, and supplements.	NBDPS identified more than 30 selected major birth defects among live births, stillbirths, and (in selected sites) elective terminations through surveillance programs in 10 states.	All adjusted models include the following covariates selected a priori: maternal age, maternal education, periconceptional folic acid use, study year and study site.
Pasternak, 2013	population based cohort retrospective	National Prescription Registry used to identify prescriptions	The National Patient Register for major birth defects and spontaneous abortion Medical Birth Registry for Preterm delivery, infants born small for gestational age or low birth weight and stillbirth.	Propensity-score matching. Estimation of propensity scores then women who had been exposed to ondansetron were matched, in a 1:4 ratio, to unexposed women in accordance with the nearest-neighbor–matching algorithm. Additionally matched on gestation age for spontaneous abortion and stillbirth.
Shahraki, 2016	randomized controlled trial	Pregnant females were randomly assigned to receive Package “A” contained ondansetron tablets (4 mg) or package “B” vitamin B6 tablets (40 mg), one tablet twice daily. Treatments were initiated on an average of 4 to 16 weeks gestation.	Pregnant females were routinely followed up until delivery and neonatal outcomes including any congenital anomaly, weight, height and head circumference at birth were finally assessed and compared between the two groups.	No adjustment. Randomisation.
Werler, 2014	case control	Mothers were interviewed by telephone within 12 months after delivery about medication use, including indication, product, timing, and frequency.	Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina. Mothers were then interviewed and an orthopedist reviewed the children’s pediatric and orthopedic records (77% agreed). Controls identified from birth certificates or hospital records.	Odds ratios were adjusted for study site, first born, sex, body mass index, and maternal smoking through Lunar Months 4. Confounding by the use of multiple medications was assessed. Analysis with exclusion of first-degree history of clubfoot.
Zambelli-Weiner (Unexposed control, NOS), 2019	nested case control	Medical administrations of ondansetron were obtained from the MarketScan Commercial database, which comprised of adjudicated data mostly from self-insured companies. First trimester exposure was defined as the 91 days following the estimated conception date.	Inpatient and outpatient medical care and other resource utilization were obtained from the MarketScan Commercial database, which comprised of adjudicated data mostly from self-insured companies. Cases were identified as having one or more claims with a relevant diagnosis code.	OR are adjusted for: mother’s age, infant year of birth, and infant gender.
Zambelli-Weiner (Unexposed control, sick), 2019	nested case control	Medical administrations of ondansetron were obtained from the MarketScan Commercial database, which comprised of adjudicated data mostly from self-insured companies. First trimester exposure was defined as the 91 days following the estimated conception date.	Inpatient and outpatient medical care and other resource utilization were obtained from the MarketScan Commercial database, which comprised of adjudicated data mostly from self-insured companies. Cases were identified as having one or more claims with a relevant diagnosis code.	OR are adjusted for: mother’s age, infant year of birth, infant gender and for confounding by Indication

master protocol