Ondansetron

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Andersen
2013 		Denmark
1997 - 2010
population based cohort retrospective 		Medical Birth Registry, National Hospital Register and National Prescription Register First trimester users of ondansetron unexposed (general population or NOS)
Non-users of ondansetron 		1st trimester 1248 / 895770 Probable Typographic mistake (it should be considered OR = 2.0 (95% CI: 1.3–3.1) instead of OR = 2.0 (95% CI: 0.3–3.1) as mentioned in Danielsson 2014 and an other abstract of Andersen 2013 available in internet.
National Prescription Register
Bérard
2019 		Canada
1998 - 2015
population based cohort propective 		Quebec Pregnancy Cohort (QPC) Exposure was defined as having filled at least one prescription for ondansetron within the first trimester of pregnancy. unexposed (general population or NOS)
Pregnancies without prescription for doxylamine-pyridoxine, metoclopramide, or ondansetron within the first trimester of pregnancy. 		1st trimester 31 / 179106 EXPOSURE: 45,623 pregnancies exposed to doxylamine-pyridoxine; 958 to metoclopramide; 31 to ondansetron. TOTAL: 45770.
The Quebec Prescription Drug Insurance Plan administered by the Régie de l’assurance maladie du Quebec (RAMQ)
Colvin
2013 		Australia
2002 - 2005
retrospective cohort (claims database) 		Australian Pharmaceutical Benefits Scheme (PBS) linked to datasets in the Western Australian Data Linkage System (WADLS) All births in Western Australian (WA) where the mother was dispensed ondansetron under the Australian Pharmaceutical Benefits Scheme (PBS). unexposed (general population or NOS)
All other births during the same period 		1st trimester, during pregnancy (anytime or not specified) 263 / 98062
The Australian Pharmaceutical Benefits Scheme (PBS)
Danielsson
2014 		Sweden
1998 - 2012
population based cohort retrospective 		Swedish Medical Birth Register, Birth Defect Register (previously called the Register of Congenital Malformations), discharge diagnoses from hospitalizations, and the Swedish Register of Prescribed Drugs. Infants exposed in early pregnancy for ondansetron. unexposed (general population or NOS)
All infants of the cohort. 		early pregnancy 1349 / 1501434 The remaining malformations were called ”relatively severe” but may contain a few minor or poorly specified conditions. This concept broadly corresponds to major malformations.
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).
Einarson (Control exposed to other antiemetics)
2004 		Canada and Australia
A two year period
prospective cohort 		The Motherisk Program and the The Mothersafe Program Women who called either service, were taking ondansetron and were less than three months pregnant at the time of call (most were between 5 and 9 weeks of gestation) exposed to other treatment, sick
Women who called either service and who also suffered from NVP but were not exposed to ondansetron, they had used other anti-emetics, which included Diclectin, metoclopramide, phenothiazines and ginger. 		1st trimester 176 / 176
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.
Einarson (Unexposed control)
2004 		Canada and Australia
A two year period
prospective cohort 		The Motherisk Program and the The Mothersafe Program Women who called either service, were taking ondansetron and were less than three months pregnant at the time of call (most were between 5 and 9 weeks of gestation) unexposed, disease free
Women who called either service and were exposed to other drugs considered safe to use in pregnancy or those who had not used any medication. 		1st trimester 176 / 176
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.
Fejzo (Mainly exposed to other treatements, sick)
2016 		USA
2007 - 2014
retrospective cohort 		A larger investigation evaluating the genetics and epidemiology of Hyperemesis Gravidarum (HG) Women with a history of HG whose pregnancies were treated with ondansetron (O ) exposed to other treatment, sick
Women with a history of HG whose pregnancies were not treated with ondansetron (68.2% treated (iv/metoclopramide/promethazine)) 		1st trimester 1070 / 771
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.
Fejzo (Unexposed control, disease free)
2016 		USA
2007 - 2014
retrospective cohort 		A larger investigation evaluating the genetics and epidemiology of Hyperemesis Gravidarum (HG) Women with a history of HG whose pregnancies were treated with ondansetron (O ) unexposed, disease free
Women with no history of HG whose pregnancies were not treated with ondansetron (nor any medication/treatment for nausea/vomiting of pregnancy) 		1st trimester 1070 / 1555
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.
Huybrechts
2019 		USA
2000 - 2014
retrospective cohort (claims database) 		Medicaid Analytic eXtract (MAX) - Mother- infant–linked cohort nested in MAX. Women were considered exposed if a claim for Healthcare Common Procedure Coding System code J2405 indicating ondansetron injection was recorded during the first trimester of pregnancy. unexposed (general population or NOS)
Women without exposure to either oral or intravenous ondansetron from 3 months before the start of pregnancy through the end of the first trimester. 		1st trimester 23877 / 1762018 Women exposed to known teratogenic mediations were excluded from the cohort (ie, warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide).
Prescriptions filled on an outpatient basis. (As described previously in Huybrechts, 2018)
Huybrechts (Control exposed to other treatment)
2018 		USA
2000 - 2013
retrospective cohort (claims database) 		Medicaid Analytic eXtract (MAX) Women who filled at least 1 ondansetron prescription during the first 3 months of pregnancy. exposed to other treatment, sick
Women who filled a prescription during the first 90 days of pregnancy for pyridoxine (with or without doxylamine), promethazine, metoclopramide, or any of these alternative pharmacological treatments 		1st trimester 88467 / 185876 Exclusion of pregnancies to a known teratogenic medication (ie, warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) during the first trimester (n = 3562) and with a chromosomal abnormality (n = 3156)
Prescriptions filled on an outpatient basis.
Huybrechts (Unexposed control)
2018 		USA
2000 - 2013
retrospective cohort (claims database) 		Medicaid Analytic eXtract (MAX) Women who filled at least 1 ondansetron prescription during the first 3 months of pregnancy. unexposed (general population or NOS)
Women who did not fill a prescription for ondansetron during the 3 months before the start of pregnancy through the end of the first trimester. 		1st trimester 88467 / 1727947 Exclusion of pregnancies to a known teratogenic medication (ie, warfarin, antineoplastic agents, lithium, isotretinoin, misoprostol, thalidomide) during the first trimester (n = 3562) and with a chromosomal abnormality (n = 3156)
Prescriptions filled on an outpatient basis.
Lemon
2019 		USA
2006 - 2014
retrospective cohort (claims database) 		Magee–Womens Hospital of the University of Pittsburgh Medical Center (UPMC) Ondansetron exposure (intravenous and oral) during the first trimester of pregnancy. unexposed (general population or NOS)
Unexposed to ondansetron. 		1st trimester 3733 / 29944 Routes of administration were combined, as route is not expected to impact the association with VSD (n = 3171 oral; n = 1074 intravenous; n = 18 injection).
Extracted from both the inpatient electronic medical record for treatment administered within the hospital and through insurance claims for outpatient prescriptions.
Marciniak
2015 		Poland
Not specified
randomized controlled trial 		Not specified Patients were received 8 mg of intravenous ondansetron. unexposed, sick
Patients were received 10 ml of isotonic sodium chloride. 		late pregnancy 35 / 34 Birth weight, pH and
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).
Oofuvong
2018 		Thailand
2016 - 2017
randomized controlled trial 		Clinical trial in Songklanagarind Hospital Women receiving intravenously ondansetron 0.05 mg/kg (group O1) or ondansetron 0.1 mg/kg (group O2) (maximal dose of 8 mg). unexposed, sick
Women receiving intravenously either normal saline (group NS) 		late pregnancy 143 / 72 Results of Apgar scores not reported because they were presented as continuous variables (with Interquartile range).
Before spinal anesthesia was performed, the 4 mL clear solution containing the allocated treatment was administered intravenously five min before spinal anesthesia.
Ozdemirci
2014 		Turkey
2006 - 2011
retrospective cohort 		The computerized database of hyperemesis gravidarum (HG) patients at Simav Government Hospital Pregnancies less than 13 weeks treated with 8 mg ondansetron once a day intravenously exposed to other treatment, sick
Pregnancies less than 13 weeks treated with 12.5 mg chlorpromazine twice a day intravenously 		1st trimester 100 / 85
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.
Pasternak
2013 		Denmark
2004 - 2011
population based cohort retrospective 		Medical Birth Registry and the National Patient Register in Denmark Pregnant women who receive ondansetron throughout the exposure time window unexposed (general population or NOS)
Pregnant women who did not receive ondansetron throughout the exposure time window were categorized as “unexposed.” and propensity-score–matched 		1st trimester, during pregnancy (anytime or not specified), early pregnancy -9 / -9 Exposure time windows: the first trimester (through 12 GW) for any major birth defect, any time before 37 GW for preterm delivery, any time during pregnancy for birth weight, week 7 to 22 for spontaneous abortion, and week 7 until birth for stillbirth.
National Prescription Registry used to identify prescriptions
Shahraki
2016 		Iran
2014 - 2015
randomized controlled trial 		Amir-Almomenin hospital Ondansetron tablets (4 mg) to take one tablet twice daily, initiated on an average of 4 to 16 weeks gestation exposed to other treatment, sick
Vitamin B6 tablets (40 mg) to take one tablet twice daily, initiated on an average of 4 to 16 weeks gestation. 		during pregnancy (anytime or not specified) 88 / 100 No differences between the neonates in ondansetron and vita- min B6 groups regarding birth-weight (p = 0.67), height at birth (p = 0.75) and head circumference at birth (p = 0.56).
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.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Anderka
2012 		USA
1997 - 2004
case control 		The National Birth Defects Prevention Study (NBDPS) All infants with any of more than 30 selected birth defects. Controls without birth defects. 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. 1st trimester 4524 / 5859 No superposition of data between Anderka 2012 and Parker 2018, using both the NPBDS dataset: for the 4 defects studied by both, the study periods were 1997-2004 and 2005-2011, respectively.
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.
Clements
2015 		USA
1997 - 2010
case control 		The Partners HealthCare electronic health record (EHR) from a large Massachusetts health-care system. Infants who had at least one ICD-9 code of 299 (pervasive developmental disorder) or with ICD-9 code of 314.x (attention-deficit hyperactivity disorder (ADHD)). Infants not having any prior history of Autism Spectrum Disorder (ASD), attention-deficit hyperactivity disorder (ADHD) or intellectual disability (ICD9 of 299, 314 or 317–319). The Partners HealthCare EHR includes medication data. 1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), early pregnancy, preconception-only 2243 / 5631 1377 children with ASD matched to 4022 healthy control children and 2243 with ADHD (but no ASD diagnosis) matched to 5631 healthy control children.
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.
Fejzo
2015 		USA
2007 - 2011
case control 		A part of a larger investigation evaluating the 44 genetics and epidemiology of Hyperemesis gravidarum (HG) Children exposed to hyperemesis gravidarum (HG) with neurodevelopmental delay. Children exposed to hyperemesis gravidarum (HG) with a good outcome. Participants were asked to submit their medical records and complete an online survey regarding treatment. during pregnancy (anytime or not specified) 138 / 174 Main analysis: case control related to the impact of the HG illness (treated or not) on child outcomes. Then impact of 37 medications/treatments (1st and/or 2nd trimester) on child outcome was investigated (none was significantly associated with delay).
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.
Kerr
2018 		USA and Canada
1993 - 2015
case control 		Slone Epidemiology Center Birth Defects Study (BDS) Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”), Nonmalformed live-born infants. 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. 1st trimester, 2nd trimester, 3rd trimester 166 / 12059 Authors analyzed separately “isolated” microcephaly and “non-isolated” microcephaly. Only isolated microcephaly are indexed in MetaPreg.
Cases and controls were ascertained at participating hospitals or birth defect registries in the same areas.
Lind
2013 		USA
1997 - 2007
case control 		The National Birth Defects Prevention Study (NBDPS). Male infants with isolated second- or third-degree hypospadias, defined as the urethral opening at the penile shaft, scrotum, or perineum. Male liveborn with no major birth defects selected randomly from vital records or birth logs. 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). 1st trimester 1537 / 4314 National Birth Defects Prevention Study excludes first-degree hypospadias. Arkansas, California, Georgia, Iowa, and Texas also include pregnancies that are diagnosed prenatally.
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.
Parker, BDS study
2018 		USA
1997–2014
case control 		Birth Defects Study at Slone Epidemiology Center. Live births, stillbirths, and elective terminations with any major birth defects. Liveborn neonates without malformations. 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. 1st trimester 8533 / 5873 1st trimester definition: the 2 weeks before and 98 days after the estimated date of conception.
Case and control participants were identified by review of discharge records or registry data at participating hospitals or birth defect registries.
Parker, NBDPS study
2018 		USA
1997–2011
case control 		The National Birth Defects Prevention Study (NBDPS) Infants (live births, stillbirths, and (in selected sites) elective terminations) with one of the more 30 selected major birth defects studied A random sample of liveborn neonates without birth defects identified from birth certificates or birth hospitals in the same geographic regions and time periods as those in the case group 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. 1st trimester 14667 / 6751 No superposition of data between Anderka 2012 and Parker 2018, using both the NPBDS dataset: for the 4 defects studied by both, the study periods were 1997-2004 and 2005-2011, respectively. NBDPS: 1st trimester: first 90 days after the date of conception
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.
Werler
2014 		USA
2007 - 2011
case control 		The Slone Epidemiology Center Birth defect study - A population-based case-control study of medical record–confirmed clubfoot. All infants less than 11 months of age with a diagnosis of talipes equinovarus or clubfoot (without a known chromosomal anomaly, inherited syndrome, bilateral renal agenesis, Potter syndrome, or neural tube defect). Random samples of children born in the same years as cases but without known malformations. Mothers were interviewed by telephone within 12 months after delivery about medication use, including indication, product, timing, and frequency. 1st trimester 646 / 2037 Ondansetron is one of the medications studied by authors. 'On the basis of the timing of clubfoot development, the exposure window of interest is lunar months (LMs) 2–4, which is 29–112 days after the first day of the last menstrual period.'
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.
Zambelli-Weiner (Unexposed control, NOS)
2019 		USA
2000 - 2014
nested case control 		A large, proprietary, US administrative health care database, the Truven Health MarketScan Commercial Database Infants diagnosed with birth defects (cardiovascular, orofacial clefts, other circulatory defects, diaphragmatic hernia or renal collecting system anomalies) Infants with all birth defects with ICD-9 codes 740.xx-759.xx, excluding the a priori birth defects of interest. 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. 1st trimester -9 / 802253 Nested case-control study. Exclusion of chromosomal anomalies and exposure to known teratogens: infection (toxoplasmosis, syphilis, varicella- rubella, ...), or prescription for thalidomide or isotretinoin in the pre-birth period.
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.
Zambelli-Weiner (Unexposed control, sick)
2019 		USA
2000 - 2014
nested case control 		A large, proprietary, US administrative health care database, the Truven Health MarketScan Commercial Database Infants diagnosed with birth defects (cardiovascular, orofacial clefts, other circulatory defects, diaphragmatic hernia or renal collecting system anomalies) Infants with all birth defects with ICD-9 codes 740.xx-759.xx, excluding the a priori birth defects of interest. 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. 1st trimester -9 / 802253 Nested case-control study. Exclusion of chromosomal anomalies and exposure to known teratogens: infection (toxoplasmosis, syphilis, varicella- rubella, ...), or prescription for thalidomide or isotretinoin in the pre-birth period.
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.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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