Motherisk Int J 2020;1:10
Gideon Koren MD(1-2), Yusuf Cem Kaplan MD(3)
Adelson Faculty of Medicine, Ariel University(1), Motherisk Israel Program (2) and Terafar - Izmir Katip Celebi University Teratology Information Center, Turkey (3)
Address for Correspondence:
Adelson Faculty of Medicine, Ariel University, Ariel Israel 40700
GK serves as a paid consultant for Duchesnay Inc., Quebec, Canada
Nausea and vomiting of pregnancy (NVP) is the most common medical condition during gestation, affecting an estimated 80% of expecting mothers (1). While mild cases are typically managed by dietary and lifestyle changes, moderate and severe cases often necessitate pharmacotherapy. Over the years, a variety of medications have been used for NVP symptoms, most commonly different combinations of antihistamines, dopamine modulators and metoclopramide (2). Since the introduction of ondansetron for cancer chemotherapy and post-anesthesia vomiting, it has slowly emerged as an anti- emetic choice for women with NVP, with special focus on moderate – to severe symptoms (3). While the drug has never received a formal indication for NVP from any government regulatory agency based on data submitted by its manufacturers, the introduction of generic forms of ondansetron and the consequent steep fall in its price has led to dramatic increase in its use by pregnant women. It has been recorded that the use of ondansetron for the treatment of NVP has steadily increased from 50,000 prescriptions per month in 2008 to 110,000 at the end of 2013(3). The prevalence of ondansetron increased from 1% before 2000 to 13% by the end of 2014 (4).
With the increasing numbers of exposures, observational studies have begun to address the issue of fetal safety of ondansetron. While the first studies appeared to be reassuring (5-7), later research has been mixed, ranging from no evidence for increased teratogenic risk, to increased risk of oral cleft (-8) and cardiac malformations (9-11). In addition to large observational studies, there have been attempts at systematic reviews and meta -analyses of the accumulating data (5, 10, 12).
These has led the European regulators to issue in 2019 an instruction to all ondansetron manufacturers to issue a warning to pregnant women not to use the drug during gestation, and to use contraception while taking the drug prior to pregnancy (13). Not surprising, there are hundreds of law suits in the USA by parents of malformed children claiming that it is the ondansetron causing them (13).
Potential Sources for the Controversy:
Many of the published studies have been large and have attempted to address potential confounders. Because most women with NVP are young and otherwise healthy, the typical confounding by indication cannot be easily considered as a source for opposing results among studies. Yet, there are still some potential confounders that have not been well addressed, and we will touch upon them now:
1) Most recommendations made by professional societies call for using ondansetron only as a second line anti emetic, which means-in more severe cases of NVP where other medications have failed. However, present statistics show that in most American cases ondansetron is used as a first line drug, which means a mixture of severity of the NVP
Why may this be important?
There is ample evidence that in its mild and moderate forms, NVP renders protection against different congenital malformations, possibly due to a more favorable hormonal milieu (14). Czeizel and colleagues compared the prevalence of severe NVP in mothers of cases with congenital abnormalities to matched controls without any defect, using the Hungarian Case-Control Surveillance System of congenital abnormalities between 1980 and1996 (15). From 22,843 cases with 25 different congenital abnormality groups, 1713 (7.5%) cases had mothers with treated severe NVP. Of 38,151 matched population controls, 3777 (9.9%) had mothers with severe NVP (adjusted prevalence OR = 0.74 with 95% CI = 0.68–0.79).When analyzing the association of individual congenital malformations with the severity of NVP, cases with cleft lip with or without cleft palate (aOR = 0.50, 95% CI = 0.37–0.70), posterior cleft palate (aOR = 0.53, 95% CI = 0.32–0.89), renal a/dysgenesis (aOR = 0.23, 95%CI = 0.06–0.96), obstructive defects of urinary tract (aOR = 0.32, 95%CI = 0.18–0.58), and cardiovascular malformations (aOR = 0.68, 95%CI = 0.57–0.81) had mothers with a lower prevalence of severe NVP. Twenty two of the 25 congenital abnormality groups had OR lower than 1 in the presence of NVP. Overall, mothers of cases with congenital abnormalities were 26% less likely to have had severe NVP than the mothers of population controls without congenital abnormalities.
Asker and colleagues  used prospectively-ascertained information on drug
use during pregnancy from the Swedish Medical Birth Register from 1995 to 2002. They studied antiemetic drugs (antihistamines, dopamine modulators and ondansetron) used by pregnant women primarily for NVP treatment. Neonates born to women who used any of the anti-emetics had a reduced risk for congenital malformations (OR = 0.9, 95%CI = 0.84–0.96).The same group studied delivery outcome in 16,536 women who reported the use of meclozine in early pregnancy, compared with all 540,660 women who gave birth in Sweden from July 1, 1995 until2001 . Here too, meclozine use was associated with a reduced rate of congenital malformations.
On the same note, a study conducted by the Motherisk Program has shown that in more severe cases of NVP (but without hyperemesis gravidarum-HG) rendered higher IQ in the offspring(18 ). In contrast, there is accumulating evidence that in cases of HG the offspring is not doing as well, possibly due to prolonged nutritional deficiencies (19).
Because ondansetron is used now for the whole range of severity of NVP, it is conceivable that different studies may have different proportions of severity of NVP symptoms and, hence NVP severity becomes an uncontrolled variable among different studies, which may lead to opposing results on the safety of ondansetron.
2) Several recent studies have examined whether a dose-response curve exists, with higher, injectable or intravenous ondansetron rendering a higher risk of birth defects. Zambelli –Weiner and colleagues detected such an effect (20), as did Lemon et al (11). In contrast, Huybrechts and colleagues could not detect such an effect (21). Again, this can be a mixed effect of a pharmacological dose-response plus the effect of the severity of NVP.
3) In a recent meta-analysis, Kaplan and colleagues (12) have identified an additional potential source of variability that needs to be considered:
While the overall risk of oral cleft and cardiac malformations was not increased in their analysis, major congenital malformations and heart defect risks became significant when the authors undertook sensitivity analyses which substituted the results of two studies which utilised an overlapping data source in Denmark (7, 22) . This may mean that one of the overlapping studies, which was reassuring in its results, “diluted” an apparent effect into a non-significant signal (7). Because the other study was published as an abstract, which provided limited information regarding the methodology, it was not possible to discuss the probable causes of these conflicting findings further (22).
What should a clinician do?
Not surprising, the opposing safety results delineated above have led to great confusion. This is well reflected by the fact that, while the European authorities have issued a warning not to use the drug in pregnancy, the FDA has not, after two separate discussions on the issue.
The following points appear to be logical for the clinician treating women with NVP and HG who may need anti-emetics:
a) We could not find information sources suggesting ondansetron as first line drug for NVP and HG. There are medications with better established fetal safety records and reasonable efficacy, such as antihistamines and the combination of doxylamine succinate and pyridoxine hydrochloride, which is the only drug labeled for NVP in increasing numbers of countries, including the USA, Canada, South Korea, Singapore, UK and Israel (3). Similarly, although not labelled for NVP, metoclopramide does not appear to increase malformation rates.
b) Use ondansetron only as a second line anti emetic agent.
In term of research agenda, we believe it will be important for future studies to address the sources of potential bias identified herein, in an attempt to resolve the opposing results of the large number of existing studies.
1) Clark SM, Dutta E, Hankins G. The outpatient management and special considerations of nausea and vomiting in pregnancy. Semin Perinatol. 2014 Dec;38(8):496-502
2) Matthews A, Haas DM, O'Mathúna DP, Dowswell T. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2015 Sep 8;(9):CD007575. doi: 10.1002/14651858.CD007575.pub4.
3) Koren G: Treating morning sickness in the United States—changesin prescribing are needed. Am J Obstet Gynecol. 2014 Dec;211(6):602-6
4) Parker SE, Van Bennekom C, Anderka M, Mitchell AA; National Birth Defects Prevention Study. Obstet Gynecol. 2018 Aug;132(2):385-394. doi: 10.1097/AOG.0000000000002679.
5) Lavecchia M1, Chari R, Campbell S, Ross S. Ondansetron in Pregnancy and the Risk of Congenital Malformations: A Systematic Review. J Obstet Gynaecol Can. 2018 Jul;40(7):910-918. doi: 10.1016/j.jogc.2017.10.024. Epub 2018 May 10.
6) Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G. The safety of ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. BJOG. 2004 Sep;111(9):940-3.
7) Pasternak B, Svanström H, Hviid A.Ondansetron in pregnancy and risk of adverse fetal outcomes. N Engl J Med. 2013 Feb 28;368(9):814-23.
8) Huybrechts KF1, Hernández-Díaz S2, Straub L1, Gray KJ3, Zhu Y1, Patorno E1, Desai RJ1, Mogun H1, Bateman BT1,4. Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring. JAMA. 2018 Dec 18;320(23):2429-2437. doi: 10.1001/jama.2018.18307.
9) Danielsson B, Wikner BN, Källén B.Use of ondansetron during pregnancy and congenital malformations in the infant. Reprod Toxicol. 2014 Dec;50:134-7
10) Carstairs SD. Ondansetron Use in Pregnancy and Birth Defects: A Systematic Review. Obstet Gynecol. 2016 May;127(5):878-83. doi: 10.1097/AOG.0000000000001388.
11) Lemon LS, Bodnar LM, Garrard W, Venkataramanan R, Platt RW, Marroquin OC, Caritis SN. Ondansetron use in the first trimester of pregnancy and the risk of neonatal ventricular septal defectS. Int J Epidemiol. 2019 Dec 20. pii: dyz255. doi: 10.1093/ije/dyz255. [Epub ahead of print]
12) Kaplan YC, Richardson JL, Keskin-Arslan E, Erol-Coskun H, Kennedy D. Use of ondansetron during pregnancy and the risk of major congenital malformations: A systematic review and meta-analysis. Reprod Toxicol. 2019 Jun;86:1-13. doi: 10.1016/j.reprotox.2019.03.001. Epub 2019 Mar 5.
13. https://pink.pharmaintelligence.informa.com/PS140648/EU-Warns-Of-Birth-Defect-Risks-With-AntiNausea-Drug-Ondansetron 2/2. Aug 2019
14. Koren G, Madjunkova S, Maltepe C. The protective effects of nausea and vomiting of pregnancy against adverse fetal outcome--a systematic review. Reprod Toxicol. 2014 Aug;47:77-80
15. Czeizel AE, Puho E, Acs N, Banhidy F. Inverse association between severe nauseaand vomiting in pregnancy and some congenital abnormalities. Am J Med GenetA 2006;140:453–62.
16. Asker C, Norstedt Wikner B, Kallen B. Use of antiemetic drugs during pregnancyin Sweden. Eur J Clin Pharmacol 2005;61:899–906.
17. Kallen B, Mottet I. Delivery outcome after the use of meclozine in early preg-nancy. Eur J Epidemiol 2003;18:665–9.
18. Nulman I, Rovet J, Barrera M, Knittel-Keren D, Feldman BM, Koren G. Long- term neurodevelopment of children exposed to maternal nausea and vomiting of pregnancy and diclectin.J Pediatr. 2009 Jul;155(1):45-50, 50.e1-2.
19. Koren G, Ornoy A, Berkovitch M. Hyperemesis gravidarum-Is it a cause of abnormal fetal brain development. Reprod Toxicol. 2018 Aug;79:84-88
20. Zambelli-Weiner A, Via C, Yuen M, Weiner DJ, Kirby RS. First trimester ondansetron exposure and risk of structural birth defects.Reprod Toxicol. 2019 Jan;83:14-20.
21. Huybrechts KF, Hernandez-Diaz S, Straub L, Gray KJ, Zhu Y, Mogun H, Bateman BT. Intravenous Ondansetron in Pregnancy and Risk of Congenital Malformations. JAMA. 2019 Nov 15. doi: 10.1001/jama.2019.18587. [Epub ahead of print]
22. Andersen JT, Jimenez-Solem E, Andersen NL, Poulsen HE, Ondansetron use in
early pregnancy and the risk of congenital malformations - a register-based nationwide
cohort study. Abstract 25 ISPE 2013, Pharmacoepidemiol. Drug Saf.