Lets discuss ondansetron
I received an email last week from a GP who was concerned about prescribing ondansetron off license during pregnancy. They through it was contraindicated in the BNF for use in pregnancy and while the local hospital said it was fine to use they still felt nervous about it. I thought I would publish my reply for other GP’s who might have the same question and also for women who want to discuss the evidence base behind this drug with their own doctor.
Dear Dr A. GP,
Thank you for your email. I'm really pleased you got in touch to clarify this and hopefully I can answer your question enough to give you the confidence to prescribe ondansetron if it's needed in pregnancy as well as information which will support the general care for your patient.
Checking in my BNF (No. 75 March-September 2018) pregnancy is not contra-indicated, only congenital long QT syndrome is. Under pregnancy it states: "No information available; avoid unless potential benefit outweighs risk". As you say it is not licensed but then very few medications for any condition are licensed in pregnancy and in the UK no medication is licensed for pregnancy sickness or hyperemesis, not even cyclizine or prochlorperazine. The Royal College of Obstetricians and Gynaecologists have produced treatment guidelines (1) for the UK which should provide the necessary professional support to confidently prescribe for the condition however, as independent prescribers it is good practice to have a grasp of the risks/benefits in the literature to be able to support women in informed decision making.
So looking at the literature, contrary to the BNF's claim of no information, there is published information of potential harm of both using ondansetron and of not using ondansetron... currently that literature is very much in favour of using it for women whose symptoms have not been sufficiently controlled by 1st line medications (cyclizine and/or prochlorperazine). The most reassuring and largest study was a retrospective analysis of data from the Danish Birth Registry (2) which found no increased risk to the foetus. However there have been a number of smaller studies which have suggested increased risks of cleft palate (3) and cardio septal defects (4). However, it is vitally important when discussing such risks with women these are put in perspective so she can make an informed decision about the treatment. For example, the study that suggests an increased risk of cleft palate found the risk to be two fold, many women may hear this and think it means "one in two" when in fact, given that the base line rate of cleft palate is 0.1% (or 10 in 10,000), doubling that risk still only puts them at a 0.2% risk, (or 20 in 10,000)... an absolutely tiny risk for a women who is actively considering terminating her otherwise wanted baby because symptoms are so intolerable.
To make an informed decision a woman also needs to understand the potential risks associated with not treating the symptoms sufficiently to eat and drink enough. Increasing evidence is demonstrating the long term consequences of malnutrition in early pregnancy and uncontrolled hyperemesis is associated with a host of complications for the baby from Small for Gestational Date babies, low birth weight and premature birth (5) to long term cardiometabolic disturbances (6). Most complications appear to be associated with substantial maternal weight loss and where symptoms are uncontrolled into the second trimester placental dysfunction risks increase (7). Women should also be encouraged to consider the potential risks to themselves. There is a prevalent assumption in our society that women should sacrifice their own health and well-being for their foetus' however as healthcare professionals our overriding duty of care (excluding Northern Ireland) is to the mother, she is our patient. Risks associated with uncontrolled HG include but are not limited to Wernicke's encephalopathy, metabolic disturbances and venous thrombo embolism and thyrotoxicosis (1, 8); between 2006 and 2012 6 women in the UK died of complications arising from hyperemesis gravidarum (9, 10).
Finally, when weighing up this evidence consideration needs to be given to a women's mental health which can be seriously compromised by hyperemesis (11), particularly when the battle isn't just fighting the sickness day in and day out but when you have to battle to be believed and receive treatments the toll on one's sanity can be even more profound and suicidal ideation is not uncommon (12). It is very common for women to come away from doctors appointment feeling like they were simply not believed (13) and sadly it is not uncommon for women to terminate wanted pregnancies due to barriers to treatment at primary care level. I realise the reference list below is growing rather long but I would implore you to at least read the 2014 charity report by ourselves and bpas into women's experiences of termination for hyperemesis (14).
Personally, I think it is very important to remember that on the whole women do not want to take medication in pregnancy. Most plan to have natural, healthy pregnancies to give their babies the best possible start in life. But women with Hyperemesis simply don't have this luxury... without medication the baby and they are at risk from malnutrition and dehydration (malnutrition in particular being increasingly recognised as a major problem in the first trimester) and with medication they are exposing their foetus to other potential harms. However, from the currently published literature there is little doubt that the lesser harm lies with the treatment.
If you are particularly keen to avoid further levels of treatment, or for example a woman has an adverse reaction to ondansetron and other medication options, then a very low threshold for IV fluids could be a useful management strategy... if you are in an area with an Acute Care at Home team perhaps they could provide IV fluids at home? It's done in other UK areas and we have community guidelines for such a service. Very importantly ketones should not be used to assess hyperemesis or dehydration as they are not an indicator of dehydration and have been shown by systematic review to not have any correlation with hyperemesis symptom severity (15). You could also provide information about fortifying foods as you would a patient with cancer cachexia (which interestingly it seems has almost the same aetiology as hyperemesis (16)). And of course I would urge you to refer women to us (Pregnancy Sickness Support) for peer support from our registered and trained volunteers to provide emotional support and reduce the isolation.
I realise this is a very long email for a busy GP but of course there is so much more I could tell you (I've written a whole book on the subject!). I really hope it helps with your confidence treating this tricky and frustrating condition.
If you would like to speak on the phone I would be happy to go through all of this and more with you and if you have a patient you are struggling to get symptoms under control with I would be happy to discuss the particular case (I am a registered nurse, background in practice nursing now specialising in hyperemesis and doing my PhD in it).
Additionally we would be happy to do a teaching session at your practice for yourself and your colleagues if that would be of interest?
Once again, I hope this has helped and please don't hesitate to ask any further questions
Chair Trustee, Pregnancy Sickness Support
2. Pasternak B. 2013. Ondansetron in Pregnancy and Risk of Adverse Fetal Outcomes. New England Journal of Medicine 368(22):2146-2146.
3. Anderka M., Mitchell A., Louik C., Werler M., Hernandez-Diaz S., S. R. 2012. National Birth Defects Prevention Study. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Research Part A: Clinical and Molecular Teratology 94:22-30.
4. Danielsson B, Wikner BN, Källén B. 2014. Use of ondansetron during pregnancy and congenital malformations in the infant. Reproductive Toxicology 50:134-137.
5. Veenendaal MV, van Abeelen AF, Painter RC, van der Post JA, Roseboom TJ. 2011. Consequences of hyperemesis gravidarum for offspring: a systematic review and meta-analysis. BJOG 118(11):1302-13.
6. Grooten I, Painter R, Pontesilli M, van der Post J, Mol B, van Eijsden M, Vrijkotte T, Roseboom T. 2015. Weight loss in pregnancy and cardiometabolic profile in childhood: findings from a longitudinal birth cohort. BJOG 122(12):1664-73.
7. Bolin M, Akerud H, Cnattingius S, Stephansson O, Wikstrom A. 2013. Hyperemesis gravidarum and risks of placental dysfunction disorders: a population-based cohort study. Bjog-an International Journal of Obstetrics and Gynaecology.
8. Veenendaal MV, van Abeelen AF, Painter RC, van der Post JA, Roseboom TJ. 2011. Consequences of hyperemesis gravidarum for offspring: a systematic review and meta-analysis. BJOG 118(11):1302-13
9. Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D et al. Saving Mothers’ Lives Reviewing maternal deaths to make motherhood safer: 2006–2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG. 2011 Mar;118(Suppl. 1):1-203.
10. Knight M, Nair M, Tuffnell D, Kenyon S, Shakespeare J, Brocklehurst P, et al. Saving Lives, Improving Mothers’ Care: Surveillance of maternal deaths in the UK 2012–14 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009–14. Oxford: MBRRACE-UK; 2016.
11. Mitchell-Jones N, Gallos I, Farren J, Tobias A, Bottomley C, Bourne T. 2017. Psychological morbidity associated with hyperemesis gravidarum: a systematic review and meta-analysis. BJOG 124(1):20-30.
12. Dean C, Bannigan K, Marsden J. 2018. Reviewing the effect of hyperemesis gravidarum on women’s lives and mental health. British Journal of Midwifery 26(2):109-119.
13. Sykes C, Swallow B, Gadsby R, Barnie-Adshead A, Dean C, Moran E, Kitching H. 2013. Seeking medical help for Nausea and Vomiting in Pregnancy (NVP) and Hyperemesis Gravidarum (HG) in primary care. Midirs 9:13-15.
14. Dean C, Murphy C. 2015. I could not survive another day: Improving treatment and tackling stigma: lessons from women's experiences of abortion for severe pregnancy sickness. London: Pregnancy Sickness Support and BPAS
15. Niemeijer MN, Grooten IJ, Vos N, Bais JMJ, van der Post JA, Mol BW, Roseboom TJ, Leeflang MMG, Painter RC. 2012. Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis. American Journal of Obstetrics & Gynecology 211(2):150.e1-150.e15.
16. Fejzo MS, Sazonova OV, Sathirapongsasuti JF, Hallgrímsdóttir IB, 23andMe Research Team., Vacic V, MacGibbon KW, Schoenberg FP, Mancuso N, Slamon DJ et al. . 2018. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nature Communications 9(1178):1-9.