Jennifer:
Welcome to this evening’s webinar: Nausea & Vomiting in Pregnancy & Hyperemesis gravidarum. My name is Jennifer, your RACGP representative for this evening. We are joined by our presenters, Associate Professor Sandra Lowe, Elizabeth Heiner and Dr Rachel James.
Before we get started, I would like to make an acknowledgement of country. We recognise the traditional custodians of the land and sea of which we live and work, and we pay our respects to elders past, present and emerging. I would also like to extend that acknowledgement to any Aboriginal and Torres Strait Islander colleagues that may have joined us online this evening.
So, tonight’s webinar is a part of a two-webinar series. So, the second webinar we will discuss this topic, but we will also be using a case scenario. So, please do not forget to register.
I just want to introduce our presenters for this evening. Sandra is a consultant obstetric physician at the Royal Hospital for Women and Prince of Wales Private Hospital and a clinical associate professor at the University of New South Wales. Sandra regularly speaks at national and international conferences on obstetric medicine and has a longstanding interest in teaching obstetric medicine, so welcome Sandra.
Elizabeth is a registered pharmacist with career experience across community pharmacy, poisons and drug information and clinical pharmacy practice. She currently works both at Children’s Hospital Westmead and MotherSafe at the Royal Hospital for Women. Welcome Elizabeth.
Rachel is a GP obstetrician with a special interest in community paediatrics and contributes to the PHN program for enhancing paediatrics in primary care. She also has a role as the rural director of training at the New South Wales Health, Education & Training Institute involved in the New South Wales Rural Generalist Training Program. So, welcome Rachel.
I would also like to acknowledge that this presentation was developed with contributions from Dr Debra Kennedy, Director of MotherSafe, Royal Hospital for Women and Section Staff Specialist at Royal Hospital for Women. Staff from the MotherSafe Team, members from the Medication Safety Team, Clinical Excellent Commission and Project Team from Health & Social Policy Branch for the Ministry of Health, and I am just going to pass over to Rachel to go through our learning objectives for this evening.
Dr Rachel James:
Hi welcome everybody, and I am your GP facilitator for this evening and thank you for joining. So, by the end of this online CPD activity you should be able to discuss nausea and vomiting in pregnancy and hyperemesis, summarise the emotional, physical, psychological, psychosocial and social economic impacts of nausea and vomiting in pregnancy including hyperemesis. Describe how to use the validated scoring system for classifying symptoms severity for nausea and vomiting in pregnancy including hyperemesis and outline the best practice principles for assessment and management and outline prescribing considerations for pregnant women with nausea and vomiting in pregnancy including hyperemesis. So now we are going to hand you over to Associate Professor Sandra Lowe who is going to give the first part of the presentation and then this would be followed by our lovely pharmacist, Elizabeth. Thank you.
Associate Professor Sandra Lowe:
Thanks Rachel and thanks Jennifer and thank you very much for allowing me to speak tonight about a subject I am very passionate about and really what we want to prove by the end of this evening is that nausea and vomiting in pregnancy (NVP) and hyperemesis gravidarum (HG) which I am going to call HG all night is really more than morning sickness, and increase your skills and understanding of this very important condition.
So, this presentation is part of the New South Wales Health NVPHG initiative, which is a large, funded program from New South Wales Health which is aimed at providing evidence-based guidance to support consistency of practice, decision making, and care diagnosed for the diagnosis and management of NVP. It has been developed by an expert group of clinicians and is based on the current evidence as we understand it, and the full guideline is available from this website. I am going to go through some clinical aspects of the guideline tonight.
So first of all, what are the definitions of NVP and HG? Well nausea and vomiting and/or dry retching caused by pregnancy with symptoms commencing the first trimester without an alternate cause for those symptoms and the severity is based on what we call the PUQE-24 score. For pregnancy universal quotient of emesis. The PUQE score. Essentially it is a very simple scoring system. In the last 24 hours for how long have you felt nauseated? In the last 24 hours how often have you vomited and how many times have you dry retched? So, the lowest score that you can have is a 3 because if you have got no symptoms, you are still a three and the highest score is 15.
The assessment should also include questions about the woman’s quality of life and wellbeing over the last few weeks because these three questions are a very simplistic way of assessing nausea and vomiting so in addition to these questions, you need to know whether the woman has been able to tolerate oral intake both food and fluid, if she is losing weight or if she needs hospitalisation for some reason and that can occur even with PUQE score of 13. So, women with severe nausea, even if they are not vomiting may not be able to tolerate oral intake. We all know that nausea and vomiting is common in pregnancy, it tends to peak at about 5-8 weeks and then improves with most people improving either at 12-13 weeks or at around 16 weeks, but about 10% of women will continue to have symptoms right up until the end of pregnancy. In Australian observational study we performed, 72% women reported some form of NVP but 42% of them have mild symptoms, 55% were moderate and only 1% was severe.
So, if we talk specifically about the condition of HG, each of the following criteria are required for the definition. Symptoms starting in early pregnancy before 16 weeks and that is really to distinguish it from other conditions that might cause severe nausea and vomiting. I mean, the rare ones might be something like Addison’s disease or raised cerebral pressure but virtually always nausea and vomiting of pregnancy begins early. It is characterised by severe nausea and/or vomiting, an inability to eat or drink normally, it strongly limits daily activities, and those subjective symptoms can be further quantified using a validated scoring system and the one we are recommending is the PUQE-24 system. Signs of dehydration or weight loss are contributory, but they are not necessary for the diagnosis, and you can imagine if someone has started vomiting so severely so they cannot eat or drink, you do not need to wait 3 or 4 weeks for them to lose 5% body weight to call that severe. Equally importantly ketonuria is no longer considered a diagnostic feature. Pregnant women develop starvation ketosis very readily and they are very slow to clear it. So that it is not a good pointer to the severity of HG and so therefore weight loss and ketonuria are no longer part of the diagnostic criteria.
What is the cause of HG? I think the most important things to say is what is not the cause. It is not a psychological condition, and it probably is not related to human chorionic gonadotropin (HCG). There is a strong genetic basis suggested by a very large study showing that 73% of the occurrences could be related to genetics, 51% to duration and 53% severity. So, a large component of how you experience NVP is genetic. There is an association with family history and there is a strong recurrence risk in subsequent pregnancies which I will speak about later and one of the putative genes that has been identified is this thing called GDF15. Interestingly, a gene that is associated with cancer anorexia and cachexia and one of my personal observations is the profound anorexia that women get with HG. So, women with morning sickness often have nausea and vomiting but they still want to eat. Women with HG do not ever want to eat, although you can get them to eat if management is correct.
What is the impact of severe NVP and HG? Well mild to moderate NVP is actually associated with a favourable effect on pregnancy. There is a reduced risk of miscarriage. Reduced risk of congenital malformation, prematurity and childhood performance IQ, but severe cases can cause nutritional and electrolyte disturbance, a need for IV hydration and electrolyte replacement or even enteral feeding or total parental nutrition, maternal death has definitely been described in this condition. It can also have developed Mallory-Weiss tears, splenic rupture, Wernecke’s encephalopathy, all of those things are extremely rare with appropriate recognition and management but still occur. There is also a high risk of adverse maternal and foetal outcomes later in pregnancy with an increased risk of preterm birth, low birth weight, placental abruption and pre-eclampsia.
Some very recent studies interesting showing that low birth weight is particularly associated with the failure to regain weight in the second trimester. So that if we can control NVP in the first trimester and allow normal weight gain to occur after that then the risk of these subsequent adverse events is reduced.
What we need to do is change the culture around nausea and vomiting of pregnancy. These are direct quotes from women who have experienced it. Women felt their distress to nausea and vomiting was trivialised by their doctors whilst doctors appeared uncertain with a respect to appropriate medical treatment. Women themselves are sceptical about using medicine, particularly in the first trimester while pregnant and avoidance was sought despite feeling ill. So, we need to change attitudes through research, education and evidence-based guidance and through good teaching which I hope we will be able to do tonight.
Investigations with NVP or HG. Most people do not need any investigations. If they have got mild-to-moderate symptoms, it is occurring at the time you would expect it, particularly if they have experienced it before they do not have any specific investigations, unless there are clues to another diagnosis, for example, if they have got fever then you need to investigation for infection particularly urine tract infection but if they have severe nausea and vomiting; at least at the first presentation; we recommend checking their sodium, potassium, chloride, bicarb, urea, creatinine, magnesium, calcium and phosphate, their liver function test, we suggest doing an obstetric ultrasound to exclude multifoetal which is obviously associated with a greater risk of severe NPV or HG or even gestational trophoblastic disease. We only recommend testing for thyroid function if there are symptoms of thyrotoxicosis. There is an association between raised thyroid hormone and hyperemesis gravidarum, but we do not tend to treat it unless the women are very symptomatic. You know that you need to use the normal trimester-specific ranges for thyroid function tests in pregnancy. There is a fall ins TSH in the first trimester, although it does not occur until about 7 or 8 weeks gestation and then it will rise to nonpregnant ranges by about the second trimester and as I said an MSU if you have symptoms or signs of urinary tract infection.
So, it is really very minimal investigations unless you are considering another diagnosis.
So, let’s get onto the management. So, we always want to start with the least risky management in pregnant, the least drugs that we can use, the least interventions. So, let’s start with nonpharmacological interventions. Things that might help an individual patient are changing their activities to minimise fatigue and gain more rest and I must say that since women have been able to work from home, it has made a huge difference often to their symptoms. Changing their dietary habits can help, but I would suggest you not be too prescriptive. Whatever they can eat, whenever they can eat and there are culturally appropriate foods. My Asian patients tend to want soups that their mothers have made. My Mediterranean patients often want pasta. My Caucasian patients want toast with vegemite or Kentucky Fried. It is really interesting what food cravings women will have despite having nausea and vomiting and just encourage them to eat whatever they can, don’t be too fussy about the quality of eating.
Acupressure bands do have some evidence behind them and can certainly be used, they are a very safe option. The evidence-based interventions that I am going to call nonpharmacological are firstly discontinuing the multivitamins that many women are taking. 2/3 of women report an improvement in their NPV symptoms after discontinuation of an iron-containing prenatal multivitamin, but we still want them to take the critical micronutrients which are particularly folic acid and iodine, and they can be given as separate components.
So, when we start talking about treatments for mild NVP we start with at the mild end, the nondrug options of ginger and pyridoxine. Ginger foods are not going to give you an adequate dose of ginger to treat NVP, so we recommend ginger tablets, somewhere between 200 mg and 600 mg every 8 hours and pyridoxine 10-50 mg, often comes in 25 mg tablets so 25-50 mg, 3-4 times a day can be very effective, very safe, sometimes given them a little heartburn but both available over the counter and be aware that if they are using naturopathic or other complementary products they may contain multiple ingredients and we don’t want to do that, we want to use these specific components and that is what I would recommend.
What’s the best treatment for moderate-to-severe NVP? Well, it is not just antiemetics and that is what I really want to stress tonight. We need to use interventions to reduce nausea, retching and vomiting but we also have to manage the associated gastric dysmotility that all these women have. All pregnant women have an element of gastric dysmotility which causes gastro-oesophageal reflux, constipation and reduced gastric emptying and if you do not address that in the moderate-to-severe group you won’t get control of the nausea and vomiting. We need to maintain adequate hydration and electrolyte replacement and maintenance of adequate nutrition including provision of vitamin supplements where required. Very, very importantly we have to provide psychosocial support. So, I just said to you that it is not the cause of NVP or HG, but it is definitely a consequence. We use validated mental health screening tools if we suspect mood disturbance and we repeat those regularly if the woman continues to have symptoms and then we refer early to perinatal mental health. Now just as a practice tip in at least in my hospital we can’t access perinatal mental health until the woman is booked in for her maternity care. So, organising early booking for maternity care may be part of your management package and of course want to prevent side effects of the disease and side effects of our treatment. HG is not a psychological disorder, but it does have significant effects on mood. It causes the overwhelming relentless symptoms with physical deconditioning and dehydration, malnutrition, women are isolated, they feel guilty, and it has a financial and employment impact and all of that is implicated in psychological impact.
An international survey of women with a history of HG; 15% reported having at least one elective termination of pregnancy because of the condition with the most common reason being they felt there was no hope of relief. Women with a history of HG have high levels of post-traumatic stress syndrome and it is associated with negative outcomes after pregnancy including inability to breastfeed, marital problems, financial problems and inability to self-care and for course impacts on subsequent pregnancies. So, it is critical that we provide empathetic and quality care.
The targets for therapy have to be realistic. Essentially, I would say to you we are not going to be able to control all nausea or all vomiting, but what we should be able to achieve with good treatment is ability to eat and drink, ability to function even in a limited capacity e.g., if they can’t work, at least being able to participate in family activities, maintain their mental health, recognise and explain to women that their symptoms are self-limiting and that most of them will recover by 12-13 weeks with another group by 16 weeks. We need to support their caregivers and we need to provide appropriate employment expectations.
We often need to commence treatment before the usual pathways to maternity care have been commenced. So, as I said consider early antenatal booking and find out what the appropriate pathway is for severe NVP and HG in your area. So, sometimes it will be through the Emergency Room, sometimes it will be through an early pregnancy service, sometimes it will be through the Maternity Care Coordinators or any specialists that you have access to that has expertise in this area. So, I am an obstetric physician at Royal Hospital for Women, and we have expertise, and a number of the large maternity hospitals have obstetric physicians. In other places it may be a gastroenterologist, it may be an obstetrician, maybe a GP, whoever had the best most expertise is the person we should get help from. It is very important to time the administration of your therapy to reflect that woman’s symptoms patent and I can’t stress enough how individual these treatments need to be. So, if the women doesn’t have morning sickness but has predominant afternoon sickness, maximise her treatment in the afternoon. If the woman has predominant gastro-oesophageal reflux with a lot of dry retching, maximise that treatment over antiemetics. The choice of antiemetics needs to be individualised based on her symptoms, her previous response to treatment and potential side effects. We use the PUQE score to guide out initial therapy by determining whether the woman has mild, moderate or severe therapy, but once you have commenced therapy you use the algorithm, I am going to show you to titrate their therapy up and down.
When you are considering choices, obviously oral therapy is usually commenced first, and parenteral treatment is reserved for refractory cases. Written instructions need to be given, particularly regarding the complex regimes that we often require and also advice about titrating therapy up and down and I will show you an example of a written patient plan that we would use, and you need to review therapy regularly because it is a very dynamic condition. At least two-weekly if not more frequently and as well as giving treatment support you are giving psychosocial support.
So this is the first page of the patient information leaflet that is provided on the NSW Health website, which women are finding very, very helpful and very reassuring for them and their families and this is an example of a care plan template where we will list the drugs that they are getting for nausea, the drugs that they are getting for stomach acid, the drugs they are getting for constipation and any other drugs that we recommend. We then say if you feel worse you could try this, if you feel better, you can try that, and there is a second page to this care plan which allows the woman to give us feedback between visits and they are meant to bring that along to their subsequent visits. So, this, is also available on the guideline.
So, let’s start talking about this pharmacological therapy. So, we are going to start antiemetics based on the PUQE-24 score. If you start an antiemetic and it is partially effective, then try to optimise the dosage and the timing and then add a different class of antiemetic if you have not got a complete relief. If the first drug you try is ineffective at maximal dose, don’t leave it and keep adding drugs, discontinue that drug before you commence an alternate agent. Add laxatives early, I can’t say this strongly enough. Virtually all these women are constipated. We use high doses of docusate without senna. You can use macrogol containing laxatives, 1-2 a day. Lactulose is sometimes better tolerated because the volume of the macrogol containing laxatives can be very difficult for these women to manage and they may need enemas and we commence acid suppression therapy early when there is moderate-to-severe NVPHG with symptoms of gastro-oesophageal reflux or significant vomiting.
So, now I bring you to our algorithm which is your starting point for treatment and outlines the drugs we recommend as being safe and effective for women with NVP and HG. So, for the mild group we have already spoken about. For the moderate group we recommend starting one of these drugs which I will speak about in more detail and/or ondansetron at the same time as we add laxatives, at the same time we add acid suppression. Moderate-to-severe disease we are starting to use the same sort of drugs or combinations and we start to consider the addition of drugs such as corticosteroids. We usually cease our H2 antagonist and commence a proton pump inhibitor but very occasionally we use both. We may start to use IV fluids intermittently preferably as an outpatient, adding in thiamine and here is where we are starting to consider enteral nutrition if oral intake is not adequate and if the woman is severely debilitated we may consider VTE prophylaxis and by the time a woman has refractory symptoms and requires admission we are using combinations of these often intravenously as well as some form of support and nutrition. I have been asked a question about a question about pyridoxine and how it helps in HG. It doesn’t help in HG: it helps in mild nausea and vomiting. We don’t know how it works. Most of the data is with pyridoxine combined with doxylamine but many women do get relief from ginger and pyridoxine alone in mild NVP.
What about these antiemetics for moderate-to-severe NVP or HG. We recommend starting with histamine and dopamine antagonists. These are old-fashioned drugs for which we have a lot of experience, and we have efficacy evidence. So, doxylamine, cyclizine, metoclopramide, promethazine, prochlorperazine and diphenhydramine. They are useful for moderate NVP and HG. Doxylamine is generally the drug of choice to trial first because it has got a large evidence base, but it is very sedative, and I would suggest to you it is most useful for nighttime dosing. Metoclopramide has benefits because it has some prokinetic effects on that gastroparesis but there are issues with extrapyramidal side effects, and it is not recommended for prolonged usage.
So, when nausea is present most of the day, we need regular dosing rather than prn dosing. So, the mild group may just use prn metoclopramide or prn doxylamine but for women who have got moderate-to-severe disease they will need coverage throughout the day with tds dosing, and as I said don’t double-up on agents within the same class of medication.
A couple of practice tips. Administer the first dose before getting out of bed. Suggest that they want, and they try to drink and eat before they mobilise, otherwise they tend to jump out of bed and tend to vomit straight away and this can be very effective if they take their antiemetics before they get out of bed. These antiemetics have sedative potential, all of them, although it is varying. I would suggest to you prochlorperazine metoclopramide are perhaps sedating than doxylamine and cyclizine and we frequently quarter and halve these tablets to adjust the dosing. So, if the histamine dopamine antagonist are ineffective or not tolerated that is the point to suggest adding ondansetron. It is superior to the combination of doxylamine and B6 for reduction in nausea and vomiting. It is superior to metoclopramide for reduction of vomiting but not nausea and HG.
So, although you think it is a much better antiemetic, I think it is very good to stop vomiting. I don’t think it is that much better at stopping nausea and it is often the nausea that is most troublesome. Dosing between 4 mg and 8 mg tds with a maximum dose of 16 mg in 24 hours. I would suggest to you that 8 mg is twice as constipating but not necessarily twice as good an antiemetic. The wafer is given sublingually but it is not absorbed sublingually. It is dispersible and therefore needs to be swallowed and has quite a bit of taste and a lot of women can’t tolerate it, intend to dribble it out. So, yes if they can tolerate the wafers, they can have it, but I suggest that the small tablets may be better tolerated and the side effect is profound constipation, you need to add laxatives immediately. Use the minimum dosage in the morning and the afternoon and then perhaps use doxylamine at night, and it is expensive.
I am getting a few questions about dosing and duration of metoclopramide and other antiemetics. The specific dosing information is available on the NSW Guideline website. So, I am not going in to too much detail but when we discuss the case scenario in two weeks, we will discuss dosing in a lot more detail. We recommend a maximum of 5 days of metoclopramide because of the risk of extrapyramidal side effects.
For severe NVP or HG that has been unresponsive to other treatments we go to third line treatment with corticosteroids. The indications for this are refractory, NVP or HG, inability to eat or drink despite a trial of multimodal therapy, ongoing requirement for IV fluids and/or nutritional support, unable to tolerate antiemetics because of the side effects. We start with oral prednisone if they are able to tolerate it or IV hydrocortisone. If it is in effective and that is probably between 20% and 30% of women we cease the trial after 48 hours, but I would suggest to you that a large percent, if you select women carefully and you are sure that they have got HG then many of them will get an improvement with steroids. The dosage again recommendations in the guideline how to start and how to stop. I will speak a bit about weaning.
The side effects of those of high-dose steroids that you are very familiar with, insomnia, agitation and mood disturbance. The potential maternal and pregnancy side effects are both dose and duration dependant and if they are on treatment for more than 1-2 weeks you do need to discuss the long-term side effects and I would suggest to you at that point they should be seeing a specialist, but I think it is quite reasonable for a GP to commence corticosteroids if you feel comfortable and Elizabeth is going to speak a little bit more about safety of drugs in pregnancy.
When we use prednisone, we are using 50 mg for 3 days the new wean like this; 12.5 then we wean roughly down to the minimum effective dose which tends to be somewhere between 7.5 mg and 12.5 mg, or 15 mg and they may need that until the natural resolution of the condition at 13 weeks or even 16 weeks. If they remain on steroids discuss the side effects and they include hyperglycaemia, hypertension, weight gain, osteoporosis, immunosuppression and modo disturbance. As I said I think that should be under specialist care.
Prednisone is lipophilic so it can cross the placenta, but the foetal uptake is limited by placental enzymes which break it down and there is no evidence for an increase in overall congenital malformations with corticosteroid use even in the first trimester. There are some controversial data about an increased risk of cleft lip and pallet, but the absolute risk would be very small. Again, we are using it not in women that have the option of not treatment, we are using it in women that are already on a massive amount of therapy usually. So, the consequences of a small increased risk or cleft lip and pallet seem minor compared to the risk of termination of pregnancy. Corticosteroids are less well studied in comparison to other antiemetic medications and should be considered third-line treatment.
So, let’s go on to some of the drugs in addition to the antiemetics that we might need to us. Antacids have a role in women with mild disease but in general we need decent acid suppression. So, we are either going to use something like famotidine or nizatidine or one of the proton pump inhibitors. These drugs have got no associated increased risk of congenital malformations. They are very-well tolerated, and we may start with IV if they are very severe, but generally oral. What you are noticing here is the very high doses that we use, 20 mg of omeprazole twice a day, 20 mg of rabeprazole twice a day and that is because pregnant women have high GFRs, they excrete drugs very rapidly, they have high volume of distribution, and we often need to use high dosage and shorter dose interval levels. We reserve fluid therapy for women with more moderate -to-severe disease but it is very effective in reducing nausea as well as effective for dehydration. The aim is for outpatients’ administration as much as possible. The less disruption to family life the less withdrawal from their normal lives the better their psychosocial wellbeing. So that depends on your setting, where that outpatient administration may be. It may be in the Emergency Room; it may be in your general practice. It may be in a day surgery or Day Assessment Unit, wherever it is feasible to give outpatient fluids. You do need to check electrolytes, calcium, magnesium, phosphate and liver function tests prior to the first administration, and you may repeat them is you are requiring ongoing IV fluids.
We give the fluids very rapidly because these are young women who can tolerate IV fluids rapidly. They are not going into cardiac failure. So, we often give 1 L over 1 hour or 2 L over 2 hours. We generally use normal saline. Again, see the Guideline. We recommend against using dextrose-containing solutions. These women are not using dextrose as a food. We are using fluid as a hydration aid. There is a risk of Wernicke’s encephalopathy if you use dextrose-containing solutions. We still add thiamine even when we rare giving saline or Hartmann’s. We do not use ketones for the reasons I have already explained, and these women may require 2-3 fluid boluses a week until the natural recovery of the condition, but if it keeps them out of hospital and it keeps them safe it is a small price to pay. IV fluids are a complement to other therapies, not a substitute. We occasionally find women who don’t want to take medication in pregnancy and use IV fluids as their therapy and I would strongly discourage that. I think it is a poor use of resources and it is a poor understanding of the safety data that we have for many of our medications. We want to administer these fluids in a safe, relaxing, appropriately resourced setting and it can be a good time to ensure that they are getting their psychosocial assessment. There are validated mental health scoring and appropriate support. These women can become very isolated and become very sick if you are not seeing them regularly.
Triggers for hospital admission will include women with electrolyte disturbances, women with acute kidney injury, a creatinine > 90, remembering that the creatinine falls in normal pregnancies often < 60. If they have a concurrent significant comorbidity that requires ongoing treatment such as Type 1 diabetes, poorly controlled epilepsy, women on immunosuppressive drugs that are essential or any other essential medication and sometimes those essential medications are psychiatric medications. If they have had demonstrating features of malnutrition or continuing weight loss despite therapy or a ketoacidosis as compared to ketonuria then that may require admission to hospital and associated conditions requiring inpatient management such as infection of haematemesis.
If you want more information about hyperemesis NVP there are two sources; one is the NSW Health Guidelines but the Society of Obstetric Medicine of Australia and New Zealand also have a guideline which covers a number of other areas particularly management of thyroid disease in HG, recurrence, risk and preconception of counselling and it can be accessed and downloaded from this website, and I would encourage you to look at that if you want more information.
So, I would like to hand over to Elizabeth Heiner who is a teratology pharmacist who is going to speak about MotherSafe.
Dr Rachel James:
Just before we cross over Sandra, just one question here that will get you to answer before we go onto Elizabeth.
How about hydrolyte ice blocks with nausea [overlapping of two people talking]
Associate Professor Sandra Lowe:
Again, I would consider that part of nutritional support, if they can handle the taste of Hydralyte then that is great. Some of the foods that I encourage are anything frozen because anything frozen tends to have no smell and these women are very sensitive to smell so Hydralyte is one option but any frozen ice block, frozen grapes, frozen watermelon, anything they can eat and drink, I don’t care if its Coca Cola. I don’t care if it its ginger beer, don’t get too fussy, but Hydralyte they don’t particularly need electrolyte replacement really until they are quite severe, so it is the fluid that is important rather than the electrolytes and the Hydralyte and I find that women often don’t like the taste of Hydralyte but if they like it, they can certainly have it.
Elizabeth Heiner:
Ok. Great. So, I think I might jump in. Good evening, everybody. I am Elizabeth and I one of the teratology information specialists that works at MotherSafe. Hopefully most of you are aware of our service but for those of you that aren’t we will just run through a little bit about what MotherSafe is.
MotherSafe is an NSW state, free telephone advice service about exposures in pregnancy and breastfeeding and we’re based at The Royal Hospital for Women, and we are directed by Dr Debra Kennedy. We are a very unique service. We are actually the only one of our kind in Australia. The main difference with our service and other obstetric information services is that we will provide information about exposures in addition to just medications, so we will give advice to anybody about infections, radiation, food, chemical exposure, occupation exposures, whole range of things so just not medications. Out service is intended for consumers as well as healthcare professionals, obstetricians, psychiatrists, lactation consultants, anybody can give us a call and our standard operating hours are 9 to 5 at the normal Mother Safe service but as part of the NSW NVP and HG initiative we have actually got extended hours at the moment until 9 pm at night and that is where we will specifically providing support for women who are suffering from nausea and vomiting in pregnancy. So, we have a bit more of a tailored support system for women who are ringing our services, so we go through the assessment tools, the PUQE score, some guidance about treatment and we also do some follow-up for those women as well to see how the treatments are working for them. So, obviously because I talk about medication safety all the time in my job what I am hoping to do tonight is to walk you through some of the, I suppose, concerns or perhaps barriers that you might experience when your prescribing medications in pregnancy and some guidance on how to deal with these issues.
So, if we start with first principles, obviously when it comes to prescribing in pregnancy the idea is that all medications should be rationalised. So, as Sandra has mentioned with nausea and vomiting in pregnancy sometimes it might require polypharmacy to manage but every single drug in somebody’s regime of treatment should be rationalised so as Sandra said if there is benefit to a medication, great, but it something is not working then it should be ceased and then moved onto the next agent.
Now when we are considering the safety of medications in pregnancy people will often refer to risk versus benefit, but what I would say about this is that I find in my job that sometimes people aren’t necessarily applying the risk versus benefit to the right things. So, what I find often happens is that people just look at the drug individually and so they are just looking at “Is this drug associated with these particular side effects or risks” and then the fact that if you don’t use a drug there isn’t any, and I think what people need to remember to do is that you need to consider the use of the drug in the context of the woman. So, what you should be looking at is what are the risks associated with the use of medication to treat the particular condition as opposed to what are the risks of not treating the particular condition. The other thing that I would mention is that a lot of the time there is a lot of focus on foetal safety, and I think that when we are talking about risk and benefits, we do have to remember there is a woman as well. So, a really good example that Sandra alluded to earlier is metoclopramide. So, what we see is that metoclopramide is a category A medication, lots of people are very comfortable with its safety in pregnancy but what we find is that people get blinded by the category A and they often forget to follow-up with the normal counselling that they might do for anybody else. So, again if you were giving Maxolon to anybody else people would usually canvas the very rare potential that somebody could develop some dystonic symptoms but often what we see at MotherSafe is that people will often be prescribed a box of 100 metoclopramide with this idea that it is safe and there will be no follow-up or instructions on duration or appropriate use of that medication because people are just so comfortable with the safety. So, just remember that risk versus benefits applies to the mother as well as the baby and always consider the clinical context of your assessment. The other way to say it would be just to remember as well that no medication use doesn’t always mean no risks in pregnancy.
Applying knowledge to practice. If we apply the risk versus benefit concept to ondansetron. We have to first acknowledge that there is a background risk of babies being born with a birth defect of around 3-5% for all pregnancies and this is something that should be alluded to when it is in discussions with any medication use in pregnancy. It is always important again to remember the context. So, when we are looking at the available data on ondansetron you see pregnancy, there is no evidence that the use of medication is associated with an overall increased risk of major malformations above that baseline risk. Now the other thing that we can say with certainty is that after 10 weeks gestation there would be no biological plausibility for an increased risk of birth defects because we know that the conceptus after that period of time would be beyond the embryonic period. So, what is a little bit more of an issue would be the use of the medication before 10 weeks’ gestation and that is because there are quite a number of studies out there with ondansetron and some of them have suggested that there might be an increased risk of specifically orofacial clefts and/or ventricular defects, but what is really important to understand when it comes to interpreting this data is that there has been no consistent evidence of harm. So, there is no proven increased risk. The data in conflicting and if there is a true association the absolute increased risk above baseline would be very small. So, we absolutely can’t rule it out, but it may exist but if it does exist it is extremely small above the baseline risk. So, what does that mean so this is one of the reasons that ondansetron has been reserved as a second line agent for patients and intended for use in patients in whom first line treatments have not worked. So, if we apply this risk versus benefit concept you can see that if somebody requires ondansetron before 10 weeks’ gestation then this is probably someone who has got quite significant symptoms that have not have been able to be managed with first line treatments and then you would need to have a discussion about the potential for an increased risk that shas not been proven against the risk of not treating that condition for that particular individual.
We would be very reassuring if someone was ringing MotherSafe about ondansetron and remind them that it is something that is quite extensively used in pregnancy but also trying to keep it in perspective for them.
The next thing that seems to be a bit of an obstacle to prescribing in pregnancy will be off-label use of medicines. Off-label use is obviously the use of medications that is outside the approved licensing for a drug and many of the medications for nausea and vomiting in pregnancy and HG are considered off-label because there use for this indication or in this population group is not part of the approved labelling by the TGA. Now doctors and pharmacists need to be reassured that off-label use is legal and unfortunately it is very common and often unavoidable in paediatrics and obstetric and maternal care, but what is a critical consideration when you are using off label treatments is that you need to make sure your use of the medication is supported by good-quality evidence and/or formal guidelines and so what we want to do in this talk is reassure you that the NSW health guidelines that we have just presented would be some supporting evidence for off-label use. There are obviously other reputable references that you could use as well. It does require informed consent of the patient, so, again those risk versus benefit discussions are extremely important so that somebody is in a position to be able to make an informed choice about their medication use in pregnancy. It also needs to be appropriately documented and often because it is off label will not be supported by the PBS so it does involve private prescriptions and for father guidance you can certainly have a look at some of the references listen on this slide.
The next thing that I thought I would bring up is just about availability of products. So, as I have mentioned pharmacists can also do off label supply as well, so many of the first line NVP medications can be supplied by a pharmacist without a script but there is a catch on some of these products so in terms of scheduling some products in a S3 schedule or a Pharmacist-Only Schedule will actually have restrictions placed on the indication. So, with respect to nausea and vomiting in pregnancy, prochlorperazine so Stemetil has a restriction in its class of S3 as only being able to be used for nausea associated with migraine only. So, what that means for a pharmacist is if somebody comes in with nausea and vomiting in pregnancy and they ask for prochlorperazine, a pharmacist isn’t legally allowed to give it to them as an S3. For that indication it has to be an S4 and it has to go on a script. Conversely if we have a look at doxylamine. So, doxylamine is marketed for insomnia in Australia and it is an S3, so it is a pharmacist only medication but in the SUSMP there is no restriction in the Guideline about indication for doxylamine and what that means is that a pharmacist is free to give doxylamine off label for nausea, vomiting and pregnancy even where it has been marketed for insomnia but just so you know doctors are aware, that yes if you want your patient to be using prochlorperazine it is something that you do need to give on script even where there is an S3 product available.
Okay. So, this is the big one. So TGA pregnancy categories. It is impossible I think to be dealing with medications in pregnancy in Australia without discussing categories and so many people think that they know the categories but I often find that they might not completely be inline with exactly with what they mean, so, I just think that we will just go really quickly through what the definitions are and then we are going to talk about some of the limitations of the category system and why you might find yourself a bit confused.
So, if we start with category A medications. Category A most people feel really comfortable with, so category A drugs are drugs that have been used by a large number of women. They are not associated with an associated risk of birth defects, and they are also not supposed to be associated with any side effects in the infants.
So, most people are going to feel pretty comfortable about category As.
It is the category Bs that tend to cause a bit more problems. If we just speak to what the definition is. So, the definition of a category B is really drugs that do not have a lot of human data if any. So, they are limited human data. They are not drugs that have been associated with an increased risk of birth defects, but at the same time usually these drugs do not have any human data, and so what happens with category Bs is that there is a subset, B1, B2, and B3 and those subcategories are based on animal data alone. So, there is nothing to do with human data, but those subcategories are to do with the animal data that is presented. Now most new drugs that come into the country will probably be given a category B and that is because obviously there is ethical and legal restrictions about including pregnant women in drug safety trials. So, absolutely when drugs get first put to the market you would expect that most of them will be put in category B, and in fact there are more category B medications than there are any other category of drugs. The biggest issue with category B drugs is that once they have been on the market for a while it is very hard to get them out of category B. We are going to talk about that on the next slide. So, the definition of category B, is that it is limited human data.
Category C medications are actually quite similar in many ways to As. They are not medications that are associated with teratogen risk. The main difference between an A and a C in my view would be that there is something about the drug for a C, some kind of pharmacological effect that can cause some symptoms in a neonate. So, these are going to be your medications that can cause some withdrawal symptoms in a baby, or they might be things like cardiovascular medication that can affect blood pressure, those kinds of medications but they are not associated with any teratogenicity.
Now there are no category D or X medications included in the NSW Health Guidelines, but I am just going to take this opportunity just to canvas what D and Xs are just to make sure there is clarity. So, D and Xs are often confused with each other. Ds are often treated a though they are Xs. So, just to be very clear both of these classes contain medications that have teratogenic potential, but the very big difference between a D and an X is that an X if a drug that you would never ever ever justify being used in a pregnant person ever and when somebody accidentally gets exposed to a category X then that is a situation that where they need to be referred for specialist advice about management because there is significant risk with that. With a category D these are the medications where there is a very big emphasis on risk versus benefit discussions. They are medications that might be associated with some kind of permanent effects of on the baby, but you might still be able to use them in certain circumstances. So, the Ds are drugs that, yes may cause risk but the reason they are in a D and not an X is because there still might be some reason to justify their use in a pregnancy and of course there is things to consider like dose and development stage and disease for use. But I won’t go into that because it is beyond the scope of this talk, but just so you know Ds are not the same Xs.
Alright, problems with the category systems. There are many limitations of the category system. The first one is that it is a very simplified system. So, having letter categories leads to a lot of misinterpretation of risk and one of the most common misinterpretations of risk is that people assume that the letter code is a graduated ranking of risk, and it isn’t. So, if we refer back to the previous slide, medications are in category C are often considered safe than those in category B because if we think about the definition of category Bs. Category Bs are drugs that we don’t have human data on. So, there is a lot of unknown risk with a category B the deserves its category B. The assigned category does not always reflect the current safety information and this is one of the biggest issues with the TGA categories is that they do not get reviewed very often, particularly in the scenario where there is reassuring data. So, our system it works very well as a risk adverse system.
So, when you have a category B medication for example, that has been on the market for a while, we certainly do often gather information postmarketing. So, there will either be inadvertent exposures to that medication, or it might be pregnancy registries, or some observational studies and we will gather information about medications over time. Where there is information that is reassuring, we do not usually see that there is a change in a category. So, we have lots of examples where there are medications that have categories Bs that suggest there is no human data that actually can have significant human data and clinical experience supporting their use and may even be in some formalised guidelines and we have that in this situation. So, it makes the situation difficult because what it means is that on the category B alone you cannot assess risk. So when you are looking at a category B you really can’t tell from the category whether or not it actually truly deserves its category B which there are many that do deserve them and don’t have any data and then you have also got the drugs that actually there will be quite a lot of more information about safety than what the category suggests and this will explain why sometimes you will go to your Australian Medicines Handbook and you will have a reference that will say “Considered safe to use” or “Extensive clinical information” and then you will look at your category B and think “How can the two co-exist”, this is how it can co-exist. It co-exists because this system has limitation in that it does not get reviewed very often. It is dependent on the manufacturers applying for the drug to be reviewed by the TGA and that does tend to work to protect people because where there are evidence of harm we do find that companies are quite reactive and we often do get, well not often but occasionally do get category Bs move to category Ds if there is concerns, but what we find is that it does not seem to work in reverse.
So at the end of it what we would be saying to people is that doctors and patients can be reassured that any of the category Bs that are recommended in this guideline have supporting evidence of their safety in pregnancy, so when you do hand your script of the proton pump inhibitor, the omeprazole to your patient and they say “why are you giving me a drug that hasn’t been studies”, the way that you explain is that “Actually it has been studied and the category is not keeping up with the current information”. So, hopefully that helps you guys.
Now moving onto category Cs. Another issue with the category system is that it doesn’t consider stage of development, so it is just a single letter that has been given to three very different trimesters of pregnancy and when it comes to category C medication as I have mentioned, the category C grading is given to a drug because of its potential to produce a pharmacological effect on a newborn and so this typically is relevant towards delivery and generally speaking would not be pertinent to the use of the medication at any other time in the pregnancy. So, if we have a look at the two category C medications that are in the New South Wales Guideline we have got prochlorperazine and certainly if you use prochlorperazine toward delivery it definitely does have a risk that it can cause some neonatal neurological disturbances but certainly using it in the first trimester is not associated with any increased risk and that is why it is one of the first line agents for NVP.
So, some of the other pregnancy category limitations I have just listed, very quickly, is that the categories don’t differentiate between drugs of significant risk compared to drugs that are associated with less risk. They do not provide information about relative risk of the same medication at different doses or dose forms. I have already mentioned that it does not consider stage of pregnancy and it certainly does not provide a clinical context to risk which is so important. So, as a take home message, the TGA categories; they do have limitations. They are never to be used as an absolute reference. They are overly simplistic, and this is what often does lead to misinterpretation of risk and false assumptions about safety and so where you are in a position where you feel like the category does not line up with something that has been currently and peer reviewed, it is usually because the category is not reflective of the current information.
So, in terms of counselling points; what I would suggest is that keep the information as simple but as evidence-based as possible for your patients, tailor it to the situation, but also remember the impact of your word choice and phrasing. I find that in the area of talking about teratogenicity the word choice is important, the references will often guide you, but you will see a lot of terms like “Considered safety to use”, “Not associated with an increased risk above baseline”, those kinds of phrases where you are really giving them the actual information, you’re not implying more of safety than there is but at the same time you want to be reassuring and realistic with our advice. My experience is that you should acknowledge and address any potential issues about medication use at the time that you prescribe, so, there is certainly in the Australian Medicine Handbook they have taken a position to not include the categories in their medication profiles and certainly I can understand why with all the limitations but my experience as a teratology specialist is that even if you choose not to mention the category to your patients, maybe the pharmacist will when they dispense it or maybe they will notice it in the packaging information when they go to get their medication or somebody will tell them or they will see it online. So, while we have a national pregnancy category system it probably is something that you should mention, especially where you know it may cause concern, such as a category B or category C where people are likely to misunderstand what that is. So, in my advice I would say as you are prescribing it is probably worth mentioning, “I know that this is a category B, but actually there is multiple limitations to the category system and in this situation this category B does not reflect the current evidence base for this particular drug”, so, getting in front of the information is really important.
Obviously, encouraging regular medication review as well as symptoms assessments because obviously symptoms can change and you need to be always going back to that risk versus benefit, “Do we actually need this drug anymore? Is it working? What is the benefit etcetera?” and obviously please refer to MotherSafe if you are unsure of you feel that patients should or could benefit from further advice and discussion. One of the issues with MotherSafe is that you might be on the phone waiting for us for a while but that is because when we do get a caller we take the time to make sure that we unpick any of their concerns, any of their worries and make sure that they really do understand the information to encourage them to proceed with treatments and be able to make an informed choice. So, I will pass it back to Sandra, I think.
Associate Professor Sandra Lowe:
Thanks, that is all we were going to say, but in conclusion. Unfortunately, we have run out of time, but inadequately treated NVP and HG can lead to serious maternal and foetal complications. Appropriate and timely therapy which will always include polypharmacy’s available are effective in most cases. You will need to individualise management plans, document that and share it with the woman and all members of the treating team and if you need more information, the NSW Health Guideline is there and MotherSafe is there and I hope you will feel more confident in following these medication recommendations as they have been developed buy an expert group of clinicians and are based on the most current literature and extensive clinical use. Doctors can reassure women about the safety of these medications in pregnancy and help them have confidence. So, thank you very much and I will hand back to Rachel.
Dr Rachel James:
Thanks everybody. It looks like we have run out of time for questions, so I think Jennifer from RACGP has an email here that you can email for any further questions, and we will endeavour to answer them. Is there anything more that we need to do Jennifer?
Jennifer:
I just wanted to extend my thanks to yourself, Rachel, Sandra and Elizabeth for presenting this evening and also everyone who has joined us online. We do hope that you enjoyed this session and of course enjoy the rest of your evening.