Mirtazapine is an effective treatment for refractory Hyperemesis Gravidarum

Mirtazapine is an effective treatment for refractory Hyperemesis Gravidarum | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 10 July 2025 V1 Latest version Share on Mirtazapine is an effective treatment for refractory Hyperemesis Gravidarum Authors : Sumithra Giritharan 0009-0001-7753-7231 [email protected] , Sing Ching Lee , Pushpa Sivakumar , Phoebe Fitzgerald , Katie Lussenberg , Jennifer Pontré 0000-0003-3244-4039 , and Dorothy Graham Authors Info & Affiliations https://doi.org/10.22541/au.175211287.78573862/v1 557 views 287 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective To investigate the efficacy of mirtazapine for the treatment of refractory hyperemesis gravidarum (HG). Design Single centre retrospective observational study. Setting King Edward Memorial Hospital, Perth, Western Australia: December 2022 to April 2024. Population Women with PUQE score ≥7 after standard first and second line treatment for HG. Methods Fourteen women were commenced on mirtazapine and the dose was increased until women reported adequate symptom control. Symptom improvement was assessed by measuring PUQE score before and after treatment with mirtazapine. Side-effect profile, obstetric and neonatal data was collected. Main Outcome Measure The primary outcome measure was the number of women who reported symptom improvement, the number of women who reported complete symptom resolution, the change in PUQE score with mirtazapine treatment and time to symptom improvement. Results All women reported HG symptom improvement upon commencing mirtazapine. Complete resolution of symptoms was reported in six women (42.9%). The mean change in PUQE score was 6.8 ± 3.7 (p<0.001) and the mean time to improvement was 6 ± 4 days. Eight women (61.5%) exceeded IOM targets for gestational weight gain. Two women (14.3%) delivered before 37 weeks gestation; one for severe HG and one for twin pregnancy. No major congenital malformations were detected. Seven babies (46.7%) were admitted the neonatal intensive care unit but none of these admissions were related to mirtazapine use. Conclusion Mirtazapine is an effective treatment for refractory HG. No major obstetric or neonatal side-effects were observed. Title Mirtazapine is an effective treatment for refractory Hyperemesis Gravidarum Authors Sumithra Giritharan 1 , Sing Ching Lee 1 , Pushpa Sivakumar 2 , Phoebe Fitzgerald 2 , Katie Lussenberg 3 , Jennifer Pontré 4 , Dorothy Graham 1,5 Affiliations 1. Department of Obstetric Medicine, Women and Newborn Health Service, King Edward Memorial Hospital, Perth, Western Australia 2. Department of Dietetics, Women and Newborn Health Service, King Edward Memorial Hospital, Perth, Western Australia 3. Adult Special Care Unit and Emergency Centre, Women and Newborn Health Service, King Edward Memorial Hospital, Perth, Western Australia 4. Department of Obstetrics and Gynaecology, Women and Newborn Health Service, King Edward Memorial Hospital, Perth, Western Australia 5. School of Medicine, University of Western Australia, Crawley, Western Australia Corresponding Author Sumithra Giritharan Department of Obstetric Medicine, Women and Newborn Health Service, King Edward Memorial Hospital, Perth, Western Australia +61413135432 [email protected] Running Title Mirtazapine for Refractory Hyperemesis Gravidarum Objective To investigate the efficacy of mirtazapine for the treatment of refractory hyperemesis gravidarum (HG). Design Single centre retrospective observational study. Setting King Edward Memorial Hospital, Perth, Western Australia: December 2022 to April 2024. Population Women with PUQE score ≥7 after standard first and second line treatment for HG. Methods Fourteen women were commenced on mirtazapine and the dose was increased until women reported adequate symptom control. Symptom improvement was assessed by measuring PUQE score before and after treatment with mirtazapine. Side-effect profile, obstetric and neonatal data was collected. Main Outcome Measure The primary outcome measure was the number of women who reported symptom improvement, the number of women who reported complete symptom resolution, the change in PUQE score with mirtazapine treatment and time to symptom improvement. Results All women reported HG symptom improvement upon commencing mirtazapine. Complete resolution of symptoms was reported in six women (42.9%). The mean change in PUQE score was 6.8 ± 3.7 (p<0.001) and the mean time to improvement was 6 ± 4 days. Eight women (61.5%) exceeded IOM targets for gestational weight gain. Two women (14.3%) delivered before 37 weeks gestation; one for severe HG and one for twin pregnancy. No major congenital malformations were detected. Seven babies (46.7%) were admitted the neonatal intensive care unit but none of these admissions were related to mirtazapine use. Conclusion Mirtazapine is an effective treatment for refractory HG. No major obstetric or neonatal side-effects were observed. Funding Source None Keywords Hyperemesis Gravidarum, Nausea and Vomiting in Pregnancy, Mirtazapine Main Text Introduction Hyperemesis gravidarum (HG) is the most severe and incapacitating form of nausea and vomiting in pregnancy and affects between 0.3 and 3.0% of pregnancies(1-3).HG can be complicated by severe dehydration, electrolyte imbalance, weight loss, nutritional deficiencies, renal impairment, Wernicke’s encephalopathy and oesophageal injury(4) . It can result in increased time away from work, deterioration in maternal mental health and even requests for termination of a desired pregnancy(5-8). Neonates of pregnancies affected by HG are at increased risk of low birth weight and preterm birth(9-11). Long term follow-up of these offspring shows an increased risk of neurodevelopmental disorders, anxiety and sleep disturbance (12, 13). One study demonstrated that insulin sensitivity was 20% lower in pre-pubertal children born to mothers with severe HG as compared to controls (14). A Canadian cohort study of more than 1.1million children followed from birth to age 16 years, showed that exposure to maternal HG was a stronger risk factor for childhood hospitalisation than preeclampsia(15). HG is the main cause of hospitalisation in the first trimester of pregnancy(3, 16). A recent Australian based cohort study reported that 29.7% of pregnancies impacted by HG involved multiple hospital or emergency department visits (1). Ambulance services data from the Newcastle Gateshead Clinical Commissioning Group England over a 12-month period revealed that 80.7% of pregnancy related nausea and vomiting calls resulted in an emergency ambulance dispatch(17). As such, effective treatment may prevent maternal morbidity, mitigate adverse offspring sequalae and reduce healthcare costs. Unfortunately, management of refractory cases remains challenging due to a dearth of high-quality evidence(18-20). Furthermore, current recommended treatments are targeted to symptoms of nausea and vomiting with limited focus on other aspects of HG, such as mood disturbance. Mirtazapine is a noradrenergic and specific serotonergic antidepressant that acts on multiple receptors in the brain (3, 21). It inhibits presynaptic α- adrenergic receptors and blocks serotonin 5HT2 and 5HT3 receptors(3, 21, 22). It is thought that antagonism of the 5HT3 receptor provides its anti-emetic properties(4). Its enhancement of the serotonergic and noradrenergic systems in the brain is associated with its antidepressant, anxiolytic and appetite stimulating effect(3, 21, 23). Thus, it provides a unique option for the management of HG. We carried out an observational study to investigate the efficacy of mirtazapine for the management of refractory HG. The secondary aim was to report on its impact on obstetric and neonatal outcomes. Method We prospectively collected data on women prescribed mirtazapine for HG in our centre from December 2022 to April 2024. Data was obtained through direct patient interview, from digital medical records and the STORK database. We defined hyperemesis gravidarum as severe nausea and vomiting starting before 16 weeks gestation limiting normal oral intake and causing severe limitation to daily living. This is in keeping with the Windsor definition of HG (24). Symptom severity before and after treatment with mirtazapine was assessed using the Pregnancy Unique Quantification of Emesis and Nausea (PUQE) scoring index (Appendix 1). Data regarding biochemical derangement, HG related hospital presentations and need for intravenous therapy was collected. Mirtazapine was initiated in women who continued to experience moderate to severe symptoms of HG (PUQE score ≥7) after a reasonable period of treatment with first- and second-line agents. Appropriate first- and second-line treatments included histamine antagonists, dopamine antagonists, phenothiazines, ondansetron and acid suppression therapy. The starting dose of mirtazapine was 7.5mg nocte and this was gradually increased by increments of 7.5mg every few days until symptoms were controlled to the satisfaction of the woman. Once this was achieved, women were directed to wean off mirtazapine gradually. The speed of weaning was individualised based on women’s individual response. Women were followed up until delivery and potential side-effects, obstetric complications and neonatal outcomes were recorded. Statistical analysis was performed with IBM SPSS Statistic for Windows (Version 29.0.2.0, Armonk, NY: IBM Corp). Continuous variables were compared with t -test. Categorical variables were compared with a Chi -squared test or Fisher exact test. A P< 0.05 was considered statistically significant. Birth centiles were calculated using Global Bulk Centile Calculator (BCC version 8.0.6.2). This study was approved by the Governance, Evidence, Knowledge and Outcomes (GEKO) committee of our hospital (Approval number 50968). All women consented to treatment with mirtazapine. Results During the study period a total of fourteen women were prescribed mirtazapine on the ward or through the obstetric physician clinic for refractory hyperemesis gravidarum. Prior to treatment with mirtazapine, medications trialled for HG comprised dopamine agonists in 78.6% of women, ondansetron in 71.4%, histamine antagonists in 57.1%, phenothiazines in 42.9%, proton pump inhibitors in 35.7% and H2 antagonists in 14.3%. The baseline characteristics of our cohort are presented in Table 1. Mean gestational age that HG was diagnosed in our cohort was 7.8 ± 2.7 weeks. Most women experienced complications related to HG (Table 2). Women who experienced weight loss due to HG had more presentations to the emergency department than those who did not (6 ± 5 vs 2 ± 3 episodes, P=0.042). When compared with women who did not lose weight, a higher percentage of women who experienced weight loss had deranged liver function tests (42.9% vs 0%), hypokalaemia (51.7% vs 0%) and acidaemia (42.9% vs 33.3%). Response to treatment All women reported improvement in symptoms after commencing mirtazapine. Six women reported complete symptom resolution (PUQE score 3), five women reported mild residual symptoms (PUQE score 4 to 6) and two women reported moderate residual symptoms (PUQE score 7 to 12). Post treatment PUQE score was unavailable in one patient. The mean change in PUQE score was 6.8 ± 3.7(p<0.001). Four women (28.6%) reported improvement within 3 days of treatment initiation. The mean time to symptom improvement was 6 ± 4 days. Mean gestational age of commencement of mirtazapine was 13.3 ± 5.8 weeks. Eleven women (78.6%) commenced mirtazapine prior to 14 weeks gestation. One woman requested to start mirtazapine at a dose of 3.75mg per day due to concerns about potential side-effects and this dose was effective for her (Table 3). Three women (21.4%) required on-going treatment with mirtazapine after 28 weeks gestation. After an initial period of improvement, two women did not continue to experience sustained improvement with mirtazapine treatment. One woman had a previous diagnosis of an eating disorder with mental health issues and continued to have hospital admissions for electrolyte imbalance and low mood. The second woman reported drowsiness attributed to mirtazapine and had variable adherence to medication. She was trialled on oral prednisolone but after a brief improvement she self-ceased this due to her concerns about side-effects from steroid use in pregnancy. It was noted that 61.5% of women exceeded the Institute of Medicine (IOM) recommended gestational weight gain targets. This occurred in 57.1% of singleton pregnancies with a pre-pregnancy BMI between 18.0 and 24.9, 50.0% of women with a pre-pregnancy BMI between 25.0 and 29.9 and all women with a pre-pregnancy BMI greater than 30. Recommended gestational weight gain was not exceeded in the woman with twin pregnancy. The difference in duration of mirtazapine use was not statistically significant between the women who exceeded target gestational weight gain and those who did not (53 ± 26 versus 72 ± 54 days, P=0.51). Total gestational weight gain was less in women who had experienced weight loss with HG as compared to those who did not (10.9kg vs 20.3kg, P=-0.027). No other maternal side-effects were observed. Obstetric and neonatal outcome Two women delivered before 37 weeks gestation (Table 4). One woman underwent induction of labour at 35 weeks at 6 days gestation for hyperemesis gravidarum. The other woman underwent an elective Caesarean section at 35 weeks and 5 days gestation for twin pregnancy. Excluding the twin pregnancy, birth centiles of neonates born to women who experienced greater than 10% weight loss due to HG was lower than those neonates born to women who did not (31.4 ± 11.9 versus 71.6 ± 28.0, P =0.004). Excluding the twin pregnancy, birth centiles of neonates born to women who exceeded the target gestational weight gain was not different compared to neonates born to women who did not (63.5 ± 27.1 versus 59.5 ± 39.4, P= 0.864). No major congenital malformations were detected in our cohort. Seven babies required admission to the neonatal intensive care unit. One neonate was admitted due to maternal HIV infection. One of the twins was admitted due to poor feeding. One required intravenous antibiotics due to meconium stained liquor. Four babies were admitted to the neonatal intensive care unit for respiratory support; one was delivered under general anaesthetic, one was delivered preterm as part of a twin pregnancy, one baby was born to a mother with type 1 diabetes, and one was born to a mother with gestational diabetes. None of the neonates born to women requiring mirtazapine in the third trimester were admitted to the neonatal intensive care unit. Discussion Main Findings All women reported HG symptom improvement with mirtazapine treatment as demonstrated by a significant improvement in pre and post treatment PUQE score. Sustained improvement was observed in 85.7% of women and complete resolution of symptoms was observed in 42.9%. In terms of side-effects, most women exceeded the recommended gestational weight gain target. We did not detect a correlation between duration of mirtazapine use and total gestational weight gain. Due to severe HG, one woman was delivered before 37 weeks. There were no major congenital abnormalities detected in our cohort. None of the neonatal intensive care admissions were related to maternal mirtazapine use. Strengths and Limitations The first strength of our study was our use of the Windsor definition of HG, an internationally recognised diagnostic criteria for this disease. The second strength of our study is the use of pre- and post-treatment PUQE score. This provides a validated score to quantify symptom severity and measure change with treatment. Thirdly, our study focused on patients with severe and refractory symptoms as demonstrated by the high rate of metabolic derangement and healthcare use in our patient cohort. This represents the severe spectrum of this disease and management of women in this group remains under researched. A recent systematic review concluded that that there are too few studies of high quality evaluating the effects of treatments for HG and further research was required(20). As such our publication aims to contribute to the knowledge gap that remains in the treatment of this women. The main limitation of our study is that given its observational nature, we were not able to compare the efficacy of mirtazapine to other treatment options. We only followed women up to the immediate post-partum period and therefore we are not able to assess for potential medium- and long-term effects of mirtazapine use on neonates. Finally, our small study size and inclusion of only women with severe symptoms may limit the generalizability of our results. Interpretation The efficacy of mirtazapine for the treatment of HG has been previously described in small case series (5-8, 25-28). Case reports of women requesting termination of pregnancy due to severe HG who subsequently improved with mirtazapine and continued their pregnancies to have successful deliveries provide further evidence of its therapeutic potency(5, 7). Our finding of rapid improvement of HG symptoms is in keeping with other publications (7, 29). This reflects the drug’s rapid enteral absorption and ability to reach peak plasma concentration (C max ) within 1 to 2.1 hours of first dose(21). One of the research questions identified to be prioritised by the James Lind Alliance HG priority setting partnership steering group (comprising patients, carers and multidisciplinary professionals) was the need for a treatment to address all symptoms of HG other than just vomiting (30). Women with HG are at increased risk of developing secondary anxiety and depression (31). Several case series have described the benefit of mirtazapine in treating anxiety and depression secondary to HG (8, 25, 26). Additionally, mirtazapine exerts an appetite stimulating effect which may be beneficial to counteract the weight loss from HG (27). As such, the unique constellation of effects from mirtazapine may be preferential in women with HG symptoms not limited to nausea and vomiting. One of the barriers to mirtazapine prescription in pregnancy is the uncertainty surrounding fetal safety. Current published evidence with regards to congenital malformations and birth defects in pregnancies exposed to mirtazapine remains mixed. A multicentre prospective observational study of 357 women exposed to mirtazapine in pregnancy detected a higher rate of birth defects in the mirtazapine group as compared to controls, after excluding chromosomal and genetic abnormalities(32). This was followed by a Nordic registry based case-control study that reported a two-fold increase odds ratio for elective termination of pregnancy for fetal abnormalities between 12 and 23 weeks gestation in women exposed to mirtazapine in pregnancy(33). The primary indication for mirtazapine prescription in these populations was psychiatric disease and it is unclear how the underlying mental health condition or associated behavioural habits confound these results. Conversely, Swedish and Danish registry-based studies, did not detect significantly increased risk of birth defects in pregnancies exposed to mirtazapine(34, 35). A recent systematic review of 2343 pregnancies exposed to mirtazapine concluded the quality of the available evidence was generally low and that, results regarding congenital malformations were conflicting(36). In our series, ten patients commenced treatment before 14 weeks gestation and no major birth defects were detected in our series. Neonatal adjustment syndrome which is associated with maternal use of SSRI’s in the third trimester of pregnancy includes difficulty feeding, sleeping, jitteriness, increased muscle tone and irritability. It is seen in up to 51% of neonates in mothers prescribed SSRI ‘s for mental health diagnoses (37, 38). This condition was not documented in any of the neonates in our population. Given these uncertainties and limited data on the long-term impact on the offspring, we would advocate that mirtazapine be prescribed for the most severe cases after weighing up the risks and benefits. Through a shared decision-making process, patients and clinicians should consider the potential for mirtazapine to mitigate the short- and long-term impact of on-going refractory HG on the pregnancy. Use of mirtazapine in our cohort was reserved only for patients with the most severe form of the disease as reflected by the high rate of HG related complications. Current guidelines recommend the use of corticosteroids for cases of HG refractory to first- and second-line treatment despite conflicting data for its benefit or efficacy to prevent hospitalisations(18, 39-42). Furthermore, the side-effect profile of corticosteroids includes maternal dysglycaemia, worsening acid reflux, insomnia, acne, peripheral neuropathy, mood disorder and acute mania. Use in the first trimester has been associated with an increased risk of cleft palate defect in the offspring. The American College of Obstetrics and Gynaecology cautions the use of corticosteroids for HG beyond 6 weeks, to limit serious maternal adverse effects(18). A clear need to investigate novel treatment modalities for HG has been identified (43). Mirtazapine may provide a favourable alternative to steroids for the treatment of refractory hyperemesis gravidarum. Following on from this study we are planning a randomised controlled trial evaluating the efficacy of mirtazapine compared to prednisolone for the treatment of refractory HG. In this study, we also plan to measure the effects of mirtazapine on other aspects of HG such as mood and insomnia. Conclusion In conclusion, our study demonstrates that mirtazapine is a highly effective treatment for severe HG resulting in an improvement of symptoms of nausea and vomiting as measured by the PUQE score. There were no adverse obstetric or neonatal outcomes attributed to mirtazapine in our series. Weight gain is a recognised side-effect of mirtazapine. However, it is unclear how this compares to other treatments for severe HG, for example corticosteroids. Treatment of women with refractory HG can often be challenging and should extend beyond the management of symptoms of nausea and vomiting only. Mirtazapine may provide a unique multimodal therapeutic option in the management of women with severe HG. Our findings justify the need for a randomised controlled trial comparing mirtazapine to other recommended treatment options for HG. Declaration Contribution of Authorship SG was responsible for data acquisition, data analysis, drafting the manuscript and approval of the final version of the manuscript. SL was responsible for conception of the study, data analysis and final approval of the manuscript. PS was responsible for conception of the study, data analysis and final approval of the manuscript. PF was responsible for conception of the study, data analysis and final approval of the manuscript. KL was responsible for conception of the study and final approval of the manuscript. JP was responsible for conception of the study and final approval of the manuscript. DG was responsible for conception of the study, data acquisition, data analysis and final approval of the manuscript. Funding Statement None Acknowledgement None Conflict of Interest Nothing to declare Details of Ethical Approval This study was approved by the Governance, Evidence, Knowledge and Outcomes (GEKO) committee of Women and Newborn Health Services, King Edward Memorial Hospital, Perth, Western Australia (Approval Number 50968) on 10 May 2024. References 1. Pont S, Bond DM, Shand AW, Khan I, Zoega H, Nassar N. Risk factors and recurrence of hyperemesis gravidarum: A population-based record linkage cohort study. Acta Obstet Gynecol Scand. 2024.2. Nurmi M, Rautava P, Gissler M, Vahlberg T, Polo-Kantola P. Incidence and risk factors of hyperemesis gravidarum: A national register-based study in Finland, 2005-2017. Acta Obstet Gynecol Scand. 2020;99(8):1003-13.3. London V, Grube S, Sherer DM, Abulafia O. Hyperemesis Gravidarum: A Review of Recent Literature. Pharmacology. 2017;100(3-4):161-71.4. Abramowitz A, Miller ES, Wisner KL. Treatment options for hyperemesis gravidarum. 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Systematic evidence map of evidence addressing the top 10 priority research questions for hyperemesis gravidarum. BMJ Open. 2022;12(9):e052687. Supplementary Material File (table 1.docx) Download 14.42 KB File (table 2.docx) Download 16.58 KB File (table 3.docx) Download 21.38 KB File (table 4.docx) Download 18.43 KB Information & Authors Information Version history V1 Version 1 10 July 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords antenatal care early pregnancy maternal medicine medical disorders in pregnancy Authors Affiliations Sumithra Giritharan 0009-0001-7753-7231 [email protected] King Edward Memorial Hospital View all articles by this author Sing Ching Lee King Edward Memorial Hospital View all articles by this author Pushpa Sivakumar King Edward Memorial Hospital View all articles by this author Phoebe Fitzgerald King Edward Memorial Hospital View all articles by this author Katie Lussenberg Women and Newborn Health Service Western Australia View all articles by this author Jennifer Pontré 0000-0003-3244-4039 Women and Newborn Health Service Western Australia View all articles by this author Dorothy Graham King Edward Memorial Hospital View all articles by this author Metrics & Citations Metrics Article Usage 557 views 287 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Sumithra Giritharan, Sing Ching Lee, Pushpa Sivakumar, et al. Mirtazapine is an effective treatment for refractory Hyperemesis Gravidarum. Authorea . 10 July 2025. DOI: https://doi.org/10.22541/au.175211287.78573862/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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