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Om-08-0046 34.37Termination is not the treatment of choice for severehyperemesis gravidarum: Successful managementusing prednisolone E Al-Ozairi MBChB MRCP*, J J S Waugh MBBS MRCOG† and R Taylor MD FRCP* *Directorates of Medicine; †Directorate of Obstetrics, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK Summary: Severe hyperemesis gravidarum causes profound maternal morbidity. Termination of pregnancy is still offered before the use of medical therapy. This report describes management of a woman who had undergone two previous terminations for hyperemesis, and additionally presents the dosage profile of prednisolone used to successfully manage a consecutive series of 33 women with severe hyperemesis gravidarum. The treatment protocol is described. The group had a median weight loss in pregnancy of 5.5 kg (range 2.0 – 12.5 kg), had been admitted on a median of 3.0 (range 0 – 9) occasions and had spent 7.5 (range 0 – 25) days on i.v. fluids. Continuing vomiting prevented oral steroid therapy in 14 women and i.v. hydrocortisone (50 mg t.i.d.; two women required 100 mg t.i.d.) was used initially for 24 – 48 h. Nineteen women commenced prednisolone 10 mg t.i.d. and this achieved suppression of vomiting within 48 h in all but two women who required 15 mg t.i.d. Two distinct subtypes of hyperemesis gravidarum were identified.
Remitting hyperemesis spontaneously ceases between 14 and 22 weeks gestation and accounts for approximately 80% of cases.
In contrast, full-term hyperemesis persists until minutes after delivery. These separate sub-types have not previously been described.
Steroid treatment of hyperemesis should be considered in women who fulfil the criteria of severe disease.
Keywords: hyperemesis, prednisolone, steroid therapy, vomiting, termination of pregnancy Hyperemesis gravidarum occurs with a range of severity, and A 28-year-old woman was referred for pre-pregnancy advice when vomiting is unremitting and unresponsive to standard about hyperemesis. She had suffered severe hyperemesis antiemetics, therapeutic termination is sometimes considered.
during her ﬁrst pregnancy in 2001 with weight loss from Two small series describing successful therapy using high-dose 72 kg to approximately 58 kg and admission to hospital for steroids were reported over a decade ago.1,2 A multicentre i.v. ﬂuids every one to two weeks throughout the pregnancy.
double-blind placebo-controlled one-week trial of prednisolone Therapeutic termination at eight weeks gestation was advised therapy in hyperemesis demonstrated signiﬁcant beneﬁts of because of severe hyperemesis in both 2003 and 2004. She steroids with respect to wellbeing, food intake and weight and her husband were extremely concerned about the prospect gain at one week, but did not have the power to demonstrate of frequent hospital admissions and debilitating illness during effect on readmission.3 Two prospective randomized studies the planned pregnancy that they very much wanted. She had have conﬁrmed that steroid treatment is superior to standard been offered admission during the ﬁrst 12 weeks of pregnancy antiemetic therapies.4,5 We have previously reported that by her local maternity unit. Apart from asthma she was healthy.
steroid therapy is uniformly effective in a consecutive series Her mother had suffered severe vomiting during pregnancy.
of women with severe hyperemesis as deﬁned by the criterion She was advised of the high likelihood of occurrence of of weight loss of .5% of pre-pregnant weight.6 However, severe hyperemesis in a fourth pregnancy. The effectiveness knowledge about steroid dosage regimens to achieve control of high-dose prednisolone in controlling hyperemesis was of hyperemesis is not widespread. In this report, we describe described. The potential maternal side-effects of steroids were successful management of a woman who had undergone two explained. The lack of clear evidence of side-effects on the previous terminations for hyperemesis, and document the baby was discussed. The possibility of requirement for predni- route and dosage of steroid therapy used in a consecutive ﬁve- solone throughout pregnancy was explained. She wished to proceed with conception on the basis that prednisolonetherapy would be commenced at the onset of severe nausea.
Prednisolone tablets were provided together with writteninstructions to take 10 mg t.i.d. from the time of onset ofsevere vomiting and to telephone for further advice.
She became pregnant within three months and experienced the onset of nausea and vomiting many times each day at six Obstetric Medicine 2009; 2: 34 – 37. DOI: 10.1258/om.2008.080046 Al-Ozairi et al. Successful management of hyperemesis using prednisolone weeks gestation. Prednisolone was commenced as instructed.
The vomiting continued and the dose was increased to45 mg, then 55 mg daily over a three-day period. The vomitingthen stopped although nausea continued. By 10 weeks ges-tation, vomiting remained controlled on prednisolone 10 mgt.i.d. Severe nausea persisted and breakthrough vomiting at12 weeks necessitated short-term increase of prednisolone to atotal of 35 mg per day. By 18 weeks gestation she was wellenough to return to work on prednisolone 20 mg daily.
Several trials of decreasing the dosage below 15 mg per daywere all followed by return of vomiting and she remained onthis dose for the rest of the pregnancy.
Weight increased from 78.1 kg pre-pregnancy to 82.0 kg at 36 weeks gestation. She did not require hospital admission duringthe pregnancy. There were no obstetric complications and ahealthy baby was delivered at term. Bone densitometry sixmonths post-partum showed a z score in the normal range.
A consecutive series of 33 pregnancies complicated by severehyperemesis were identiﬁed in the preceding ﬁve years andcase-notes were available for the entire group. Each had beenreferred by her obstetrician to the obstetric medical service Newcastle guideline for management of hyperemesis.
and was judged to meet the criteria for commencement of Notes: (1) Initial i.v. fluid should be normal saline with 20 mmol steroid therapy. The index case is part of the case series. All potassium. Change to 10% Dextrose with potassium 24 hours women had received antiemetics without beneﬁt. The severity after thiamine first given (note that lactate administration usingHartmanns is not optimal and also contraindicated before thia- of the hyperemesis is reﬂected by the clinical characteristics.
mine replacement). (2) Vomiting may temporarily settle with The group had a median weight loss in pregnancy of 5.5 kg bed rest and i.v. fluids, allowing oral prednisolone to be com-menced. (3) Use ranitidine orally or i.v. if heartburn is present.
(range 2.0–12.5 kg) and had been admitted on a median of (4) Once vomiting is controlled and food intake has resumed, 3.0 (range 0–9) occasions. The mean duration of i.v. ﬂuid continue the required dose of prednisolone for 10 days, then requirement was 7.5 (range 0 –25) days. At the time of referral, advise decrease every week thereafter by 5 – 10 mg dependingon the degree of wellbeing. If vomiting recurs, go back to 27 of 31 women had marked wasting of leg muscles as shown immediately previous dose. (5) Prednisolone 1 mg is approxi- by inability to stand up from a squatting position without use of arms. There were 28 Caucasian, four Asian and oneAfrican woman. Other clinical features are shown in Table 1.
All women received thiamine prior to use of steroid.
days. Discharge from hospital was usually possible within Prednisolone or hydrocortisone therapy was administered as 48 hours of oral steroid therapy. Nausea usually persisted to shown in Figure 1. Continuing vomiting prevented oral a variable degree and ptyalism, if present, persisted for steroid therapy in 14 women, and for these women intravenous several weeks. In one woman ptyalism lasted throughout the hydrocortisone at a dose of 50 mg t.i.d. was used initially to pregnancy despite control of vomiting.
control vomiting and this was required for 24 –48 hours. Two After discharge, the dose of prednisolone was decreased at a women required hydrocortisone 100 mg t.i.d. to induce remis- rate of approximately 5 mg per week. Written instructions were sion of vomiting sufﬁcient to commence oral prednisolone.
provided so that if severe vomiting recurred, a return to the pre- Nineteen women commenced prednisolone 10 mg t.i.d. and vious dosage level was undertaken immediately. It was this achieved suppression of vomiting within 48 hours in all observed that most women reached a stable dose around but two women who required 15 mg t.i.d. After control of 15 mg per day and attempts to reduce below this level typically vomiting, the dose was continued unchanged for seven to 10 led to recurrence of vomiting until the natural history of hyper-emesis had run its course. The nausea remitted with character-istic suddenness between 14 weeks and 22 weeks in mostwomen and, thus, steroid dose could rapidly be decreased without return of symptoms. This did not occur in six women who experienced hyperemesis requiring suppression with prednisolone until term. In the latter women, nausea remitted within minutes of delivery. There was no difference in any of the presenting clinical features between those women whose condition remitted and those with full term hyperemesis. The dose requirement of prednisolone for each of these groups of women in relation to gestation is shown in Figure 2. The median duration of steroid use was eight (4 –20) weeks in the spontaneously remitting group and 25 (22 –28)weeks in the full-term hyperemesis group.
Steroid therapy has been used for severe asthma and inﬂammatory bowel disease for many years, and manystudies have not identiﬁed evidence of any harmful effect onthe fetus.12– 17 The transplacental passage of prednisolone islimited to around 10%.18 Some animals are susceptible to orofa-cial clefts after high-dose cortisone.19 Although the study ofRodriguez-Pinilla and Martinez-Frias is often quoted as demon-strating a signiﬁcant effect of ﬁrst trimester steroid use and cleftlip and palate, three of the ﬁve identiﬁed cases appear unlikelyto be relevant.20 One of the three received only two doses of Change in daily prednisolone dosage (mean + SD) for the remitting hyperemesis group (n ¼ 27) and for the full-term prednisolone after eight weeks gestation when lip fusion hyperemesis group (n ¼ 6). One woman in the remitting group would have already occurred, another was associated with required steroids for an unrelated condition in late pregnancy multiple abnormalities and a third was receiving replacementdoses of hydrocortisone. One of the largest studies (20,820 mal-formed infants) found oral cleft rates to be similar between con- trols and those taking steroids in the ﬁrst trimester.21 A recent Steroid therapy for hyperemesis has been used in Newcastle study of 1141 babies with cleft lip and/or cleft palate identiﬁed since 1994 and cases prior to the present series have previously 33 cases in which the mother reported use of inhaled, topical or been reported.2,6 The main purpose of this report is to describe systemic steroids. Only one case related to use of steroids solely the expected pattern of prednisolone usage to achieve control of around the time of lip fusion (5– 7 weeks), although if steroids symptoms in addition to drawing attention to the possibility of were reported to have been taken from week one to week eight, avoiding termination. The case described involving therapeutic six cases were identiﬁed and this was greater than the risk of terminations for hyperemesis is far from unique and more orofacial clefts in controls. For women reporting steroid use widespread recognition of available medical treatment would only in the four weeks prior to pregnancy there was also an association. In this study no association was found with iso- Central to the discussion of management of hyperemesis is lated cleft palate. The data about use of steroids solely after the matter of deﬁning severity. The condition manifests a ﬁve weeks duration do not allow clear conclusion about wide range of intensity, from frequent vomiting but intake of safety, but any absolute risk of orofacial clefts associated with some food on most days to life-threatening prostration. We steroid use must be close to background rates. Using the have previously suggested that severe hyperemesis is best same methodology, Carmichael et al.22 have demonstrated deﬁned by weight loss of .5% of pre-pregnant body weight.6 that stressful events are associated with increased risk of cleft The present series is based upon this deﬁnition, with the excep- lip and palate, and it has to be considered that the stress of tion of women who have previously had severe hyperemesis the underlying illness for which steroids are used may contrib- and present in a subsequent pregnancy with classical symp- ute to any excess risk. This clearly indicates that illness itself is a toms. The deﬁnition was chosen as a guide to deﬁne a group potential confounder of any association. Taking all of the pub- for whom steroid treatment was clearly justiﬁed, but should lished information together, commencing steroid therapy after be interpreted as part of the overall clinical assessment.
ﬁve weeks gestation appears safe. There were no serious maternal Symptoms are affected by physical movement and the apparent side-effects of steroid therapy. In particular, no glucose intole- remission during hospital bed-rest, but recurrence on discharge rance was observed despite regular postprandial testing and has reinforced the view quoted in obstetric textbooks that the no effect on blood pressure was observed. In the present series condition has a psychological basis.7– 10 Professionals dealing no women had type 1 diabetes, but we have previously reported with hyperemesis are sometimes less than sympathetic as how this may be managed in the context of steroid treatment for reﬂected by patient websites (see www.hyperemesis.org.uk; hyperemesis.23 One woman became acutely depressed on the initial dose of steriods, but this resolved and maintenance The characteristic time-course of severe hyperemesis is not dosage of prednisolone was well tolerated. A degree of steroid well-recognized. It universally manifests before eight weeks acne was evident in approximately 20% of women and this gestation (usually 4– 6 weeks), is at its worst early in pregnancy and spontaneously remits in over 80% of women between 14 Some exceptions to the general pattern of prednisolone dose and 22 weeks (remitting hyperemesis). In the remaining response outside the period of the present case series require group with full-term hyperemesis, symptoms continue until mention. Three of approximately 70 women have required pred- delivery and although symptoms may ﬂuctuate in intensity, nisolone 60 mg to achieve remission. Very recently, during the there appear to be no intermediate phenotypes. Remitting preparation of this report, a single case of hyperemesis failed to hyperemesis does not relapse in the rest of pregnancy.
respond to high-dose steroid therapy. This is the sole non- However, full-term hyperemesis requires treatment throughout responder in our cumulative experience of approximately 100 pregnancy to avoid the return of severe vomiting, dehydration cases. Subsequently, this woman had a pregnancy with remit- and weight loss. The two groups were similar in age (median ting severe hyperemesis, which did respond to steroid 28.9 versus 26.7 years) and gestational age at onset (median therapy. Hence, although the dose of steroid required to 5.8 versus 5.2 weeks) for remitting and full-term hyperemesis, induce remission of vomiting does vary, non-response is rare.
respectively; 22/27 and 6/6 women were Caucasian. Previous The general good care of women with severe hyperemesis detailed description of the natural history of severe hyperem- extends beyond the use of steroid therapy. Thiamine replace- esis is lacking and the present observations allow correction ment, possibly with other water-soluble vitamins is required of the textbook deﬁnition of hyperemesis as ‘severe vomiting if vomiting has been prolonged in order to avoid Wernicke’s encephalopathy.24,25 Deﬁciency can arise after lack of food Al-Ozairi et al. Successful management of hyperemesis using prednisolone intake for several weeks. Thiamine is an essential cofactor for 7 Buckwalter JG, Simpson SW. Psychological factors in the etiology and critical enzymes of carbohydrate metabolism and it is import- treatment of severe nausea and vomiting in pregnancy. Am J Obstet Gynecol2002;186:S210 –14 ant that it is replaced before carbohydrate is given. However, 8 Deuchar N. Nausea and vomiting in pregnancy: a review of the problem with once thiamine has been replaced, provision of calories as i.v.
particular regard to psychological and social aspects. Br J Obstet Gynaecol 10% Dextrose (which provides 400 kcal/L) hastens recovery.
Signiﬁcant heartburn is frequently caused by the regurgitated 9 Matteson S, Roscoe J, Hickok J, Morrow GR. The role of behavioral gastric acid and this requires treatment with ranitidine.
conditioning in the development of nausea. Am J Obstet Gynecol2002;186:S239 –43 Finally, mobilization must be gradual as physical movement 10 Uddenberg N, Nilsson A, Almbren PE. Nausea in pregnancy: psychologic and exacerbates the underlying nausea. Discharge is not wise as psychosomatic aspects. J Psychosom Res 1971;15:269 –76 soon as i.v. ﬂuids are no longer necessary, as this may be associ- 11 Fagan E. Disorders of the gastrointestinal tract. In: De Swiet M, ed. Medical ated with loss of control precipitated by the journey home. Full Disorders in Obstetric Practice. Oxford: Blackwell Science Ltd, 1995:383 –7 12 Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans.
and sympathetic explanation of the condition and likely prog- nosis is also part of routine management.
13 Schaltz M, Patterson R, Zeitz S. Corticosteroid therapy for the pregnant It has been suggested that total parenteral nutrition or enteral asthmatic. J Am Med Assoc 1975;233:804 –7 tube feeding can be used in the management of severe hyper- 14 Schatz M, Harden K, Forsythe A, et al. The course of asthma during emesis.26,27 While these approaches may minimize weight loss pregnancy, post partum, and with successive pregnancies: a prospectiveanalysis. J Allergy Clin Immunol 1988;81:509–17 and prevent adverse nutritional consequences for the fetus, 15 Schatz M, Harden K, Kagnoff M, Zeiger RS, Chilingar L. Developmental there are substantial drawbacks. Total parenteral nutrition is follow-up in 15-month-old infants of asthmatic vs. control mothers. Pediatr associated with potentially serious hazards including septicae- mia.28 A naso-gastric tube is uncomfortable and is also associ- 16 Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The safety of asthma and allergy medications during pregnancy. J Allergy Clin Immunol ated with hazards.29 Both modalities leave the woman in hospital or at least attached to tubes and are inferior to 17 Vender RJ, Spiro HM. Inﬂammatory bowel disease and pregnancy. J Clin steroid therapy in restoring wellbeing.
Steroid therapy achieves remission of vomiting in women 18 Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The transplacental with hyperemesis severe enough to cause marked muscle passage of prednisone and prednisolone in pregnancy near term. J Pediatr1972;81:936– 45 wasting and loss of weight. This severity of hyperemesis is 19 Fraser FC, Kalter H, Walker BE, Fainstat TD. The experimental production of rare, and occurred at a rate of 1.2 per 1000 live-births in our cleft palate with cortisone and other hormones. J Cell Physiol Suppl series. The decision to use steroids requires careful discussion with the individual woman. It is a choice which should be 20 Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts: a case-control study. Teratology 1998;58:2– 5 considered before therapeutic termination of pregnancy.
21 Czeizel AE, Rockenbauer M. Population-based case-control study of teratogenic potential of corticosteroids. Teratology 1997;56:335 –40 22 Carmichael SL, Shaw GM, Yang W, Abrams B, Lammer EJ. Maternal stressful life events and risks of birth defects. Epidemiology 2007;18:356 –61 23 Dashora UK, Taylor R. Maintaining glycaemic control during high-dose None of the authors have any competing interests. This paper prednisolone administration for hyperemesis gravidarum in Type 1 diabetes.
was presented to the MacDonald Obstetric Medicine Society 24 Lavin PJ, Smith D, Kori SH, Ellenberger Jr C. Wernicke’s encephalopathy: a predictable complication of hyperemesis gravidarum. Obstet Gynecol1983;62:13s–15s 25 Ohkoshi N, Ishii A, Shoji S. Wernicke’s encephalopathy induced by hyperemesis gravidarum, associated with bilateral caudate lesions oncomputed tomography and magnetic resonance imaging. Eur Neurol 1 Nelson-Piercy C, de Swiet M. Corticosteroids for the treatment of hyperemesis gravidarum. Br J Obstet Gynaecol 1994;101:1013–15 26 Christodoulou DK, Katsanos KH, Makrydimas G, Tsanadis G, Tsianos EV.
2 Taylor R. Successful management of hyperemesis gravidarum using steroid Peripheral parenteral nutrition in protracted hyperemesis gravidarum –report of two cases and a literature review. Acta Gastroenterol Belg 2008;71:259 –62 3 Nelson-Piercy C, Fayers P, de Swiet M. Randomised, double-blind, 27 Vaisman N, Kaidar R, Levin I, Lessing JB. Nasojejunal feeding in hyperemesis placebo-controlled trial of corticosteroids for the treatment of hyperemesis gravidarum – a preliminary study. Clin Nutr 2004;23:53 –7 28 Holmgren C, Aagaard-Tillery KM, Silver RM, Porter TF, Varner M.
4 Bondok RS, El Sharnouby NM, Eid HE, Abd Elmaksoud AM. Pulsed steroid Hyperemesis in pregnancy: an evaluation of treatment strategies with therapy is an effective treatment for intractable hyperemesis gravidarum. Crit maternal and neonatal outcomes. Am J Obstet Gynecol 2008;198:e1 –4 29 Hutchinson R, Ahmed AR, Menzies D. A case of intramural oesophageal 5 Safari HR, Fassett MJ, Souter IC, Alsulyman OM, Goodwin TM. The efﬁcacy dissection secondary to nasogastric tube insertion. Ann R Coll Surg Engl of methylprednisolone in the treatment of hyperemesis gravidarum: a randomized, double-blind, controlled study. Am J Obstet Gynecol1998;179:921 –4 6 Moran P, Taylor R. Management of hyperemesis gravidarum: the importance of weight loss as a criterion for steroid therapy. Quart J Med 2002;95:153 –8
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