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Three Part Question

In [patients with intractable hyperemesis gravidarum] does [a trial of steroid therapy] lead to [symptomatic relief]?

Clinical Scenario

A 22-year-old woman, who is currently 12 weeks pregnant, presents to the emergency department complaining of a four week history of severe nausea and vomiting. She appears to be clinically dehydrated and urinalysis confirms she is ketotic. Immediate management includes intravenous fluids and standard anti-emetics. Unfortunately she gets minimal relief and continues to vomit. You recall from your recent oncology placement, the beneficial effect of steroid therapy on chemotherapy induced vomiting, and wonder if a trial of steroids might be useful to control the symptoms of severe hyperemesis gravidarum (HG)

Search Strategy

EMBASE 1980 to 2011 week 23 and Medline 1948 to June week 2 2011 via the OVID interface using the following search strategy: {(exp hyperemesis gravidarum/ OR hyperemesis gravidarum.mp) AND (exp steroids/ OR steroids.mp OR exp prednisolone/ OR prednisolone.mp OR exp hydrocortisone/ OR hydrocortisone.mp OR exp methylprednisolone/ OR methylprednisolone.mp)}. LIMIT to humans and English.

Search Outcome

A total of 197 papers were found, of which 9 were considered relevant to the three-part question and of sufficient quality.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Nelson-Piercy et al 1994 UK	4 patients with intractable HG, treated with high dose steroids	Case series	Symptomatic relief from vomiting	All 4 patients were asymptomatic within 24 hours	Small number of patients. Level 4 evidence
Taylor 1996 UK	7 patients with severe HG were treated with high dose steroid therapy	Case series	Symptomatic relief from vomiting	Vomiting ceased in all within 3 hours	Small number of patients. Level 4 evidence
Safari et al 1998 USA	18 patients with intractable HG were given 3 days of 48mg / day i.m. methylprednisolone (then tapered dose)	Case series	Symptomatic relief from vomiting	94% patients were free of vomiting within 3 days of treatment. Recurrence in 53% during or after tapering.	Small number of patients. Level 4 evidence
Safari et al 1998 USA	40 patients with intractable HG Randomised to 16mg oral methylprednisolone tds (then tapered dose) or 25mg oral promethazine tds for 2 weeks	Prospective randomised double-blind controlled trial	Symptomatic relief from vomiting or ability to tolerate oral fluids within 2 days. Readmission to hospital within 2 weeks.	No significant difference – 17/20 in steroid group and 18/20 in promethazine group improved within 2 days. Significantly lower readmission in steroid group: 0/17 in steroid group and 5/17 in promethazine group readmitted (p<0.0001).	Pilot study - no formal power calculation. No placebo group. Groups non-comparable at baseline - duration of HG longer in promethazine group (P=0.03).
Nelson-Piercy et al 2001 UK	25 patients with intractable HG Randomised to 7 days of 20mg bd oral prednisolone (or iv equivalent, followed by oral tapered dose) or placebo	Prospective multi-centre randomised double-blind placebo-controlled trial	Vomiting scores at 1 week (0-4). Dependence on iv fluids at 1 week .	No significant difference: median reduction of 1.5 in placebo and 2.0 in steroid group (p=0.26). No significant difference: 3/12 patients in each arm still dependant on iv fluids at 1week.	Underpowered study – 45 subjects required by power calculation, only 25 recruited (none after publication of interim analysis). Groups non-comparable at baseline – higher number previously admitted patients and higher gestational age in steroid treated.
Moran et al 2002 UK	25 patients (30 pregnancies) of ≥8 weeks gestation with intractable HG Subjects given flexible dose and route of steroid and response compared to 25 cases HG not requiring steroids	Retrospective observational study	Requirement for iv fluids	73% and 90% patients in steroid group no longer required iv fluids at 24 and 48 hours respectively. (No data for controls)	Small sample size. Non-comparable at baseline. End points poorly defined. Variable dosage of steroids given to the patients in study group
Yost et al 2003 USA	110 inpatients of ≤20 weeks gestation with intractable HG Randomised to single bolus of 125mg iv methyl-prednisolone (followed by oral tapered prednisolone) or placebo	Prospective randomised double-blind placebo-controlled trial	Number requiring subsequent readmission for HG within 2 weeks.	No significant difference in readmission rates: 34% steroid treated readmitted v 35% in placebo group (p=0.89).	16/126 patients lost to follow-up. All study patients also given regular conventional anti-emetics.
Ziaei et al 2004 Iran	80 patients of gestational age 6-12 weeks with HG treated on out-patient basis Randomised to 10 days oral prednisolone 5mg od or promethazine 25mg tds	Prospective randomised controlled trial	Response in first 48 hours, days 3 – 10 and day 17, of : Severity of nausea (VAS 0-100mm). Median number of vomits per day. Subjective response to treatment.	Nausea scores in first 48 hours were lower in promethazine group (p<0.02). No other significant differences. Number of vomits lower in promethazine group in first 48 hours: median 1 (95% CI 0-4) in promethazine group v 3 (95% CI 1-7) in steroid group (p<0.04). No other significant differences. Higher in promethazine group: 75% v 50% reported improvement in first 48 hours (p<0.04). No other significant differences.	Pilot study. No formal power calculation. Patients not blind to treatment. Low dose of steroid used. Out-patient setting – patients excluded if dehydrated or had abnormal electrolytes
Bondok et al, 2006 2006 Egypt	40 patients with intrauterine pregnancy of ≤16 weeks gestation with intractable HG requiring ITU admission Randomised to 7 day tapering course of iv hydrocortisone or 10mg tds iv metoclopramide	Prospective randomised double-blind controlled trial	Mean number of vomiting episodes per day. Readmission to ITU within 2 weeks.	Significantly reduced in hydrocortisone group at days 2, 3 and 7 (p<0.0001). Significantly lower in hydrocortisone group: 0/20 readmitted in hydrocortisone group v 6/20 in metoclopramide group (p<0.0001).	Small sample size. Patients only recruited from ITU setting, although reason for ITU admission not stated.

Comment(s)

Despite several case series and an observational study advocating the use of steroids in intractable HG, the evidence from randomised controlled trials appears less convincing. Ethical considerations were cited by several authors as the reason preventing comparison of steroids with placebo in this patient group, and neither of the two placebo-controlled RCTs (Nelson-Piercy et al and Yost et al) provided any statistically significant primary results in favour of steroid use over placebo. Nelson-Piercy et al did note a significant improvement in favour of steroids with regards to secondary end-points (such as well-being rating and food intake scores) whilst a non-significant trend towards lower vomiting scores was observed. Of note the study was terminated prematurely and under-powered due to lack of patient recruitment. Three RCTs compared steroids with established anti-emetics (Safari et al, Ziaei et al and Bondok et al). The latter ITU-based study showed a significant benefit in symptom relief and subsequent ITU readmission in those treated with iv hydrocortisone over iv metoclopramide. Safari et al showed oral methylprednisolone to be as efficacious as oral promethazine in symptom relief within 48 hours, as well as significantly reducing the need for subsequent hospital readmission. Ziaei et al found promethazine to significantly reduce severity of nausea and number of vomits within 48 hours compared to low dose oral prednisolone on an out-patient cohort of patients. No study reported any serious side-effects of steroid treatment.

Editor Comment

HG, hyperemesis gravidarum; IM, intramuscularly ITU, intensive treatment unit; IV, intravenously.

Clinical Bottom Line

There appears to be weak evidence to support the use of steroids in intractable HG, however further high quality research is required.

References

1. Nelson-Piercy C, de Swiet M Corticosteroids for the treatment of hyperemesis gravidarum Br J Obstet Gynaecol 1994;101:1013-5.
2. Taylor R Successful management of hyperemesis gravidarum using steroid therapy Q J Med 1996;89:103-7
3. Safari H, Alsulyman O, Gherman R, et al Experience with oral methylprednisolone in the treatment of refractory hyperemesis gravidarum. Am J Obstet Gynecol 1998; 178:1054-8
4. Safari H, Fassett M, Souter I, et al. The efficacy of methylprednisolone in the treatment of hyperemesis gravidarum: A randomized, double-blind, controlled study. Am J Obstet Gynecol 1998;179:921-4.
5. Nelson-Piercy C, Fayers P, de Swiet M Randomised, double-blind, placebo-controlled trial of corticosteroids for the treatment of hyperemesis gravidarum. Br J Obstet Gynaecol 2001;108:9-15
6. Moran P, Taylor R. Management of hyperemesis gravidarum: the importance of weight loss as a criterion for steroid therapy. Q J Med 2002;95:153-8.
7. Yost N, McIntire D, Wians F, et al. A randomized, placebo-controlled trial of corticosteroids for hyperemesis due to pregnancy Obstet Gynecol 2003;102:1250-4
8. Ziaei S, Hosseiney F, Faghihzadeh S The efficacy low dose of prednisolone in the treatment of hyperemesis gravidarum. Acta Obstet Gynecol Scand 2004;83:272-5.
9. Bondok R, El Sharnouby N, Eid H, et al. Pulsed steroid therapy is an effective treatment for intractable hyperemesis gravidarum. Crit Care Med 2006;34:2781-3.