1 Nausea and Vomiting in Pregnancy Tekoa L. King CNM, MPH June 7, 2016 Disclaimer • I do not have any financial relationships with any of the products mentioned in this presentation Objectives • Review of epidemiology of NVP • Discuss efficacy and safety of pharmacologic treatments • Algorithm for diagnosis and treatment of NVP A modern day presentation…… • Sarah is G1 P0 now7 weeks after her LMP presenting for her first prenatal visit • c/o “nausea all day” vomits once or twice and retches when she brushes her teeth. Sensitive to smells. Sx present x 2 weeks • Wearing sea bands her sister gave her but they are not helping • Urinating less frequently than usual and urine sp gr is 1030
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1
Nausea and Vomiting in Pregnancy
Tekoa L. King CNM, MPHJune 7, 2016
Disclaimer• I do not have any financial relationships with any of
the products mentioned in this presentation
Objectives• Review of epidemiology of NVP
• Discuss efficacy and safety of pharmacologic treatments
• Algorithm for diagnosis and treatment of NVP
A modern day presentation……• Sarah is G1 P0 now7 weeks after her LMP presenting for her
first prenatal visit
• c/o “nausea all day” vomits once or twice and retches when she brushes her teeth. Sensitive to smells. Sx present x 2 weeks
• Wearing sea bands her sister gave her but they are not helping
• Urinating less frequently than usual and urine sp gr is 1030
2
How Would You Treat Her?A. Review non-pharmacologic
treatments and schedule a return visit in a week
B. Prescribe Diclegis, metoclopramide, or another anti-emetic and offer IV hydration
C. Admit for IV hydration, NPO, start ondansetron
D. Other
R e vi e w
n o n- p h
a r ma c o
l o g ..
P r es c r i
b e Di c l e
g i s , m e
t o c .. .
A d mi t f o
r I V h y d
r a t io n ,
. . . O t he r
48%
2%9%
41%
Nausea and Vomiting of Pregnancy (NVP)
Niebyl JR 2010 NEJM, Lacroix R 2000, Matthews A et al Cochrane review 2014
• 50-80% of all pregnant women experience NVP– 50% experience retching– 25% have nausea only– 25% unaffected
• Mean onset is ~ 5th wk s/p LMP, peaks at 9th wk– 60% resolve by 12-14 weeks– 90% resolve by 20 weeks– 5% will have symptoms throughout pregnancy
• Second most common reason for prenatal hospitalizations in US (11.4% of all non-delivery antenatal admissions)
Women’s Reports of NVP• Effect of NVP
– 50% say NVP affects their ability to work– 25% require time off from work– 50% say it affects their relationship– 55% report being depressed
• Effect of severe NVP or hyperemesis:– 76% changed plans for future children– 15% terminated pregnancy secondary to hyperemesis– 7% with long-term psychologic sequelae
• Yet, 75% of women with NVP are worried that drugs to treat NVP are teratogenic
Miller F 2002, O’Brien B 1992, Poursharif B 2007, Baggley 2004
Modified “PUQE” INDEX
Score: MILD: < 6; MODERATE: 7-12; SEVERE: ≥ 13
1. On an average day, for how long do you feel nauseated or sick to your stomach?
> 6 hrs(5 pts.)
4-6 hrs(4 pts)
2-3 hrs(3 pts)
≤1 hr(2 pts)
Not at all(1 pt)
2. On an average day how many times do you vomit or throw up?
7 or more(5 pts)
5-6 (4 pts)
3-4 (3 pts)
1-2 (2 pts)
None (1 pt)
3. On an average day how many times do you have retching or dry heaves without bringing anything up?
7 or more(5 pts)
5-6 (4 pts)
3-4 (3 pts)
1-2 (2 pts)
None (1 pt)
Lacasse A et al 2008, Koren G 2005, Ebrahimi N 2009
3
Pathways that Mediate Nausea and Vomiting Offer Several Targets for Pharmacologic Treatments
to qid• Approved by FDA for NVP in 1956• Dicyclomine removed from product in 1970’s• 1980: lawsuits and media coverage resulted in Bendectin
being discontinued in 1983• Remained in use in Europe and Canada
• Efficacy: in treating NVP in 2 RCTs – RR 0.53 (95% CI 0.41-0.68)
• Safety: Pooled RR for fetal malformation in multiple studies– RR 0.98 (95% CI 0.93-1.02)
Magee LA et al 2002, Koren G 2015, Jewel Cochrane 2003
Time-Trend of NVP Hospitalization RateLimb Reduction Deformities, and Bendectin Usage
(1974-1994)
NVP-18McKeigue PM et al 1994
NVP Hospitalizations*
Limb Reduction Deformities
Bendectin Sales
*NVP hospitalizations per 10,000 live births
5
2013: FDA Approves Diclegis Diclegis• 10 mg doxylamine and 10 mg pyridoxine in a delayed release
tablet– Usual dose is 2 tablets at night– If insufficient response add 1 tablet taken in the morning– Max dose is qid: 1 in morning, 1 in afternoon and 2 tabs at
night• Instructions
– Take on an empty stomach as some foods inhibit absorption
– Needs to be taken regularly and not prn because the delayed release is a critical component of effectiveness
Diclegis• Contraindications
– Known hypersensitivity to doxylamine or ethanolamine derivative antihistamines, or pyridoxine
– MAO inhibitors intensify and prolong anticholinergic and CNS effects
• Warnings– Classified as an antihistamine: may cause somnolence– Not recommended if drinking alcohol or taking sedatives– Anticholinergic effects: persons with asthma, narrow angle
glaucoma, stenosing peptic ulcer, or urinary bladder neck obstruction should use it with caution
Diclegis• Few interesting notes:
– Mechanism of action is not known
– Pharmacokinetics are interesting:• Peak concentration is 5-7 hours• No pregnancy induced changes in pharmacokinetics• Doxylamine accumulates but pyridoxine does not• Terminal half life is 12.5 hr and 0.5 hr respectively
– Has not been studied in adolescents or women with hyperemesis
– Breastfeeding women should not take Diclegis– Fatalities reported following pediatric overdose
Matok et al 2014, Duschesney Prescribing information for Diclegis
6
Studies of Diclegis• Efficacy:
– Significant reduction of nausea and vomiting and improvement in quality of life
– Koren G 2010: Double blind RCT, N = 261• Mean change in PUQE score from before treatment to
after 3 days of treatment– 4.8 ± 2.7 in Diclegis group vs 3.9 ± 2.6 in Placebo
group (P = .006)– Similar differences in global assessment of
wellbeing– No difference in reports of adverse effects between groups
• Overall in older studies this drug combination results in an average of 70% reduction in NVP
Koren G 2010, Magee LA 2002, ACOG 2015
Studies of Diclegis• Safety:
– More than 170,000 women in case control and cohort studies found no increase in adverse fetal/newborn effects
Punchline:• Initiation before symptoms is more effective than waiting for
symptoms to appear• Diclegis is more effective than homemade combinations because
the extended release formulation appears to work better than short-acting over-the-counter formulations
• ACOG recommends this combination of doxylamine/pyridoxine as the first-line drug if non-pharmacologic measures are not effective
Koren G 2010, Magee LA 2002, ACOG 2015, McKeigue KM 1994
• Effectiveness: – Effective in � vomiting– RR 0.34 (95% CI 0.27-0.43)– OR for drowsiness 2.19 (95% CI 1.1-4.4)
• Safety: – 24 RCTs of various antihistamines– First trimester exposure to antihistamines is associated with a
slightly lower risk of major/minor malformations • OR 0.76 (95% CI 0.60-0.94)
Magee AL et al 2002, Seto A et al 1997 Jewell DA 2003
AnticholinergicsDicyclomine (Bentyl) and Scopolamine (Transderm)
• Dicyclomine – No evidence of effectiveness – No evidence of risk in Bendectin studies
• Scopolamine– Used in non-pregnant persons for N&V– Transdermal patch– Effectiveness: No studies on effectiveness in NVP– Safety: Two observational studies of ~336 women with 1st
trimester exposure found no evidence of � risk to fetus
Mazzotta & Magee 2000, Magee LA 2002
7
Dopamine antagonist: Phenothiazines
Promethazine (Phenergan) and Prochlorperazine (Compazine)• Effectiveness
– 3 RCT for severe NVP, (n= approx. 400)– � NVP: RR 0.31 (95% CI 0.24-0.42)– Consistently effective but modestly effective
• Safety:– No � risk for congenital malformations
• Summary– Widely used, with proven efficacy for NVP – More helpful in stopping vomiting than antihistamines– Dystonic reactions rare but � following prolonged use– Sedation can be a problematic side effect
Mazzotta & Magee 2000
Dopamine Antagonist: Metoclopramide (Reglan)
• Both dopamine and serotonin antagonist. Has central and peripheral effects, � gastric emptying. Can be used orally, IV, or SQ
• Effectiveness– No controlled trials found
• Safety– No � risk for congenital malformations in large Danish
database of 28,486 exposed women– Crosses blood/brain barrier and more likely to elicit dystonic
reaction than other antiemetics– Cross reacts with prochlorperazine (Compazine)
Matok I NEJM 2009, Magee et al 2002, Pasternak B 2013
Dopamine Antagonist:Droperidol (Inapsine)
• Effectiveness– No RCTs performed to date– One study (n=80): Continuous infusion of
droperidol/diphenhydramine was associated with �hospitalization stay and need for parenteral nutrition in women admitted with hyperemesis
– 15% had some extrapyramidal side effects despite diphenhydramine
• Safety– No � risk for congenital malformations– Small association with prolonged QT interval– Some risk of dystonic reaction
Summary: FDA Black Box warning about prolonged QT interval and ACOG recommends “use with caution”
Nageotte M 1996, ACOG 2004, Magee et al 2002Magee et al 2002, ACOG 2015
Serotonin Antagonist:Ondansetron (Zofran)
• Efficacy: – Equal to promethazine and metoclopramide for resolving NVP– Better than doxylamine/pyridoxine ?
• Safety– Studies on congenital malformation are conflicting
• Possible association with cleft palate and cardiac septal defects in 2 studies
• No � risk for congenital malformations in other studies– Associated with prolonged QT interval and FDA warns to use
with caution– Do not use more than 16 mg– Multiple drug-drug interactions
Carstairs SD 2016, Danielsson et al 2014, Pasternak B NEJM 2014
8
Corticosteroids• Efficacy
– Equal to promethazine in improving NVP for women hospitalized with hyperemesis
– Unclear effect on � readmissions
• Safety – No � risk for major congenital malformations– Small but significant � risk for oral cleft malformations– ? � in PPROM following chronic use
Summary: ACOG recommends that steroids be avoided prior to 10 weeks gestation
ACOG 2004, Mazzotta & Magee 2000, Magee LA 2002
Anti-emetics: Summary• Vit B6 effective for nausea but not vomiting
• Doxylamine/pyridoxine combination first-line choice for outpatient management of mild-moderate NVP
• Antihistamines and phenothiazine treat vomiting, not nausea and they cause sedation which leads to discontinuing treatment
Anti-emetics: Summary• Dopamine antagonists:
– Metoclopramide causes dystonic reactions, cross reacts with prochlorperazine (Compazine)
– Ondansetron (Zofran), expensive, • may be associated with small increase in cardiac defects
• Serotonin antagonist: – Droperidol has significant adverse profile and black box
warning about prolonged QT interval
A modern day presentation……• Sarah is G1 P0 now 7 weeks after her LMP presenting for her
first prenatal visit
• c/o “nausea all day” vomits once or twice and retches when she brushes her teeth. Sensitive to smells. Sx present x 2 weeks
• Wearing sea bands her sister gave her but they are not helping
• Urinating less frequently than usual and urine sp gr is 1030
9
How Would You Treat Her?A. Review non-pharmacologic treatments
and schedule a return visit in a weekB. Prescribe Diclegis, metoclopramide, or
another anti-emetic and offer IV hydration
C. Admit for IV hydration, NPO, start ondansetron
D. Other
R e vi e w
n o n- p h
a r ma c o
l o g ..
P r es c r i
b e Di c l e
g i s , m e
t o c. . .
A d mi t f o
r I V h y d
r a t io n ,
. . . O t he r
17%
1%2%
80%
Algorithm for Managing NVP
ACOG 2004, Einarson A et al 2007
PUQE INDEXMILD NVP
Stop prenatal vitamins with iron
Vit B6 10 mg tid-qidand/or
Acustimulation bandsGinger as adjunct
Diet/lifestyle modifications
Algorithm for Managing NVP
ACOG 2004, Einarson A et al 2007
PUQE INDEXMODERATE NVP
No Dehydration Dehydration
IV Fluid replacement with multi-vitamins and
electrolytes
Diclegis 2 tabs at nightor
Metoclopramide 5-10 mg q 6-8 hrs PO
Note: Promethazine 25 mg suppository for breakthrough vomitingDiclegis 2 tabs at night or
Metoclopramide 5-10 mg q 6-8 hrs PO
Algorithm for Managing NVP
ACOG 2004, Einarson A et al 2007
SEVERE
IV fluid replacement with multi-vitamins and electrolytes (Banana Bag)
NPO x 24 hrs then increase as tolerated
Metoclopramide 5-10 mg q 8hr IVor
Ondansetron 1 mg/hr IV x 12-24 hrs or 8 mg over 15 min q 12 hrsor
Droperidol 1 mg/hr with Diphenhydramine 50 mg IV over 30 min q 6 hrsMethylprednisolone 15-20 mg taper dose
orMetoclopramide or Ondansetron PO
10
THANK YOUAdditional Resources
www.motherrisk.org
www.hyperemesis.org
www.otispregnancy.org
ADDITIONAL MATERIALS
Proposed Etiologies of NVP• � Endocrine (hyperthyroid, diabetes)• Placental mass (multiple gestation, mole)
– � placental mass associated with more NVP(multiple gestation, mole)
– � placental mass associated with less NVP (smokers)• Genetic predisposition (HG more frequent in families)• Psychosocial/Psychiatric• Pre-existing vestibular or GI disturbance• Infectious (H. pylori)• Evolutionary biology
Punchline: HG is a diagnosis looking for an etiology
NVP is not a Psychiatric Disorder
• Historical theory: Conversion disorder, Sexual disorder, ambivalence about pregnancy?
• Current studies have not found more psychiatric diagnoses in women with HG compared to women without NVP. However >>
• NVP results in depression and anxiety and the psychological response of “anticipatory vomiting” may be conditioned
• Psychological treatments (e.g. hypnosis) may help ameliorate NVP via their effect on “anticipatory vomiting”
• NVP is more likely in women who experience IPV• NVP may be more likely in women with preexisting eating disorders
Fairweather D 1968, Simptson SW 2001, Buckwalter 2002; Seng J 2007
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Maternal and Fetal Outcomes of NVPNVP is associated with favorable pregnancy outcomes
Yes, women who have severe NVP are more likely to have a girl fetus
Prevention?• In secondary analysis of an RCT on the effects of folic acid it
was noted that women who regularly take a multi-vitamin prior to conception were less likely to need medical attention for NVP (Creizel AZ 1992)
• Prospective descriptive study: Lack of multivitamin supplementation b/4 6 wks gestation significantly associated with � vomiting in pregnancy (Emeliannova S 1999)
Summary: Women with a Hx of severe NVP or hyperemesis can be counseled to take a multi-vitamin prior to subsequent
pregnancy
Creizel AZ et al 1992, Emelianova S 1999
Non-Pharmacologic Treatments for NVP
• Dietary Management
• Complementary/Alternative Therapies: – Acupressure and Acupuncture– Ginger– Vitamin B6
Murphy PA 1998, Hollyer et al 2002 Jewell D 2003
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Dietary Management • Most common recommendations:
– Small frequent meals– Sip fluids, cold, clear, carbonated, sour– Avoid spicy or strong smelling foods– Eliminate prenatal vitamins with iron– � intake of bland foods– High protein snacks (Jednak MA)
• Avoid triggers (stuffy rooms, strong odors)• Efficacy: no evidence-based research on effectiveness. Few
women report complete relief with diet changes • Safety: no adverse effects
O’Brien B et al 1992, Jednak MA et al 1999
Acupuncture, Acupressure, and Acustimulation “P-6” also called the “Neiguan point”Sea-Bands™
Murphy PA 1998, Steel NM et al 2001, Jewell et al 2003
Relief Bands
Acupuncture/Acupressure
• Cochrane review of 4 RCTs: “Mixed results”:– Acupuncture/Acupressure no more effective than sham therapy
for severity of nausea or frequency of vomiting. Strong placebo effect in patients who received sham therapy
– If assessing presence or absence of NVP• P6 stimulation more effective than no treatment• (OR 0.25, 95% CI 0.14-0.43)• P6 stimulation slightly more effective than sham
treatment• (OR 0.35, 95% CI 0.12-1.06)Summary: Acupressure comparable to effect of anti-emetics in
general
Murphy PA 1998, Smith C et al 2002, Rosen T 2003, Jewell D 2003, Shin HS 2007
Acupressure• Shin HC, 2007
– RCT of 66 women hospitalized for HG– � N&V and � ketonuria over 4 days of following three
acupressure sessions (Rhode score of 12 vs 22)• Summary
– Acupressure and acustimulation have a modest but possibly clinically significant effect on decreasing the severity NVP
– Some of the positive effects may be secondary to attention and placebo effect?
– Safety: No adverse effects
Murphy PA 1998, Roscoe JA 2002, Rosen T 2003, Jewell D 2003, Shin HS 2007
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Ginger• Efficacy: 6 RCTs with total N = 675 women
– Dose was 1 gm of ginger in extract form– 4 RCTs found ginger to be better than vitamin B6 in � severity
of NVP– 2 RCTs found ginger to be equal to vitamin B6 in � severity of
NVP
• Safety: 5 RCT’s evaluated safety– No adverse effects – Some side effects: headache, diarrhea, GI distress– German Commission E says ginger is contraindicated in
pregnancy– Contraindicated if patient at risk for hemorrhage
Westfall RE 2004, Smith C et al 2004, Bryer E 2005, Borrelli F 2005
Formulations of Ginger
• 1 gm standardized extract equals: – 1 tsp fresh grated rhizome– 2 droppers liquid extract (2 mL)– 4 cups (8 oz) of ginger tea pre-packaged– 4 cups (8 oz) tea made with ½ tsp grated ginger steeped for
5-10 minutes– 8 oz ginger ale, made with real ginger– 2 pieces crystallized ginger (1 inch square, ¼ inch thick)– Capsules come as 100 mg, 400 mg, 500 mg, 1000 mg– Chewable tablets 67.5 mg