UvA-DARE (Digital Academic Repository) Barriers and ... · Diagnostic markers for hyperemesis gravidarum 2 INTRODUCTION Nausea and vomiting in pregnancy (NVP) is common in early pregnancy;

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Barriers and challenges in hyperemesis gravidarum research

Grooten, I.J.

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Citation for published version (APA):Grooten, I. J. (2017). Barriers and challenges in hyperemesis gravidarum research.

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Diagnostic markers for hyperemesis gravidarum:

a systematic review and metaanalysis

MN Niemeijer, IJ Grooten, N Vos, JMJ Bais, JAM van der Post, BW Mol, TJ Roseboom, MMG Leeflang, RC Painter

American Journal of Obstetrics and Gynecology, 2014;211:150.e1-15

2

32

Chapter 2

ABSTRACT

OBJECTIVE: Currently there is no consensus on the definition of hyperemesis gravidarum (HG; protracted vomiting in pregnancy) and no single widely used set of diagnostic criteria for HG. The various definitions rely on symptoms, sometimes in combination with laboratory tests. Through a systematic review, we aimed to summarize available evidence on the diagnostic value of biomarkers for HG. This could assist diagnosis and may shed light on the, as yet, not understood cause of the disorder.

STUDY DESIGN: We searched Medline and Embase for articles about diagnostic biomarkers for either the presence or severity of HG or nausea and vomiting of pregnancy. We defined HG as any combination of nausea, vomiting, dehydration, weight loss, or hospitalization for nausea and/or vomiting in pregnancy, in the absence of any other obvious cause for these complaints.

RESULTS: We found 81 articles on 9 biomarkers. Although 65% of all studies included only HG cases with ketonuria, we did not find an association between ketonuria and presence or severity of HG in 5 studies reporting on this association. Metaanalysis, with the use of the hierarchical summary receiver operating characteristics model, yielded an odds ratio of 3.2 (95% confidence interval, 2.0-5.1) of Helicobacter pylori for HG, as compared with asymptomatic control subjects (sensitivity, 73%; specificity, 55%). Studies on human chorionic gonadotrophin and thyroid hormones, leptin, estradiol, progesterone and white blood count showed inconsistent associations with HG; lymphocytes tended to be higher in women with HG.

CONCLUSION: We did not find support for the use of ketonuria in the diagnosis of HG. H pylori serology might be useful in specific patients.

33

Diagnostic markers for hyperemesis gravidarum

2

INTRODUCTION

Nausea and vomiting in pregnancy (NVP) is common in early pregnancy; 50 to 80% of pregnant women experience daily nausea and occasional vomiting in the first half of gestation.1 In hyperemesis gravidarum (HG), nausea and vomiting are more severe. Various HG definitions combine a number of symptoms that include protracted vomiting and nausea in pregnancy, accompanied by weight loss, disturbance of electrolyte balance, ketonuria, and dehydration or hospitalization2; however there are no unequivocal diagnostic criteria for HG. HG occurs in approximately 0.3 to 2% of pregnancies3 and is the single most frequent reason for hospital admission in the first half of pregnancy.4, 5

The cause of HG is understood poorly. There is a growing body of literature on the topic of etiologic biomarkers for HG, which can be categorized into 3 pathoetiologic notions: placental growth and function,6 maternal endocrine function,6 and preexisting gastrointestinal disease.7 In addition, psychopathologic conditions could play a role in the cause of HG.8, 9 HG therefore seems to be a heterogeneous illness. Because of this heterogeneity, HG may be unsuitable for a uniform therapeutic approach.10 Currently, there are no effective therapeutic options.11 Moreover, the differential diagnosis of HG is broad and includes gastrointestinal, infectious, and metabolic conditions.2 Further research into additional therapeutic options is hampered by the fact that there is no unequivocal test or biomarker for HG. Therefore, a sensitive diagnostic test would make an attractive addition to the clinical assessment in ruling in HG but is currently lacking.Traditionally, patients who experience HG undergo a diagnostic workup that includes testing for ketonuria and thyroid function and an ultrasound scan to rule out molar pregnancy and multiple gestation. However, such a workup is not based on reliable data from literature. To summarize the available evidence on biomarkers of HG and their value in diagnosis and estimating disease severity, the identification of new indicators for HG could assist diagnosis and may also shed light on the, as yet, not understood cause of the disorder.

METHODS FOR REVIEW

Search strategyThe search strategy (Appendix) was composed by one of the authors (MNN) in collaboration with a clinical librarian. We searched PubMed and Embase from inception through January 2013 to identify articles that have reported on biomarkers in NVP

34

Chapter 2

and HG. We searched citation lists of review articles and eligible primary studies. Reference manager (version 12.0.3; Thomson Reuters, New York, NY) databases were established to incorporate the results of all the searches.

Study selection; in- and exclusion criteriaEtiologic, prognostic, predictive, and diagnostic studies that have reported on biomarkers in plasma, serum, urine, feces, or exhaled air in women with NVP or HG were included if they were written in English (n=68). At least 5 eligible articles had to be available on the biomarker that had been studied for inclusion in our review. When 2 studies reported on the same study population, only the study with the most complete data was included. Case reports were excluded. To metaanalyze diagnostic accuracy, studies were considered if they reported numeric data that allowed construction of a 2 x 2 table that cross-classified biomarker value and occurrence or severity of HG. Study selection was done in 2 stages. First, 2 reviewers (MNN, IJG) independently assessed identified titles and abstracts, after which we obtained full manuscripts of all selected studies. Second, 2 reviewers (MNN and IJG, NV or RCP) per paper independently assessed whether the studies were suitable to be included. Any disagreement was resolved by consensus meetings.

Data-extraction and quality assessmentFor each included article, data on both clinical and methodologic study characteristics were extracted independently by 2 reviewers on piloted data-extraction forms. We evaluated quality of included studies according to the quality assessment of diagnostic accuracy studies (QUADAS)-2 guidelines.12 QUADAS-2 summarizes the risk of bias of diagnostic accuracy studies in 4 domains: the study participants, the index test, the reference standard, and flow and timing. It also assesses potential concerns regarding applicability, which has to do with the representativeness of the study. Although most studies on biomarkers in HG were not diagnostic accuracy studies, but rather etiologic studies, we decided to use QUADAS-2 because we had the explicit aim to determine diagnostic biomarkers.

Case and control definition For HG, there is no clear reference standard or a standard diagnostic workup. This makes it difficult to define cases and control subjects in our study.We defined the reference test as a history of any combination of nausea, vomiting, dehydration, weight loss, or hospitalization based on nausea and/or vomiting in

35


2

pregnancy in the absence of any other obvious cause for these complaints. This definition may lead to the inclusion of patients with mild NVP symptoms but does guarantee the inclusion of biomarkers across the disease severity spectrum. Control subjects were defined as pregnant women who had no complaints of nausea and vomiting.

Data analysisFor metaanalysis of diagnostic test accuracy, we used the hierarchic summary receiver operating characteristics model,13 using the Metandi package in Stata software (Version 10.0; Stata Corporation, College Station, TX). From this model follows the summary hierarchic summary receiver operating characteristics curve and its parameters, but it is also possible to calculate a summary sensitivity and specificity from this model, if appropriate. We attempted to taper clinical heterogeneity by including studies for metaanalysis that used the same index tests and included only patients who had been diagnosed with HG and not NVP. All outcomes were evaluated with a random-effects model. Forest plots were made using Review Manager (RevMan, version 5.2; The Cochrane Collaboration, Baltimore, MD). Sensitivity and specificity were displayed in a forest plot when applicable. We followed the PRISMA statement14 and metaanalysis of observational studies in epidemiology (MOOSE)15 guidelines in writing this review.

RESULTS

Search resultsThe electronic search identified 3442 individual articles (Figure 1). We excluded several articles because there were <5 articles on the biomarker that was discussed. None of these articles were of high quality, nor did they report on a large study population. Eventually we included 81 articles in our study (Table 1). One study could not be retrieved from several national and international libraries and an e-mail address of the author could not be found. This study, however, was not feasible for our study because it was a review.16

Quality assessmentA summary of the QUADAS-2 scores for risk of bias and concerns regarding applicability is given in Supplementary Figure 1. On the risk of bias, many studies had unclear quality regarding the index test. This is caused by unclear reporting on blinding the interpretation of test results. Quality was often unclear concerning patient selection and flow and timing, caused by unclear reporting. The reference standard was well-defined in most articles (65/81 studies); however, it varied among articles.

36

Chapter 2

TAB

LE 1

. Stu

dies

incl

uded

in r

evie

w

Stu

dyYe

arC

ases

Con

trol

su

bjec

tsC

ondi

tion

Keto

nes

H p

ylor

ihC

GTh

yroi

dLe

ptin

Estr

adio

lP

roge

ster

one

WB

CLy

mph

ocyt

e

Aka

et a

l7620

0618

18H

GX

XX

Al-

Bus

aida

et a

l4820

0115

15H

GX

Al-

Yata

ma

et a

l5920

0250

50H

GX

X

Ars

lan

et a

l6120

0330

26H

GX

XX

Asa

kura

et a

l9020

0011

030

NVP

/HG

X

Asa

kura

et a

l9120

0324

20H

GX

X

Ayt

ac e

t al41

2007

5255

HG

X

Ber

ker

et a

l2220

0380

80H

GX

XX

Bou

illon

et a

l8719

8233

52H

GX

Bru

un e

t al92

1978

3557

HG

X

Cev

riog

lu e

t al23

2004

2797

HG

XX

Chi

hara

et a

l9320

0317

37H

GX

Cho

u et

al63

a20

1159

0N

VPX

X

Dem

ir e

t al82

2006

5442

HG

XX

Dep

ue e

t al68

1987

3535

HG

XX

Der

bent

et a

l2020

1111

511

0H

GX

XX

Dok

mec

i et a

l8320

0417

13H

GX

Erde

m e

t al24

2002

4742

HG

X

Evan

s et

al80

*19

8634

20

NVP

/HG

X

Fair

wea

ther

et a

l6519

6290

11H

GX

Frig

o et

al25

1998

105

129

HG

X

Goo

dwin

et a

l5219

9257

57H

GX

XX

37


2

TAB

LE 1

. Stu

dies

incl

uded

in r

evie

w (C

ontin

ued)

Stu

dyYe

arC

ases

Con

trol

su

bjec

tsC

ondi

tion

Keto

nes

H p

ylor

ihC

GTh

yroi

dLe

ptin

Estr

adio

lP

roge

ster

one

WB

CLy

mph

ocyt

e

Goo

dwin

et a

l5319

9439

23H

GX

Gun

ey e

t al26

2007

2535

HG

X

Guv

en e

t al27

2011

4040

HG

X

Hat

zivi

es e

t al28

2007

2585

HG

X

Hay

akaw

a et

al29

2000

3429

HG

X

Jaco

bson

et a

l3020

0330

75H

GX

Jarn

felt-

Sam

sioe

et a

l7919

8562

40N

VPX

Jarn

felt-

Sam

sioe

et a

l9419

8662

40N

VPX

X

Jarn

felt-

Sam

sioe

et a

l6719

8662

40N

VPX

X

Jord

an e

t al49

1999

2020

HG

XX

X

Jura

s et

al88

1983

3330

HG

X

Kara

ca e

t al31

2004

5690

HG

X

Kara

deni

z et

al32

2006

3129

HG

X

Kaup

pila

et a

l5419

7942

115

HG

X

Kaup

illa

et a

l6419

8414

12N

VPX

Kaze

roon

i et a

l3320

0254

53H

GX

Kim

ura

et a

l6919

9327

24N

VP/H

GX

X

Koca

k et

al34

1999

9511

6H

GX

Kusc

u et

al21

2003

1010

HG

XX

X

Lagi

ou e

t al95

2003

209

53N

VPX

X

Lao

et a

l8919

8851

28H

GX

Larr

az e

t al42

2002

162

156

NVP

X

38

Chapter 2

TAB

LE 1

. Stu

dies

incl

uded

in r

evie

w (C

ontin

ued)

Stu

dyYe

arC

ases

Con

trol

su

bjec

tsC

ondi

tion

Keto

nes

H p

ylor

ihC

GTh

yroi

dLe

ptin

Estr

adio

lP

roge

ster

one

WB

CLy

mph

ocyt

e

Law

son

et a

l50a

2002

920

NVP

X

Lee

et a

l3520

0540

42H

GX

Leyl

ek e

t al55

1996

2420

HG

XX

XX

Leyl

ek e

t al56

1999

3015

HG

XX

XX

Man

sour

et a

l3620

1180

80H

GX

Mas

son

et a

l5119

8565

48N

VPX

XX

Min

agaw

a et

al97

1999

1820

HG

XX

Mor

i et a

l7019

8811

141

NVP

XX

Mur

ata

et a

l8420

0644

53N

VP/H

GX

Ndu

ngu

et a

l71a

2009

720

Emes

isX

X

Pan

esar

et a

l7220

0162

58H

GX

X

Pan

esar

et a

l8120

0643

329

HG

X

Pele

d et

al57

2012

7314

6H

GX

Pere

z-Pe

rez

et a

l3719

9942

47H

GX

Reym

unde

et a

l4620

0145

44H

GX

Sal

imi-

Khay

ati e

t al38

2003

5454

HG

X

San

dven

et a

l3920

0824

424

4H

GX

Sek

izaw

a et

al73

2001

1623

HG

X

Shi

rin

et a

l43a

2004

185

0G

I sy

mpt

oms

X

Sou

les

et a

l7419

8037

9N

VP/H

GX

Sw

amin

atha

n et

al78

1989

7143

HG

XX

39


2

TAB

LE 1

. Stu

dies

incl

uded

in r

evie

w (C

ontin

ued)

Stu

dyYe

arC

ases

Con

trol

su

bjec

tsC

ondi

tion

Keto

nes

H p

ylor

ihC

GTh

yroi

dLe

ptin

Estr

adio

lP

roge

ster

one

WB

CLy

mph

ocyt

e

Tan

et a

l17a

2006

192

0H

GX

XX

Tan

et a

l18a

2006

192

0H

GX

XX

Tan

et a

l19a

2009

167

0H

GX

XX

X

Tare

en e

t al62

1995

3015

HG

XX

Task

in e

t al60

2009

2020

HG

XX

XX

XX

Thor

nton

et a

l7519

7912

12H

GX

Tlol

ka e

t al44

2010

2943

NVP

X

Tsur

uta

et a

l7719

9555

24N

VP/H

GX

X

Uns

el e

t al85

2004

4030

HG

XX

Ust

un e

t al86

2004

3539

HG

X

Wey

erm

ann

et a

l45a

2003

898

0G

I sy

mpt

oms

X

Wils

on e

t al66

1992

1050

HG

XX

Wu

et a

l47a

2000

540

GI

sym

ptom

sX

Xia

et a

l4020

0472

100

HG

X

Yone

yam

a et

al96

2002

2222

HG

XX

X

Yone

yam

a et

al98

2002

2424

HG

Xa

Not

a c

ase-

cont

rol s

tudy

. GI:

gast

roin

test

inal

; hCG

: hum

an c

hori

onic

gon

adot

ropi

n; H

G: h

yper

emes

is g

ravi

daru

m; N

VP: n

ause

a an

d vo

miti

ng in

pre

gnan

cy;

WB

C: w

hite

blo

od c

ount

.

40

Chapter 2

In 60 articles on HG, 20 articles used >3 or >4 times vomiting episodes per day as part of the reference standard; 23 articles described persistent vomiting but did not quantify the frequency of vomiting. Thirty-two articles on HG used weight loss of >5% prepregnancy weight or >3 kg, and 39 articles used ketonuria as part of the diagnosis. Other elements were dehydration (3 studies) and hospitalization (11 studies). In 13 studies, no clear reference standard was described. Of 21 articles that reported on NVP, 17 articles used nausea and vomiting, 4 articles used weight loss, and 3 articles used hospitalization as part of the diagnosis. Three articles had no description of diagnosis other than that patients had been identified as HG cases. In most studies, there were no concerns regarding applicability. Exclusion criteria were unclear in 30 of 80 articles. Patients with hepatic disorders (27 articles), thyroid disorders (46 articles), gastro-intestinal disorders (31 articles), endocrine disorders (15 articles), urinary tract infection (6 articles), psychiatric disorders (12 articles), previous treatment against Helicobacter pylori (4 articles), pregnancy complications (6 articles) and chronic medication (6 articles) were excluded from studies. Molar pregnancies were excluded in 13 studies, multiple pregnancies in 21 studies. In 3 articles, women were excluded if there was uncertainty about their gestational age. We did not exclude any studies from our review on the grounds of poor quality.

Severity of HG We found 3 studies that described biomarkers in relation to markers of disease severity.17-19 Severity was determined as readmission rate in 1 study and as a hospital stay of >4 days in the 2 other studies. These studies described the association with ketonuria, human chorionic gonadotrophin (hCG), thyroid stimulating hormone, free thyroxine 4 (FT4), estradiol, and white blood count (WBC). The grade of ketonuria, as determined through a dipstick (studies 2006, 0-3+ vs 4+ urinary ketones of a possible 4+; study 2009, 0-2+ vs 3-4+ urinary ketones) was described in relation to severity of HG. Only a minority of patients with HG had ketonuria. Ketonuria was not significantly associated with prolonged hospital stay in the study of 2006 (adjusted odds ratio, 2.1; 95% confidence interval (CI) 1.0-4.6; P = .06).17 Neither of the 2 other studies showed a significant association between the grade of ketonuria and severity of HG in terms of readmission.18, 19 HCG was increased in women with HG who were hospitalized for >4 days compared with women who were hospitalized for <4 days.19 Thyroid stimulating hormone and FT4 were not associated with a higher readmission rate.18 Estradiol of women who were hospitalized for >4 days were similar to levels of women hospitalized for <4 days.19 WBC level was not associated with severity.17-19

41


2

Records identi�ed through database searching

n = 4287

Figure 1Flowchart of the selection process of articles found in the electronic search

Records after duplicates removedn = 3442

Records excludedn = 3167

Additional records identi�ed through reference lists

n = 0

Records screenedn = 3442

Full-text articles assessed for eligibilityn = 275

Studies included in qualitative synthesisn = 81

Full-text articles excludedn = 194

Reason for exclusion:Review n= 69

Insu�cient data n= 29Case report n= 17

No biomarker n= 20Not (primarily) on HG/NVP n = 10

<10 patients n = 6No control group n = 10

Duplicate population n = 2<5 articles per biomarker n = 30

Full-text could not be retrieved n = 1Studies included in quantitative synthesis (metaanalysis)

n = 19

FIGURE 1. Flowchart of the selection process of articles found in the electronic search

Presence of HG/NVPKetonuriaKetonuria among patients with NVP was not described in any study. We found 2 studies that described ketonuria and presence of HG; Derbent et al20 (cases, 115 patients; control subjects, 110 patients) described an increase in degree of ketonuria between women with HG and pregnant control subjects (r = 0.622; P<.001). They found a median of 3+ of a possible 4+ with an interquartile range of 3+/4 in cases and 0+/4 (interquartile range, 0.5+/4) in control subjects. In a much smaller study, Kuscu et al21 (cases, 10 patients; control subjects, 10 patients) found no significant difference between ketonuria in patients with HG compared with pregnant control subjects. In this study, cases had a mean grade of ketonuria of 1.1 ± 0.3; control subjects did not

42

Chapter 2

have ketonuria. Ketonuria among patients with NVP was not described in any study. Neither of these studies reported the absolute prevalence of ketonuria among patients with HG and control patients.

Helicobacter pylori

We included 26 studies on H pylori in our review. Most studies used immunoglobulin G (IgG) antibodies against H pylori to determine whether women were infected. More than one-half of the studies showed a significant positive association between H pylori and NVP or HG compared with pregnant asymptomatic control subjects. In Figure 2, A, results for the metaanalysis on presence of positive serologic findings in women with HG compared with asymptomatic control subjects are displayed, with an overall odds ratio of 3.2 (95% CI, 2.0-5.1). In Figure 2, B, the sensitivity and specificity of these studies are displayed. Diagnostic metaanalysis of these 19 studies showed a summary sensitivity of 73% (95% CI, 62.0-81.4%) and a specificity of 55% (95% CI, 47.4-61.5%) in the diagnosis of HG, as compared to control subjects without hyperemesis.22-40 Figure 3 shows the studies that used methods other than IgG serology to determine H pylori infection in women with HG and NVP.23, 29, 32, 37, 41-45 Two studies were not displayed in forest plots because of reporting incomplete data for 2 x 2 table construction; Reymunde et al46 determined IgG in women with HG and found a significant association (P<.001) between HG and the presence of IgG antibodies. Wu et al47 determined IgG in women with gastrointestinal complaints in pregnancy but did not find a significant association between these complaints and H pylori status.

HCGWe included 35 studies on hCG, of which 18 studies showed a significant association between raised hCG levels and the occurrence of NVP or HG.20, 21, 48-64 Three studies showed a lower hCG in women with HG or NVP;65-67 the other 13 studies did not find a significant association.22, 68-79

It was not possible to perform metaanalysis on hCG, because of large clinical heterogeneity and the skewed distribution of hCG during pregnancy that was caused by the lack of matching for gestational age in most articles and the lack of reporting biomarkers in multiple of medians. This is a measure for individual test deviance from the median and is calculated by dividing the individual patient result by the median of the population. In Figure 4, we display forest plots of studies that report hCG levels and reported outcomes in a form that is suitable for forest plot display.

43


2

A

Helicobacter for Pylori 24-Jul-2017

Review Manager 5.3 1

FiguresFigure 1 (Analysis 1.1)

Figure 2, A: Metaanalysis of diagnostic accuracy of H pylori immunoglobulin G in women with hyperemesis gravidarum compared with asymptomatic control subjectsB

h pylori versus [comparator(s)] for [target condition(s)] in [participant description] 24-Jul-2017


FiguresFigure 2 (Analysis 1)

Figure 2, B: Sensitivity and specificity in individual studiesFIGURE 2. Metaanalysis, sensitivity, and specificity of Helicobacter pylori immunoglobulin G in women with hyperemesis gravidarum compared with asymptomatic control subjectsA, Metaanalysis of diagnostic accuracy of H pylori immunoglobulin G in women with hyperemesis gravidarum compared with asymptomatic control subjects. B, Sensitivity and specificity in individual studies. FN: false negative; FP: false positive; M-H: mantel-Haenszel; TN: true negative; TP: true positive.

Thyroid hormonesThyroid hormones were described in 34 included articles;20, 21, 23, 49, 52, 55, 56, 59-62, 66,

67, 69-72, 76-78, 80-93 65% of the studies showed decreased thyrotropin,20, 23, 49, 52, 59, 60,

62, 69, 70, 72, 81, 82, 84 and 67% of the studies showed increased FT4 in symptomatic

44

Chapter 2

patients compared with asymptomatic control subjects.20, 23, 52, 55, 56, 59, 61, 66, 69, 70,

72, 77, 81-83, 86, 87, 90, 91 Similar results were found for total thyroxine 4 (65%),59, 62,

87, 88 total thyroxine 3 (50%),52, 62, 83, 87 and free thyroxine (53%).55, 72, 77, 81, 82, 86-90 It was not possible to construct 2 x 2 tables from studies that reported on thyroid hormones because cutoff values were not described; therefore, no number of true- or false-positive and true- or false-negative findings can be extracted from the study, and it was not possible to perform a diagnostic metaanalysis.

A

h pylori for HG other methods 24-Jul-2017



Figure 3, A: H pylori infection determined by other methods than immunoglobulin G serology in women with hyperemesis gravidarumB

Helicobacter for Pylori 24-Jul-2017



Figure 3, B: H pylori infection dertermined by other methods than immunoglobulin G serology in women with nausea and vomiting in pregnancyFIGURE 3. Helicobacter pylori in women with hyperemesis gravidarum (measured with other methods than immunoglobulin G) or nausea and vomiting in pregnancy compared with asymptomatic control subjects A, H pylori in women with hyperemesis gravidarum. B, H pylori in women with nausea and vomiting in pregnancy. CagA: cytotoxin-associated gen A; CUBT: C urea breath test; HG: hyperemesis gravidarum; IgA: immunoglobulin A; M-H: Mantel-Haenszel; NVP: nausea and vomiting in pregnancy; PCR: polymerase chain reaction; SA: stool antigen.

LeptinFive studies reported on leptin levels. Chou et al63 showed significantly lower levels of leptin in women with severe NVP compared with women with mild NVP. Aka et al76 showed significantly higher levels of leptin in women with HG compared with asymptomatic control subjects. Aka et al and Chou et al both adjusted leptin levels for gestational age and body mass index. Demir et al82 showed no significant difference in leptin levels between women with HG and asymptomatic control subjects but did show a significant higher level of adjusted leptin levels, where leptin was adjusted for only gestational age, not body mass index. The 2 other studies did not show a significant association between leptin levels and occurrence of HG.61, 85

45


2

[Intervention] for [health problem] 24-Jul-2017



Figure 4, A: hCG, matched for gestational age




Figure 4, B: -hCG, matched for gestational age




Figure 4, C: Free hCG, hCG in 24-hour urine sample, free - and -hCG, matched for gestational age




Figure 4, D: hCG, not matched for gestational age




Figure 4, E: hCG levels in women with nausea and vomiting in pregnancy

A

B

C

D

E

FIGURE 4. Human chorionic gonadotropin levels in women with hyperemesis gravidarum or nausea and vomiting in pregnancy compared with asymptomatic control subjects A, HCG, matched for gestational age; B, β-hCG, matched for gestational age; C, Free hCG, hCG in 24-hour urine sample, free α- and β-hCG, matched for gestational age; D, HCG, not matched for gestational age; E, HCG levels in women with nausea and vomiting in pregnancy. hCG: human chorionic gonadotropin; HG: hyperemesis gravidarum; IV: inverse virance; NVP: nausea and vomiting in pregnancy; SD: standard deviation; Std: standard.

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Estradiol and progesteroneEight studies were found on estradiol levels, which showed inconsistent results. Five studies did not find a significant association22, 49, 51, 94, 95; 3 studies found increased estradiol levels in women with HG.52, 68, 96 Five studies covered progesterone, of which 3 studies reported on women with HG and 2 studies reported on women with NVP. The latter 2 found a lower progesterone level compared with control subjects.94, 95 Of the 3 studies in women with HG, 2 studies found an increased level of progesterone,58,

60 and 1 study found no association.51

WBC and lymphocytesFive studies reported on WBC,55, 56, 60, 91, 97 and 5 studies reported on lymphocytes55,

56, 60, 97, 98 in women with HG compared to women without HG. WBC differed between different studies, lymphocyte levels tended to be higher in patients in HG compared with control subjects.

COMMENT

Our systematic review of biomarkers for NVP and HG was unable to identify a single biomarker with the ability to identify HG or HG severity. Ketonuria reflects catabolism of adipose stores and could be an indicator of HG patients who are unable to tolerate oral intake or prolonged fasting. It is used frequently in the diagnostic workup for patients with HG, as is shown by the fact that 65% of the studies that were included in this review used ketonuria in the diagnosis of HG. Therefore, it is remarkable that only 5 studies have been published to date that have described the diagnostic accuracy of ketonuria in HG or its severity. The results are equivocal, although the largest study did find an association between HG and ketonuria. None of the studies that investigated ketonuria and HG severity reported an association. Based on these findings, we cannot recommend the use of ketonuria in the diagnosis of HG at his point, but further research into the relation between ketonuria and diagnosis is necessary. H pylori was associated significantly with HG. However the odds ratio of 3.2 (95% CI, 2.0-5.1) could be inflated because of comparison with asymptomatic control subjects, because in early pregnancy most women experience nausea to some extent.1 Despite the significant association with HG, which implies an etiologic association with HG symptoms, the pooled sensitivity and specificity is insufficient to warrant its diagnostic application. Despite this limitation, the findings on seroprevalence of H pylori may point towards a potentially treatable cause of HG. Mansour and Nashaat36 described 8 women with HG who were treated for H pylori infection during pregnancy. Six of

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these women showed marked improvement of nausea and vomiting; however, because there was no comparison with control subjects, this provides insufficient evidence to introduce H pylori eradication as a means of alleviating HG symptoms. It must be noted that most studies that were included in our metaanalysis were performed in non-Western countries (19/26 countries; 73%), where the prevalence of H pylori infection tends to be higher than in Western countries.99 Whether eradication of H pylori among patients with HG is a useful strategy to shorten HG symptoms has not yet been investigated accurately. Studying the effect of eradication of this bacterium during pregnancy in women with HG might reveal a new therapeutic option.Most studies showed an association between higher hCG levels and the presence of HG. This reflects the etiologic notion that rising hCG levels either affect areas of the brain involved in nausea directly or indirectly by inducing rises in other hormones (thyroid hormone, estradiol) with the ability to affect nausea. We could not perform a metaanalysis due to the skewed distribution that was caused by the fact that hCG levels show a marked peak in early gestation, thus rendering crude hCG levels that have not been standardized for the duration of pregnancy incomparable (eg, by reporting them as multiple of medians). Our findings do suggest an etiologic contribution for hCG in HG. For future research, we recommend reporting of hCG in multiples of the median to account for the steep increase in early pregnancy. HCG may have stimulatory effects on the thyrotropin receptor and, through this, control thyroid function.52 Most studies that were included in our systematic review found an association between increased thyroid activity and the presence of HG, which supports an etiologic role for thyroid function in HG symptoms. We were unable to investigate the diagnostic accuracy of thyroid function testing, however, because of the lack of reported cutoff values in the included (etiologic) studies. Based on these findings, we recommend thyroid function testing be carried out only to rule out overt thyroid disease among patients with HG but not to diagnose or dismiss HG. Based on the supposed interaction between hCG and the thyrotropin receptor, it may prove useful for future studies into hCG in HG to always include thyroid hormone testing to gain more understanding of this mechanism in the cause of HG.We included studies on a number of other biomarkers, including WBC, lymphocytes, sex hormones, and leptin. Although it is beyond the scope of this article to discuss each of these biomarkers, they have all been suggested to play an etiologic role in HG. In our systematic evaluation of the literature, we found no consistent association between these biomarkers and the presence or severity of HG, which makes an etiologic link unlikely.Our study also has some limitations. Our review aimed to investigate whether any single biomarker had the ability to identify HG cases with reasonable diagnostic

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accuracy. We used a combination of symptoms to serve as a reference standard for HG cases, although the combination we chose was arbitrary. We included etiologic and diagnostic studies. This introduced heterogeneity in our review, but we wanted to summarize all available information from a diagnostic perspective. The unclear reporting of methods in the primary studies, which is a common problem in diagnostic reviews, hindered quality assessment in our study. Poor study design and conduct can affect estimates of diagnostic accuracy,100, 101 although it is not entirely clear how individual aspects of quality may affect accuracy and to which magnitude. Of many strategies applied to account for differences in quality, none have systematically led to less optimistic estimates than that of ignoring quality in diagnostic metaanalyses102,

103; therefore, we did not exclude articles because they had low quality. Although the broad search strategy that we used could be viewed as strength of this paper, publication bias remains a potential threat. However, there are currently no robust ways to investigate publication bias in diagnostic studies.104

Of the reviewed biomarkers, only H pylori showed a clear etiological association with HG. However, we did not find a single biomarker that can diagnose or predict severity of HG. In this review, ketonuria, contrary to current beliefs, had no obvious association with HG. Therefore, we cannot recommend ketonuria as a criterion in the diagnosis of HG or for the inclusion of patients with HG in future studies. However, we do recommend future research into the relation between ketonuria and diagnosis or prognosis of HG. H pylori was associated significantly with the occurrence of HG, which may be of future therapeutic interest but requires further evaluation.

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SUPPLEMENTARY FIGURE 1. Summary of quality assessment of diagnostic accuracy studies scores

0% 20% 40% 60% 80% 100%

Patient selection

Index test

Reference standard

Flow and timing

Proportion of studies with low, high or unclear risk of bias

QUAD

AS-2

dom

ain

Low risk High risk Unclear risk

0% 20% 40% 60% 80% 100%

Patient selection

Index test

Reference standard

Proportion of studies with low, high or unclear concerns regarding applicability

QUAD

AS-2

dom

ain

Low risk Higk risk Unclear risk

QUADAS: quality assessment of diagnostic accuracy studies

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APPENDIX

Search strategy Pubmed((“Morning Sickness”[Mesh] OR hyperemesis gravid*[tiab]) OR ((pregnan*[tiab] OR gestation*[tiab] OR pregnancy[mesh]) AND (nausea[tiab] OR vomit*[tiab]))) AND (“Causality”[Mesh] OR “etiology”[Subheading] OR etiolog*[tiab] OR causal*[tiab] OR cause[tiab] OR biomarker*[tiab] OR marker[tiab] OR “analysis”[Subheading])

Embase‘hyperemesis gravidarum’/dm_et OR (‘hyperemesis gravidarum’/de OR ‘hyperemesis gravidarum’:ab,ti OR (‘nausea and vomiting’/de OR ‘morning sickness’/de OR ‘vomiting’/de OR ‘nausea’/de OR nauses:ab,ti OR vomit*:ab,ti AND (‘pregnancy’/exp OR gestation*:ab,ti OR pregnan*:ab,ti)) AND (‘etiology’/de OR ‘marker’/de OR ‘biochemical marker’/de OR ‘biological marker’/de OR etiol*:ab,ti OR causal*:ab,ti OR cause:ab,ti OR biomarker*:ab,ti OR marker*:ab,ti OR ‘breath analysis’/de OR ‘blood analysis’/de OR ‘urinalysis’/de OR analysis:ab,ti))

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UvA-DARE (Digital Academic Repository) Barriers and ... · Diagnostic markers for hyperemesis gravidarum 2 INTRODUCTION Nausea and vomiting in pregnancy (NVP) is common in early pregnancy;

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