Research www.AJOG .

org

OBSTETRICS
Diagnostic markers for hyperemesis gravidarum: a
systematic review and metaanalysis
Maartje N. Niemeijer, MD; Iris J. Grooten, MD; Nikki Vos, MD; Joke M. J. Bais, MD; Joris A. van der Post, MD;
Ben W. Mol, MD; Tessa J. Roseboom, PhD; Mariska M. G. Leeflang, PhD; Rebecca C. Painter, MD

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 labo-
ratory 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 under-
stood 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, 2.0e5.1) of Heliobacter
pylori for HG, as compared with asymptomatic control sub-
jects (sensitivity, 73%; specificity, 55%). Studies on human
chorionic gonadotropin 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.
Key words: biomarker, diagnosis, hyperemesis gravidarum, nausea
and vomiting, pregnancy

Cite this article as: Niemeijer MN, Grooten IJ, Vos N, et al. Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis. Am J Obstet Gynecol
2014;210:



.

N ausea and vomiting in pregnancy

(NVP) is common in early preg-
nancy; 50-80% of pregnant women
experience daily nausea and occasional
vomiting in the rst half of gestation.1 In
hyperemesis gravidarum (HG), nausea
and vomiting is more severe. Various HG
denitions combine a number of symp-
toms 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 0.3-2% of
pregnancies3 and is the single most
frequent reason for hospital admission in
the rst 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 gastrointes-
tinal disease.7 In addition, psychopath-
ologic condition 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

From the Department of Obstetrics and Gynecology, Medical Centre Alkmaar, Alkmaar (Drs Niemeijer, Grooten, Vos, Bais, and Painter), and the
Departments of Obstetrics and Gynecology (Drs van der Post, Mol, and Roseboom) and Clinical Epidemiology, Biostatistics, and Bioinformatics,
Academic Medical Center, Amsterdam (Dr Leeang), the Netherlands. Dr Niemeijer is currently with the Department of Epidemiology, Erasmus
MCeUniversity Medical Center, Rotterdam. Dr Grooten and Dr Painter are currently with the Department of Obstetrics and Gynecology, Academic
Medical Center, Dr Vos is with the Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, and Dr Mol is with the
Department of Obstetrics and Gynecology, School of Paediatrics and Reproductive Health, University of Adelaide, Australia.
Received Dec. 6, 2013; revised Jan. 14, 2014; accepted Feb. 11, 2014.
The authors report no conict of interest.
Presented at ESHRE Campus 2012, a symposium organized by the Special Interest Group on Early Pregnancy of the European Society of Human
Reproduction and Embryology, Amsterdam, the Netherlands, Nov. 29-30, 2012.
Reprints: Rebecca C. Painter, MD, PhD, Department of Obstetrics and Gynecology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam,
The Netherlands. r.c.painter@amc.uva.nl.
0002-9378/$36.00
2014 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2014.02.012

MONTH 2014 American Journal of Obstetrics & Gynecology 1.e1

Research Obstetrics
a uniform therapeutic approach.10 Cur-
rently, 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 addi-
tional 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 assess-
ment in ruling in HG but is currently
lacking.
Traditionally, patients who experience
HG undergo a diagnostic workup that
includes testing for ketonuria and thy-
roid 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 identication of new indicators for
HG could assist diagnosis and may also
shed light on the, as yet, not understood
cause of the disorder.
M ETHODS FOR R EVIEW
Search strategy
The search strategy (Appendix) was
composed by one of the authors (M.N.N.)
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 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
criteria
Etiologic, 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 bio-
marker that had been studied for in-
clusion in our review. When 2 studies
reported on the same study population,
1.e2 American Journal of Obstetrics & Gynecology MONTH 2014
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  2 table that cross-classied
biomarker value and occurrence or
severity of HG.
Study selection was done in 2 stages.
First, 2 reviewers (M.N.N., I.J.G.) inde-
pendently assessed identied titles and
abstracts, after which we obtained full
manuscripts of all selected studies. Sec-
ond, 2 reviewers (M.N.N. and I.J.G., N.V.
or R.C.P.) per paper independently as-
sessed whether the studies were suitable
to be included. Any disagreement was
resolved by consensus meetings.
Data extraction and quality
assessment
For each included article, data on both
clinical and methodologic study char-
acteristics were extracted independently
by 2 reviewers on piloted data-extraction
forms. We evaluated quality of included
studies according to the quality assess-
ment of diagnostic accuracy studies
(QUADAS)e2 guidelines.12 QUADAS-2
summarizes the risk of bias of diag-
nostic accuracy studies in 4 domains: the
study participants, the index test, the
reference standard, and ow and timing.
It also assesses potential concerns re-
garding 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 diag-
nostic biomarkers.
Case and control definition
For HG, there is no clear reference stan-
dard or a standard diagnostic workup.
This makes it difcult to dene cases and
control subjects in our study.
We dened the reference test as a
history of any combination of nausea,
vomiting, dehydration, weight loss, or
hospitalization based on nausea and/or
vomiting in pregnancy in the absence of
any other obvious cause for these com-
plaints. This denition may lead to the
www.AJOG.org
inclusion of patients with mild NVP
symptoms but does guarantee the in-
clusion of biomarkers across the disease
severity spectrum. Control subjects were
dened as pregnant women who had no
complaints of nausea and vomiting.
Data analysis
For metaanalysis of diagnostic test ac-
curacy, we used the hierarchic summary
receiver operating characteristics
model,13 using the Metandi package in
Stata software (version 10.0; Stata Cor-
poration, College Station, TX). From
this model follows the summary hierar-
chic summary receiver operating char-
acteristics curve and its parameters, but
it is also possible to calculate a summary
sensitivity and specicity 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 pa-
tients who had been diagnosed with HG
and not NVP. All outcomes were evalu-
ated with a random-effects model. Forest
plots were made using Review Manager
(RevMan, version 5.2; The Cochrane
Collaboration, Baltimore, MD). Sensi-
tivity and specicity were displayed in a
forest plot when applicable. We followed
the PRISMA statement14 and meta-
analysis of observational studies in
epidemiology (MOOSE)15 guidelines in
writing this review.
R ESULTS
Search results
The electronic search identied 3442 in-
dividual articles (Figure 1). We excluded
several articles because there were <5
articles on the biomarker that was dis-
cussed. 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 assessment
A summary of the QUADAS-2 scores for
risk of bias and concerns regarding
www.AJOG.org Obstetrics Research

FIGURE 1
Selection process of articles

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

Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.

applicability is given in the Supplementary
Figure. 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 re-
sults. Quality was often unclear concern-
ing patient selection and ow and timing.
The reference standard was well-dened
in most articles (65/81 studies); however,
it varied among articles. 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 dehy-
dration (3 studies) and hospitalization
(11 studies). In 13 studies, no clear refer-
ence 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 hospita-
lization as part of the diagnosis. Three
articles had no description of diagnosis
other than that patients had been identi-
ed 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),

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1.e4 American Journal of Obstetrics & Gynecology MONTH 2014

TABLE
Studies included in review
Participants, n Biomarkers
Control Heliobacter Human chorionic White blood
Study Year Cases subjects Condition Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
Aka et al76

Obstetrics
2006 18 18 HG X X X
Al-Busaida and Krolikowski48 2001 15 15 HG X
Al-Yatama et al59 2002 50 50 HG X X
61
Arslan et al 2003 30 26 HG X X X
90
Asakura et al 2000 110 30 NVP/HG X
91
Asakura et al 2003 24 20 HG X X
Aytac et al41 2007 52 55 HG X
Berker et al22 2003 80 80 HG X X X
87
Bouillon et al 1982 33 52 HG X
92
Bruun and Kristoffersen 1978 35 57 HG X
Cevrioglu et al23 2004 27 97 HG X X
93
Chihara et al 2003 17 37 HG X
63a
Chou et al 2011 59 0 NVP X X
82
Demir et al 2006 54 42 HG X X
68
Depue et al 1987 35 35 HG X X
Derbent et al20 2011 115 110 HG X X X
Dokmeci et al83 2004 17 13 HG X
24
Erdem et al 2002 47 42 HG X
80a
Evans et al 1986 342 0 NVP/HG X
65
Fairweather and Loraine 1962 90 11 HG X
Frigo et al25 1998 105 129 HG X
Goodwin et al52 1992 57 57 HG X X X
53
Goodwin et al 1994 39 23 HG X

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26
Guney et al 2007 25 35 HG X
Guven et al27 2011 40 40 HG X
28
Hatzivies et al 2007 25 85 HG X
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014. (continued)
 www.AJOG.org
TABLE
Studies included in review (continued)
Participants, n Biomarkers
Control Heliobacter Human chorionic White blood
Study Year Cases subjects Condition Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
Hayakawa et al29 2000 34 29 HG X
30
Jacobson et al 2003 30 75 HG X
79
Jarnfelt-Samsioe et al 1985 62 40 NVP X
94
Jarnfelt-Samsioe et al 1986 62 40 NVP X X
67
Jarnfelt-Samsioe et al 1986 62 40 NVP X X
Jordan et al49 1999 20 20 HG X X X
88
Juras et al 1983 33 30 HG X
31
Karaca et al 2004 56 90 HG X
32
Karadeniz et al 2006 31 29 HG X
54
Kauppila et al 1979 42 115 HG X
Kaupilla et al64 1984 14 12 NVP X
33
Kazerooni et al 2002 54 53 HG X
69
Kimura et al 1993 27 24 NVP/HG X X
34
Kocak et al 1999 95 116 HG X
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Kuscu et al21 2003 10 10 HG X X X

95
Lagiou et al 2003 209 53 NVP X X
89
Lao et al 1988 51 28 HG X
42
Larraz et al 2002 162 156 NVP X
50a
Lawson et al 2002 92 0 NVP X

Obstetrics
Lee et al35 2005 40 42 HG X
Leylek et al55 1996 24 20 HG X X X X
56
Leylek et al 1999 30 15 HG X X X X
36
Mansour and Nashaat 2011 80 80 HG X

Research
51
Masson et al 1985 65 48 NVP X X X
Minagawa et al97 1999 18 20 HG X X
70
Mori et al 1988 111 41 NVP X X
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014. (continued)
1.e5
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1.e6 American Journal of Obstetrics & Gynecology MONTH 2014

TABLE
Studies included in review (continued)
Participants, n Biomarkers
Control Heliobacter Human chorionic White blood
Study Year Cases subjects Condition Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
Murata et al84 2006 44 53 NVP/HG X

Obstetrics
71a
Ndungu et al 2009 72 0 Emesis X X
72
Panesar et al 2001 62 58 HG X X
81
Panesar et al 2006 43 329 HG X
Peled et al57 2012 73 146 HG X
Perez-Perez et al37 1999 42 47 HG X
46
Reymunde et al 2001 45 44 HG X
38
Salimi-Khayati et al 2003 54 54 HG X
39
Sandven et al 2008 244 244 HG X
Sekizawa et al73 2001 16 23 HG X
43a
Shirin et al 2004 185 0 GI symptoms X
74
Soules et al 1980 37 9 NVP/HG X
78
Swaminathan et al 1989 71 43 HG X X
17a
Tan et al 2006 192 0 HG X X X
Tan et al18a 2006 192 0 HG X X X
19a
Tan et al 2009 167 0 HG X X X X
62
Tareen et al 1995 30 15 HG X X
60
Taskin et al 2009 20 20 HG X X X X X X
Thornton et al75 1979 12 12 HG X
Tlolka et al44 2010 29 43 NVP X
77
Tsuruta et al 1995 55 24 NVP/HG X X
85
Unsel et al 2004 40 30 HG X X
86
Ustun et al 2004 35 39 HG X

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Weyermann et al45a 2003 898 0 GI symptoms X
Wilson et al66 1992 10 50 HG X X
47a
Wu et al 2000 54 0 GI symptoms X
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014. (continued)
www.AJOG.org Obstetrics Research
thyroid disorders (46 articles), gastro- Presence of HG/NVP
intestinal disorders (31 articles), endo- Ketonuria
Lymphocyte
crine disorders (15 articles), urinary Ketonuria among patients with NVP was
tract infection (6 articles), psychiatric not described in any study. We found 2
disorders (12 articles), previous treat- studies that described ketonuria and the

X
ment against Heliobacter pylori (4 arti- presence of HG: Derbent et al20 (cases,
White blood

cles), pregnancy complications (6 115 patients; control subjects, 110 pa-

articles), and chronic medication (6 tients) described an increase in degree of
Thyroid Leptin Estradiol Progesterone count

articles) were excluded from studies.
Molar pregnancies were excluded in
13 studies; multiple pregnancies were
excluded in 21 studies. In 3 articles,
women were excluded if there was un-
certainty about their gestational age. We
X
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

did not exclude any studies from our much smaller study, Kuscu et al21 (cases,
review on the grounds of poor quality. 10 patients; control subjects, 10 patients)
found no signicant difference between
X

Severity of HG ketonuria in patients with HG compared

We found 3 studies that described
biomarkers in relation to markers of
disease severity.17,18,19 Severity was
determined as readmission rate in 1
study and as a hospital stay of >4 days
Heliobacter Human chorionic
with pregnant control subjects. In this
study, cases had a mean grade of keto-
nuria of 1.1  0.3; control subjects did
not have ketonuria. Ketonuria among
patients with NVP was not described in

in the 2 other studies. These studies any study. Neither of these studies re-
gonadotropin

described the association with keto-
nuria, human chorionic gonadotropin
(hCG), thyroid-stimulating hormone,
free thyroxine 4 (FT4), estradiol, and
X
ported the absolute prevalence of keto-
nuria among patients with HG and
control patients.

white blood count (WBC). Helicobacter pylori

The grade of ketonuria, as deter- We included 26 studies on H pylori in
Ketones pylori

mined through a dipstick (studies our review. Most studies used immu-
Biomarkers

2006, 0-3 vs 4 urinary ketones of a noglobulin G (IgG) antibodies against

X

possible 4; study 2009, 0-2 vs 3-4 H pylori to determine whether women

urinary ketones) was described in
relation to severity of HG. Only a
minority of patients with HG had
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
Year Cases subjects Condition
were infected. More than one-half of the
studies showed a signicant positive as-
sociation between H pylori and NVP or

GI, gastrointestinal; HG, hyperemesis gravidarum; NVP, nausea and vomiting in pregnancy.

ketonuria. Ketonuria was not signi- HG compared with pregnant asymp-

cantly associated with prolonged hos- tomatic control subjects. In Figure 2,
HG
HG
HG

pital stay in the study of 2006 (adjusted results for the metaanalysis on presence
odds ratio, 2.1; 95% condence in- of positive serologic ndings in women
Control
Participants, n

terval [CI], 1.0e4.6); P .06).17 with HG compared with asymptomatic

22
24
100

Neither of the 2 other studies showed control subjects are displayed, with an
a signicant association between the overall odds ratio of 3.2 (95% CI,
Studies included in review (continued)

72
22
24

grade of ketonuria and severity of HG 2.0e5.1). In Figure 2, B, the sensitivity

in terms of readmission.18,19 and specicity of these studies are dis-
2004
2002
2002

HCG was increased in women with played. Diagnostic metaanalysis of these

HG who were hospitalized for >4 days
compared with women who were
hospitalized for <4 days.19 Thyroid-
stimulating hormone and FT4 were
Not a case-control study.
96
19 studies showed a summary sensitivity
of 73% (95% CI, 62.0e81.4%) and a
specicity of 55% (95% CI, 47.4e61.5%)
in the diagnosis of HG, as compared

98

not associated with a higher read- with control subjects without hyper-
Yoneyama et al
Yoneyama et al

mission rate.18 Estradiol of women emesis.22-40 Figure 3 shows the studies

who were hospitalized for >4 days
Xia et al40

that used methods other than IgG se-

TABLE

were similar to levels of women hos- rology to determine H pylori infection in

Study

pitalized for <4 days.19 WBC level was women with HG and NVP.23,29,32,37,41-45
a

not associated with severity.17-19 Two studies were not displayed in forest

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FIGURE 2
Metaanalysis, sensitivity, and specificity of Heliobacter pylori immunoglobulin G

Metaanalysis, sensitivity and specificity of H pylori immunoglobulin G in women with hyperemesis gravidarum compared with asymptomatic control
subjects. A, 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.
M-H, Mantel-Haenszel.
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.

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FIGURE 3
Heliobacter pylori

H 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 gene A; CUBT, 13C 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.
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.

plots because of reporting incomplete
data for 2  2 table construction; Rey-
munde et al46 determined IgG in women
with HG and found a signicant associ-
ation (P < .001) between HG and the
presence of IgG antibodies. Wu et al47
determined IgG in women with gastro-
intestinal complaints in pregnancy but
did not nd a signicant association be-
tween these complaints and H pylori
status.
HCG
We included 35 studies on hCG, of which
18 studies showed a signicant associa-
tion 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 NVP65-67; the other
13 studies did not nd a signicant as-
sociation.22,68-79
It was not possible to perform meta-
analysis on hCG, because of large clinical
heterogeneity and the skewed distribu-
tion 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 mul-
tiple of medians. This is a measure for
individual test deviance from the median
and is calculated by dividing the individ-
ual 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 suit-
able for forest plot display.
Thyroid hormones
Thyroid 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 thyro-
tropin,20,23,49,52,59,60,62,69,70,72,81,82,84 and
67% of the studies showed increased
FT4 in symptomatic patients com-
pared 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 to-
tal thyroxine 3 (50%),52,62,83,87 and free
thyroxine (53%).55,72,77,81,82,86,87,90
It was not possible to construct 2  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 ndings can be
extracted from the study, and it was
not possible to perform a diagnostic
metaanalysis.
Leptin
Five studies reported on leptin levels.
Chou et al63 showed signicantly lower
levels of leptin in women with severe
NVP compared with women with mild
NVP. Aka et al76 showed signicantly
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 signicant difference in lep-
tin levels between women with HG and
asymptomatic control subjects but did
show a signicant 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 signicant association between leptin
levels and occurrence of HG.61,85

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FIGURE 4
Human chorionic gonadotropin

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, b-hCG, matched for gestational age; C, Free hCG, hCG in 24-hour urine sample, free a- and b-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; IV, inverse variance; NVP, nausea and vomiting in pregnancy Std, standard.
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.

Estradiol and progesterone signicant association22,49,51,94,95; 3 reported on women with HG and 2

Eight studies were found on estradiol studies found increased estradiol levels studies reported on women with
levels, which showed inconsistent re- in women with HG.52,68,96 Five studies NVP. The latter 2 found a lower pro-
sults. Five studies did not nd a covered progesterone, of which 3 studies gesterone level compared with control

1.e10 American Journal of Obstetrics & Gynecology MONTH 2014

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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 lymphocytes
Five studies reported on
WBC,55,56,60,91,97 and ve studies re-
ported on lymphocytes55,56,60,97,98 in
women with HG compared with women
without HG. WBC differed between
different studies, lymphocyte levels ten-
ded to be higher in patients in HG
compared with control subjects.
C OMMENT
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 reects catabolism of adi-
pose stores and could be an indicator of
HG patients who 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 nd an
association between HG and ketonuria.
None of the studies that investigated
ketonuria and HG severity reported an
association. Based on these ndings, we
cannot recommend the use of ketonuria
in the diagnosis of HG at this point, but
further research into the relation be-
tween ketonuria and diagnosis is
necessary.
H pylori was associated signicantly
with HG. However, the odds ratio of
3.2 (95% CI, 2.0e5.1) could be inated
because of comparison with asymp-
tomatic control subjects, because in
early pregnancy most women experience
nausea to some extent.1 Despite the sig-
nicant association with HG, which
implies an etiologic association with HG
symptoms, the pooled sensitivity and
specicity is insufcient to warrant its
diagnostic application. Despite this lim-
itation, the ndings 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 these women
showed marked improvement of nausea
and vomiting; however, because there
was no comparison with control sub-
jects, this provides insufcient 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 reects the etio-
logic notion that rising hCG levels either
affect areas of the brain involved in
nausea directly or indirectly by inducing
rises in other hormones (thyroid hor-
mone, estradiol) with the ability to affect
nausea. We could not perform a meta-
analysis because of the skewed distribu-
tion 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 ndings 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 sys-
tematic review found an association be-
tween increased thyroid activity and the
presence of HG, which supports an
etiologic role for thyroid function in HG
symptoms. We were unable to investigate
MONTH 2014 American Journal of Obstetrics & Gynecology
Obstetrics Research
the diagnostic accuracy of thyroid func-
tion testing, however, because of the lack
of reported cut-off values in the included
(etiologic) studies. Based on these nd-
ings, 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 re-
ceptor, 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 bio-
markers, they have all been suggested to
play an etiologic role in HG. In our sys-
tematic 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 diag-
nostic 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 diag-
nostic perspective. The unclear report-
ing of methods in the primary studies,
which is a common problem in diag-
nostic reviews, hindered quality assess-
ment in our study. Poor study design and
conduct can affect estimates of diag-
nostic accuracy,100,101 although it is not
entirely clear how individual aspects of
quality may affect accuracy and to what
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
1.e11
Research Obstetrics
could be viewed as a strength of this pa-
per, 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 etiologic association
with HG. However, we did not nd a
single biomarker that can diagnose or
predict the severity of HG. In this review,
ketonuria, contrary to current beliefs, had
no obvious association with HG. There-
fore, 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 recom-
mend future research into the relation
between ketonuria and diagnosis or
prognosis of HG. H pylori was associ-
ated signicantly with the occurrence
of HG, which may be of future thera-
peutic interest but requires further
evaluation. -
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www.AJOG.org
A PPENDIX
S EARCH S TRATEGY
PubMed
((Morning Sickness[Mesh] OR hyper-
emesis 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))
www.AJOG.org Obstetrics Research

SUPPLEMENTARY FIGURE
Summary of quality assessment of diagnostic accuracy studies scores

QUADAS, quality assessment of diagnostic accuracy studies.

Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.

MONTH 2014 American Journal of Obstetrics & Gynecology 1.e15