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 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, 2.0e5.1) of Heliobacter pylori for HG, as compared with asymptomatic control subjects (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 pregnancy; 50-80% of pregnant women experience daily nausea and occasional vomiting in the first half of gestation.1 In hyperemesis gravidarum (HG), nausea and vomiting is 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 0.3-2% 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 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 Leeflang), 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 conflict 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. [email protected]. 0002-9378/$36.00 ª 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 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.
www.AJOG.org 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-classified biomarker value and occurrence or severity of HG. Study selection was done in 2 stages. First, 2 reviewers (M.N.N., I.J.G.) independently assessed identified titles and abstracts, after which we obtained full manuscripts of all selected studies. Second, 2 reviewers (M.N.N. and I.J.G., N.V. or R.C.P.) per paper independently assessed whether the studies were suitable to be included. Any disagreement was resolved by consensus meetings.
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.
Data extraction and quality assessment For 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)e2 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.
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 ¼ 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,
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 pregnancy in the absence of any other obvious cause for these complaints. This definition may lead to the
M ETHODS
FOR
R EVIEW
1.e2 American Journal of Obstetrics & Gynecology MONTH 2014
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 analysis For 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.
R ESULTS Search results The electronic search identified 3442 individual articles (Figure 1). We excluded several articles because there were 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),
MONTH 2014 American Journal of Obstetrics & Gynecology
1.e3
Studies included in review Participants, n
Biomarkers
Aka et al76
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
2006
18
18
HG
X
Al-Busaida and Krolikowski48 2001
15
15
HG
X
Al-Yatama et al59
2002
50
50
HG
X
X
2003
X
X
Arslan et al
61
30
26
HG
Asakura et al
90
2000 110
30
NVP/HG
Asakura et al
91
2003
24
20
HG
2007
52
55
HG
X
2003
80
80
HG
X
1982
33
52
HG
1978
35
57
HG
2004
27
97
HG
Aytac et al41 Berker et al22 Bouillon et al
87
Bruun and Kristoffersen
92
Cevrioglu et al23 Chihara et al Chou et al
93
2003
17
37
HG
63a
2011
59
0
NVP
82
2006
54
42
HG
68
1987
Demir et al
Depue et al
35
35
HG
Derbent et al20
2011 115
110
HG
Dokmeci et al83
2004
17
13
HG
2002
47
42
HG
1986 342
0
24
Erdem et al Evans et al
80a
Fairweather and Loraine Frigo et al25
65
1962
90
11
HG
129
HG
X X
X X X X
X
X
X X
X X
X X X X
57
HG
X X
39
23
HG
2007
25
35
HG
X
Guven et al27
2011
40
40
HG
X
2007
25
85
HG
X
X
X
(continued)
www.AJOG.org
1994
26
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
X X
57
Hatzivies et al
X X
1992
28
X
X
53
Guney et al
X
X
Goodwin et al52 Goodwin et al
X
X
NVP/HG
1998 105
X
Obstetrics
Study
Control Year Cases subjects Condition
Research
1.e4 American Journal of Obstetrics & Gynecology MONTH 2014
TABLE
Studies included in review (continued) Participants, n
Biomarkers
Control Year Cases subjects Condition
Study Hayakawa et al29 Jacobson et al
30
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
2000
34
29
HG
X X
2003
30
75
HG
Jarnfelt-Samsioe et al
79
1985
62
40
NVP
Jarnfelt-Samsioe et al
94
1986
62
40
NVP
Jarnfelt-Samsioe et al
67
1986
62
40
NVP
X
X
1999
20
20
HG
X
X
1983
33
30
HG
2004
56
90
HG
X
2006
31
29
HG
X
1979
42
115
HG
X
1984
14
12
NVP
X
2002
54
53
HG NVP/HG
Jordan et al49 Juras et al
88
Karaca et al
31
Karadeniz et al Kauppila et al
32
54
Kaupilla et al64 33
Kazerooni et al Kimura et al
69
27
24
1999
95
116
HG
Kuscu et al21
2003
10
10
HG
2003 209
53
NVP
1988
51
28
HG
2002 162
156
NVP
Kocak et al
Lagiou et al Lao et al
95
89
Larraz et al
42
Lawson et al
50a
Lee et al35 Leylek et al55 Leylek et al
56
Mansour and Nashaat Minagawa et al97 70
Mori et al
X
X
X
X
X X
X
X
X
X X
X
X
X X
2002
92
0
NVP
2005
40
42
HG
1996
24
20
HG
X
X
X
X
1999
30
15
HG
X
X
X
X
2011
80
80
HG
1985
65
48
NVP
1999
18
20
HG
X
X
1988 111
41
NVP
1.e5
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
X X
X X X
X
X
X (continued)
Research
Masson et al
51
36
X
Obstetrics
MONTH 2014 American Journal of Obstetrics & Gynecology
1993
34
www.AJOG.org
TABLE
Studies included in review (continued) Participants, n
Biomarkers
Control Year Cases subjects Condition
Study
2006
44
53
NVP/HG
71a
2009
72
0
Emesis
X
X
Panesar et al
72
2001
62
58
HG
X
X
Panesar et al
81
2006
43
329
HG
2012
73
146
HG
1999
42
47
HG
X
2001
45
44
HG
X
2003
54
54
HG
X
Sandven et al
2008 244
X
Sekizawa et al73
2001
Ndungu et al
Peled et al57 Perez-Perez et al37 46
Reymunde et al
Salimi-Khayati et al
38
39
Shirin et al
43a 74
Soules et al
Swaminathan et al
78
X
Obstetrics
Murata et al84
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
X X
244
HG
16
23
HG
2004 185
0
GI symptoms
1980
37
9
NVP/HG
X
1989
X
X X
71
43
HG
17a
2006 192
0
HG
X
X
X
Tan et al18a
2006 192
0
HG
X
X
X
2009 167
0
HG
X
Tan et al Tan et al
19a
Taskin et al
X
1995
30
15
HG
X
X X
2009
20
20
HG
X
1979
12
12
HG
X
Tlolka et al44
2010
29
43
NVP
Tsuruta et al
77
1995
55
24
NVP/HG
85
2004
40
30
HG
86
2004
Ustun et al
39
2003 898
0
Wilson et al66
1992
10
50
2000
54
0
Wu et al
X
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
X
X
X X
X
X X
HG GI symptoms
X
X
HG GI symptoms
X
X
X
X
X (continued)
www.AJOG.org
35
Weyermann et al45a 47a
X
60
Thornton et al75
Unsel et al
X
62
Tareen et al
Research
1.e6 American Journal of Obstetrics & Gynecology MONTH 2014
TABLE
Obstetrics
X
X
X
X
thyroid disorders (46 articles), gastrointestinal disorders (31 articles), endocrine disorders (15 articles), urinary tract infection (6 articles), psychiatric disorders (12 articles), previous treatment against Heliobacter 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 were excluded 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.
Not a case-control study.
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
a
HG 24 24 2002
GI, gastrointestinal; HG, hyperemesis gravidarum; NVP, nausea and vomiting in pregnancy.
Yoneyama et al
22 22 2002 Yoneyama et al
98
HG
X 96
72
100
HG 2004 Xia et al40
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte Control Year Cases subjects Condition Study
Participants, n
Studies included in review (continued)
TABLE
Biomarkers
www.AJOG.org
Severity of HG 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 in the 2 other studies. These studies described the association with ketonuria, human chorionic gonadotropin (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, 0-3þ vs 4þ urinary ketones of a possible 4þ; study 2009, 0-2þ vs 3-4þ 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], 1.0e4.6); P ¼ .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 were similar to levels of women hospitalized for
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 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, 2.0e5.1) of Heliobacter pylori for HG, as compared with asymptomatic control subjects (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 pregnancy; 50-80% of pregnant women experience daily nausea and occasional vomiting in the first half of gestation.1 In hyperemesis gravidarum (HG), nausea and vomiting is 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 0.3-2% 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 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 Leeflang), 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 conflict 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. [email protected]. 0002-9378/$36.00 ª 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 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.
www.AJOG.org 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-classified biomarker value and occurrence or severity of HG. Study selection was done in 2 stages. First, 2 reviewers (M.N.N., I.J.G.) independently assessed identified titles and abstracts, after which we obtained full manuscripts of all selected studies. Second, 2 reviewers (M.N.N. and I.J.G., N.V. or R.C.P.) per paper independently assessed whether the studies were suitable to be included. Any disagreement was resolved by consensus meetings.
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.
Data extraction and quality assessment For 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)e2 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.
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 ¼ 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,
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 pregnancy in the absence of any other obvious cause for these complaints. This definition may lead to the
M ETHODS
FOR
R EVIEW
1.e2 American Journal of Obstetrics & Gynecology MONTH 2014
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 analysis For 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.
R ESULTS Search results The electronic search identified 3442 individual articles (Figure 1). We excluded several articles because there were 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),
MONTH 2014 American Journal of Obstetrics & Gynecology
1.e3
Studies included in review Participants, n
Biomarkers
Aka et al76
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
2006
18
18
HG
X
Al-Busaida and Krolikowski48 2001
15
15
HG
X
Al-Yatama et al59
2002
50
50
HG
X
X
2003
X
X
Arslan et al
61
30
26
HG
Asakura et al
90
2000 110
30
NVP/HG
Asakura et al
91
2003
24
20
HG
2007
52
55
HG
X
2003
80
80
HG
X
1982
33
52
HG
1978
35
57
HG
2004
27
97
HG
Aytac et al41 Berker et al22 Bouillon et al
87
Bruun and Kristoffersen
92
Cevrioglu et al23 Chihara et al Chou et al
93
2003
17
37
HG
63a
2011
59
0
NVP
82
2006
54
42
HG
68
1987
Demir et al
Depue et al
35
35
HG
Derbent et al20
2011 115
110
HG
Dokmeci et al83
2004
17
13
HG
2002
47
42
HG
1986 342
0
24
Erdem et al Evans et al
80a
Fairweather and Loraine Frigo et al25
65
1962
90
11
HG
129
HG
X X
X X X X
X
X
X X
X X
X X X X
57
HG
X X
39
23
HG
2007
25
35
HG
X
Guven et al27
2011
40
40
HG
X
2007
25
85
HG
X
X
X
(continued)
www.AJOG.org
1994
26
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
X X
57
Hatzivies et al
X X
1992
28
X
X
53
Guney et al
X
X
Goodwin et al52 Goodwin et al
X
X
NVP/HG
1998 105
X
Obstetrics
Study
Control Year Cases subjects Condition
Research
1.e4 American Journal of Obstetrics & Gynecology MONTH 2014
TABLE
Studies included in review (continued) Participants, n
Biomarkers
Control Year Cases subjects Condition
Study Hayakawa et al29 Jacobson et al
30
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
2000
34
29
HG
X X
2003
30
75
HG
Jarnfelt-Samsioe et al
79
1985
62
40
NVP
Jarnfelt-Samsioe et al
94
1986
62
40
NVP
Jarnfelt-Samsioe et al
67
1986
62
40
NVP
X
X
1999
20
20
HG
X
X
1983
33
30
HG
2004
56
90
HG
X
2006
31
29
HG
X
1979
42
115
HG
X
1984
14
12
NVP
X
2002
54
53
HG NVP/HG
Jordan et al49 Juras et al
88
Karaca et al
31
Karadeniz et al Kauppila et al
32
54
Kaupilla et al64 33
Kazerooni et al Kimura et al
69
27
24
1999
95
116
HG
Kuscu et al21
2003
10
10
HG
2003 209
53
NVP
1988
51
28
HG
2002 162
156
NVP
Kocak et al
Lagiou et al Lao et al
95
89
Larraz et al
42
Lawson et al
50a
Lee et al35 Leylek et al55 Leylek et al
56
Mansour and Nashaat Minagawa et al97 70
Mori et al
X
X
X
X
X X
X
X
X
X X
X
X
X X
2002
92
0
NVP
2005
40
42
HG
1996
24
20
HG
X
X
X
X
1999
30
15
HG
X
X
X
X
2011
80
80
HG
1985
65
48
NVP
1999
18
20
HG
X
X
1988 111
41
NVP
1.e5
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
X X
X X X
X
X
X (continued)
Research
Masson et al
51
36
X
Obstetrics
MONTH 2014 American Journal of Obstetrics & Gynecology
1993
34
www.AJOG.org
TABLE
Studies included in review (continued) Participants, n
Biomarkers
Control Year Cases subjects Condition
Study
2006
44
53
NVP/HG
71a
2009
72
0
Emesis
X
X
Panesar et al
72
2001
62
58
HG
X
X
Panesar et al
81
2006
43
329
HG
2012
73
146
HG
1999
42
47
HG
X
2001
45
44
HG
X
2003
54
54
HG
X
Sandven et al
2008 244
X
Sekizawa et al73
2001
Ndungu et al
Peled et al57 Perez-Perez et al37 46
Reymunde et al
Salimi-Khayati et al
38
39
Shirin et al
43a 74
Soules et al
Swaminathan et al
78
X
Obstetrics
Murata et al84
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte
X X
244
HG
16
23
HG
2004 185
0
GI symptoms
1980
37
9
NVP/HG
X
1989
X
X X
71
43
HG
17a
2006 192
0
HG
X
X
X
Tan et al18a
2006 192
0
HG
X
X
X
2009 167
0
HG
X
Tan et al Tan et al
19a
Taskin et al
X
1995
30
15
HG
X
X X
2009
20
20
HG
X
1979
12
12
HG
X
Tlolka et al44
2010
29
43
NVP
Tsuruta et al
77
1995
55
24
NVP/HG
85
2004
40
30
HG
86
2004
Ustun et al
39
2003 898
0
Wilson et al66
1992
10
50
2000
54
0
Wu et al
X
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
X
X
X X
X
X X
HG GI symptoms
X
X
HG GI symptoms
X
X
X
X
X (continued)
www.AJOG.org
35
Weyermann et al45a 47a
X
60
Thornton et al75
Unsel et al
X
62
Tareen et al
Research
1.e6 American Journal of Obstetrics & Gynecology MONTH 2014
TABLE
Obstetrics
X
X
X
X
thyroid disorders (46 articles), gastrointestinal disorders (31 articles), endocrine disorders (15 articles), urinary tract infection (6 articles), psychiatric disorders (12 articles), previous treatment against Heliobacter 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 were excluded 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.
Not a case-control study.
Niemeijer. Diagnostic markers for hyperemesis gravidarum. Am J Obstet Gynecol 2014.
a
HG 24 24 2002
GI, gastrointestinal; HG, hyperemesis gravidarum; NVP, nausea and vomiting in pregnancy.
Yoneyama et al
22 22 2002 Yoneyama et al
98
HG
X 96
72
100
HG 2004 Xia et al40
Heliobacter Human chorionic White blood Ketones pylori gonadotropin Thyroid Leptin Estradiol Progesterone count Lymphocyte Control Year Cases subjects Condition Study
Participants, n
Studies included in review (continued)
TABLE
Biomarkers
www.AJOG.org
Severity of HG 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 in the 2 other studies. These studies described the association with ketonuria, human chorionic gonadotropin (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, 0-3þ vs 4þ urinary ketones of a possible 4þ; study 2009, 0-2þ vs 3-4þ 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], 1.0e4.6); P ¼ .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 were similar to levels of women hospitalized for
