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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

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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

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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),

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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)

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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

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Study

Control Year Cases subjects Condition

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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

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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

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34

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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)

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35

Weyermann et al45a 47a

X

60

Thornton et al75

Unsel et al

X

62

Tareen et al

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TABLE

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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

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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

Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis.

Currently, there is no consensus on the definition of hyperemesis gravidarum (HG; protracted vomiting in pregnancy) and no single widely used set of d...
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