Methods for Review
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 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 × 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.
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)–2 guidelines. 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 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 analysis
For metaanalysis of diagnostic test accuracy, we used the hierarchic summary receiver operating characteristics model, 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 statement and metaanalysis of observational studies in epidemiology (MOOSE) guidelines in writing this review.
Results
Search results
The 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 ). 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.
| Study | Year | Participants, n | Condition | Biomarkers | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cases | Control subjects | Ketones | Heliobacter pylori | Human chorionic gonadotropin | Thyroid | Leptin | Estradiol | Progesterone | White blood count | Lymphocyte | |||
| Aka et al | 2006 | 18 | 18 | HG | X | X | X | ||||||
| Al-Busaida and Krolikowski | 2001 | 15 | 15 | HG | X | ||||||||
| Al-Yatama et al | 2002 | 50 | 50 | HG | X | X | |||||||
| Arslan et al | 2003 | 30 | 26 | HG | X | X | X | ||||||
| Asakura et al | 2000 | 110 | 30 | NVP/HG | X | ||||||||
| Asakura et al | 2003 | 24 | 20 | HG | X | X | |||||||
| Aytac et al | 2007 | 52 | 55 | HG | X | ||||||||
| Berker et al | 2003 | 80 | 80 | HG | X | X | X | ||||||
| Bouillon et al | 1982 | 33 | 52 | HG | X | ||||||||
| Bruun and Kristoffersen | 1978 | 35 | 57 | HG | X | ||||||||
| Cevrioglu et al | 2004 | 27 | 97 | HG | X | X | |||||||
| Chihara et al | 2003 | 17 | 37 | HG | X | ||||||||
| Chou et al a | 2011 | 59 | 0 | NVP | X | X | |||||||
| Demir et al | 2006 | 54 | 42 | HG | X | X | |||||||
| Depue et al | 1987 | 35 | 35 | HG | X | X | |||||||
| Derbent et al | 2011 | 115 | 110 | HG | X | X | X | ||||||
| Dokmeci et al | 2004 | 17 | 13 | HG | X | ||||||||
| Erdem et al | 2002 | 47 | 42 | HG | X | ||||||||
| Evans et al a | 1986 | 342 | 0 | NVP/HG | X | ||||||||
| Fairweather and Loraine | 1962 | 90 | 11 | HG | X | ||||||||
| Frigo et al | 1998 | 105 | 129 | HG | X | ||||||||
| Goodwin et al | 1992 | 57 | 57 | HG | X | X | X | ||||||
| Goodwin et al | 1994 | 39 | 23 | HG | X | ||||||||
| Guney et al | 2007 | 25 | 35 | HG | X | ||||||||
| Guven et al | 2011 | 40 | 40 | HG | X | ||||||||
| Hatzivies et al | 2007 | 25 | 85 | HG | X | ||||||||
| Hayakawa et al | 2000 | 34 | 29 | HG | X | ||||||||
| Jacobson et al | 2003 | 30 | 75 | HG | X | ||||||||
| Jarnfelt-Samsioe et al | 1985 | 62 | 40 | NVP | X | ||||||||
| Jarnfelt-Samsioe et al | 1986 | 62 | 40 | NVP | X | X | |||||||
| Jarnfelt-Samsioe et al | 1986 | 62 | 40 | NVP | X | X | |||||||
| Jordan et al | 1999 | 20 | 20 | HG | X | X | X | ||||||
| Juras et al | 1983 | 33 | 30 | HG | X | ||||||||
| Karaca et al | 2004 | 56 | 90 | HG | X | ||||||||
| Karadeniz et al | 2006 | 31 | 29 | HG | X | ||||||||
| Kauppila et al | 1979 | 42 | 115 | HG | X | ||||||||
| Kaupilla et al | 1984 | 14 | 12 | NVP | X | ||||||||
| Kazerooni et al | 2002 | 54 | 53 | HG | X | ||||||||
| Kimura et al | 1993 | 27 | 24 | NVP/HG | X | X | |||||||
| Kocak et al | 1999 | 95 | 116 | HG | X | ||||||||
| Kuscu et al | 2003 | 10 | 10 | HG | X | X | X | ||||||
| Lagiou et al | 2003 | 209 | 53 | NVP | X | X | |||||||
| Lao et al | 1988 | 51 | 28 | HG | X | ||||||||
| Larraz et al | 2002 | 162 | 156 | NVP | X | ||||||||
| Lawson et al a | 2002 | 92 | 0 | NVP | X | ||||||||
| Lee et al | 2005 | 40 | 42 | HG | X | ||||||||
| Leylek et al | 1996 | 24 | 20 | HG | X | X | X | X | |||||
| Leylek et al | 1999 | 30 | 15 | HG | X | X | X | X | |||||
| Mansour and Nashaat | 2011 | 80 | 80 | HG | X | ||||||||
| Masson et al | 1985 | 65 | 48 | NVP | X | X | X | ||||||
| Minagawa et al | 1999 | 18 | 20 | HG | X | X | |||||||
| Mori et al | 1988 | 111 | 41 | NVP | X | X | |||||||
| Murata et al | 2006 | 44 | 53 | NVP/HG | X | ||||||||
| Ndungu et al a | 2009 | 72 | 0 | Emesis | X | X | |||||||
| Panesar et al | 2001 | 62 | 58 | HG | X | X | |||||||
| Panesar et al | 2006 | 43 | 329 | HG | X | ||||||||
| Peled et al | 2012 | 73 | 146 | HG | X | ||||||||
| Perez-Perez et al | 1999 | 42 | 47 | HG | X | ||||||||
| Reymunde et al | 2001 | 45 | 44 | HG | X | ||||||||
| Salimi-Khayati et al | 2003 | 54 | 54 | HG | X | ||||||||
| Sandven et al | 2008 | 244 | 244 | HG | X | ||||||||
| Sekizawa et al | 2001 | 16 | 23 | HG | X | ||||||||
| Shirin et al a | 2004 | 185 | 0 | GI symptoms | X | ||||||||
| Soules et al | 1980 | 37 | 9 | NVP/HG | X | ||||||||
| Swaminathan et al | 1989 | 71 | 43 | HG | X | X | |||||||
| Tan et al a | 2006 | 192 | 0 | HG | X | X | X | ||||||
| Tan et al a | 2006 | 192 | 0 | HG | X | X | X | ||||||
| Tan et al a | 2009 | 167 | 0 | HG | X | X | X | X | |||||
| Tareen et al | 1995 | 30 | 15 | HG | X | X | |||||||
| Taskin et al | 2009 | 20 | 20 | HG | X | X | X | X | X | X | |||
| Thornton et al | 1979 | 12 | 12 | HG | X | ||||||||
| Tlolka et al | 2010 | 29 | 43 | NVP | X | ||||||||
| Tsuruta et al | 1995 | 55 | 24 | NVP/HG | X | X | |||||||
| Unsel et al | 2004 | 40 | 30 | HG | X | X | |||||||
| Ustun et al | 2004 | 35 | 39 | HG | X | ||||||||
| Weyermann et al a | 2003 | 898 | 0 | GI symptoms | X | ||||||||
| Wilson et al | 1992 | 10 | 50 | HG | X | X | |||||||
| Wu et al a | 2000 | 54 | 0 | GI symptoms | X | ||||||||
| Xia et al | 2004 | 72 | 100 | HG | X | ||||||||
| Yoneyama et al | 2002 | 22 | 22 | HG | X | X | X | ||||||
| Yoneyama et al | 2002 | 24 | 24 | HG | X | ||||||||
Quality assessment
A summary of the QUADAS-2 scores for risk of bias and concerns regarding 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 results. Quality was often unclear concerning patient selection and flow and timing. The reference standard was well-defined 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 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), 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.
Severity of HG
We found 3 studies that described biomarkers in relation to markers of disease severity. 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, 0-3+ 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). Neither of the 2 other studies showed a significant association between the grade of ketonuria and severity of HG in terms of readmission.
HCG was increased in women with HG who were hospitalized for >4 days compared with women who were hospitalized for <4 days. Thyroid-stimulating hormone and FT4 were not associated with a higher readmission rate. Estradiol of women who were hospitalized for >4 days were similar to levels of women hospitalized for <4 days. WBC level was not associated with severity.
Presence of HG/NVP
Ketonuria
Ketonuria among patients with NVP was not described in any study. We found 2 studies that described ketonuria and the presence of HG: Derbent et al (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 al (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 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 , 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 with control subjects without hyperemesis. Figure 3 shows the studies that used methods other than IgG serology to determine H pylori infection in women with HG and NVP. Two studies were not displayed in forest plots because of reporting incomplete data for 2 × 2 table construction; Reymunde et al determined IgG in women with HG and found a significant association ( P < .001) between HG and the presence of IgG antibodies. Wu et al determined IgG in women with gastrointestinal complaints in pregnancy but did not find a significant association between these complaints and H pylori status.
HCG
We included 35 studies on hCG, of which 18 studies showed a significant association between raised hCG levels and the occurrence of NVP or HG. Three studies showed a lower hCG in women with HG or NVP ; the other 13 studies did not find a significant association.
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.
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