# Helicobacter pylori Infection Is Associated with an Increased Risk of Hyperemesis Gravidarum: A Meta-Analysis

Authors: Lin Li; Lingling Li; Xiaoying Zhou; Shuping Xiao; Huiyuan Gu; Guoxin Zhang
Journal: Gastroenterology Research and Practice
 (2015)

---

## Abstract

Background. Several studies have shown a possible involvement ofHelicobacter pylori(H. pylori) infection in individuals with hyperemesis gravidarum (HG), but the relationship remains controversial. This meta-analysis was performed to validate and strengthen the association between HG andH. pyloriinfection.Methods. PubMed, Embase, and Web of Science databases up to March 20, 2014, were searched to select studies on the prevalence ofH. pyloriinfection between pregnant women with HG and the normal pregnant control subjects.Results. Of the HG cases, 1289 (69.6%) wereH. pylori-positive; however, 1045 (46.2%) wereH. pylori-positive in control group. Compared to the non-HG normal pregnant controls, infection rate ofH. pyloriwas significantly higher in pregnant women with HG (OR = 3.34, 95% CI: 2.32–4.81, P
<
0.001). Subgroup analysis indicated thatH. pyloriinfection was a risk factor of HG in Asia, Africa, and Oceania, especially in Africa (OR = 12.38, 95% CI: 7.12–21.54, P
<
0.001).Conclusions.H. pylorishould be considered one of the risk factors of HG, especially in the developing countries.H. pylorieradication could be considered to relieve the symptoms of HG in some intractable cases.


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## Body

## 1. Introduction

Hyperemesis gravidarum (HG), the most severe form of pregnancy-associated nausea and vomiting, is leading to weight loss, nutritional deficiencies, and metabolic disturbance, for example, dehydration, acidosis from starvation, hypokalemia, and transient hepatic dysfunction, often requiring hospitalization and medical treatment to avoid life-threatening complications [1]. HG complicates 0.3–2% of all pregnancies and is a multifactorial disease; however, little is known about the etiology of HG. But a variety of mechanisms may play a role in this disease, such as endocrine factors like human chorionic gonadotropin (HCG), estradiol, and progesterone and immunologic factors, as well as personal factors in which increased body weight has been proposed as possible underlying cause [2]. Recently, several studies have put emphasis on the correlation betweenHelicobacter pylori(H. pylori) infection and the risk of HG [3–6].H. pylori, as a gram-negative flagellated spiral bacterium, colonizes stomach and creates the basis of pathogenesis of gastric pathologies, including chronic gastritis, duodenal and gastric ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma [7–9].H. pylori infected the stomach of 50% of the world population, and it is more prevalent in developing countries [10]. The prevalence ofH. pyloriinfection in pregnant women varies according to socioeconomic conditions, geographic area, and even the method used to testH. pylori infection.Several studies have shown a possible involvement ofH. pylori infection in individuals with HG; however, other studies did not share with them. Although three previous meta-analyses have shown the positive association betweenH. pylori and HG, the role ofH. pylori infection in the pathogenesis of HG has not reached a consensus. Moreover, the previous meta-analyses did not use the comprehensive search method, unable to include the overall studies, and did not perform a detailed analysis on subgroup to explore the potential factors in HG. On the other hand, the role of some factors such as different populations, geographic areas, ethnicity, and low socioeconomic status is unclear in HG. Therefore, our meta-analysis was undertaken to strengthen the hypothesis thatH. pylori is a risk factor of HG and to describe the underlying factors in HG.


## 2. Materials and Methods

### 2.1. Data Sources

We systematically identified studies in PubMed, Embase, and Web of Science (inception through March 20, 2014) databases by two independent investigators (LL and LLL) for all relevant literatures between the risk of HG and the infection ofH. pylori, by using the MeSH terms, “Helicobacter pylori” OR “H. pylori” OR “Helicobacterinfection” AND “hyperemesis gravidarum.” These were searched both as thesaurus terms and as text words. Even “nausea and vomiting” as text word was searched too. Finally, a Google Scholar search was done. Moreover, the references at the end of selected papers were also examined for additional relevant studies.


### 2.2. Inclusion Criteria

In our meta-analysis, the included articles had to meet the following criteria: (1) they must be case-control studies or prospective studies or cross-sectional studies; (2) studies must refer to the association ofH. pyloriinfection with HG risk and must provide raw data onH. pylori infection in both HG and control groups; (3) the participants must have had a clinical diagnosis of hyperemesis gravidarum as follows: pernicious vomiting, weight loss, and at least one positive ketonuria; (4) the confirmation ofH. pylori infection was detected by enzyme-linked immunosorbent assay (ELISA), stool antigen test, 13C-urea breath test (13C-UBT), mucosal biopsy, and polymerase chain reaction (PCR). At least one positive result was considered as confirmation of infection.


### 2.3. Exclusion Criteria

We excluded studies as follows: (1) reports without control groups; (2) reviews and duplicated publications; (3) studies in which the source ofH. pylori infection in cases and control subjects and other essential information were not offered; hyperthyroidism, multiple gestation trophoblastic neoplasia, gastrointestinal and hepatic disorders, urinary tract or other infections, psychosocial or any other maternal disorders, and any treatment with antacids or antibiotics within the previous 7 days were excluded as well.


### 2.4. Data Extraction

According to the inclusion criteria, data was carefully extracted independently by two reviewers (LL and LLL). For each study analyzed, we collected data including first author, year of publication, country of the population studied, study design, sources of pregnant women (primipara or multipara), gestational age, diagnosis of hyperemesis gravidarum, methods ofH. pyloridetection, total number of persons in cases and controls, and the numbers ofH. pylori-positive andH. pylori-negative patients in the HG group and the control group of each study which were recorded, respectively. For conflicting evaluations, an agreement was reached by consensus and agreement with another reviewer (XYZ), referring back to the original articles.


### 2.5. Statistical Analysis

We used pooled odds ratio (OR) with its corresponding 95% confidence interval (CI) to estimate the strength of the association between HG andH. pyloriinfection. Post hoc subgroup analyses were also performed to explain the heterogeneity in results. Subgroups were explored as follows: detection ofH. pyloriinfection (serumH. pylori IgG/IgM/IgA antibody by ELISA, stool antigen test, mucosal biopsy from endoscopy, orH. pylori genome by PCR), publication period (1996–2000, 2001–2005, 2006–2010, or 2011–2014), and region (Asia, North America, Europe, Africa, or Oceania).The heterogeneity of the studies included in this meta-analysis was assessed using theQ statistic test and the I
2 statistic test. The random-effects model was selected when P value < 0.1 or I
2 > 50%; otherwise, the fixed-effects model was selected. Possible publication bias was evaluated by visual inspection of funnel plots and application of Begg’s and Egger’s test [11–15]. P values of less than 0.05 from Egger’s test were considered statistically significant.All statistical analyses were done with STATA statistical software package version 12.0 (2000; STATA Corp., College Station, TX, USA);P
<
0.05 was identified as statistically significant.


## 2.1. Data Sources

We systematically identified studies in PubMed, Embase, and Web of Science (inception through March 20, 2014) databases by two independent investigators (LL and LLL) for all relevant literatures between the risk of HG and the infection ofH. pylori, by using the MeSH terms, “Helicobacter pylori” OR “H. pylori” OR “Helicobacterinfection” AND “hyperemesis gravidarum.” These were searched both as thesaurus terms and as text words. Even “nausea and vomiting” as text word was searched too. Finally, a Google Scholar search was done. Moreover, the references at the end of selected papers were also examined for additional relevant studies.


## 2.2. Inclusion Criteria

In our meta-analysis, the included articles had to meet the following criteria: (1) they must be case-control studies or prospective studies or cross-sectional studies; (2) studies must refer to the association ofH. pyloriinfection with HG risk and must provide raw data onH. pylori infection in both HG and control groups; (3) the participants must have had a clinical diagnosis of hyperemesis gravidarum as follows: pernicious vomiting, weight loss, and at least one positive ketonuria; (4) the confirmation ofH. pylori infection was detected by enzyme-linked immunosorbent assay (ELISA), stool antigen test, 13C-urea breath test (13C-UBT), mucosal biopsy, and polymerase chain reaction (PCR). At least one positive result was considered as confirmation of infection.


## 2.3. Exclusion Criteria

We excluded studies as follows: (1) reports without control groups; (2) reviews and duplicated publications; (3) studies in which the source ofH. pylori infection in cases and control subjects and other essential information were not offered; hyperthyroidism, multiple gestation trophoblastic neoplasia, gastrointestinal and hepatic disorders, urinary tract or other infections, psychosocial or any other maternal disorders, and any treatment with antacids or antibiotics within the previous 7 days were excluded as well.


## 2.4. Data Extraction

According to the inclusion criteria, data was carefully extracted independently by two reviewers (LL and LLL). For each study analyzed, we collected data including first author, year of publication, country of the population studied, study design, sources of pregnant women (primipara or multipara), gestational age, diagnosis of hyperemesis gravidarum, methods ofH. pyloridetection, total number of persons in cases and controls, and the numbers ofH. pylori-positive andH. pylori-negative patients in the HG group and the control group of each study which were recorded, respectively. For conflicting evaluations, an agreement was reached by consensus and agreement with another reviewer (XYZ), referring back to the original articles.


## 2.5. Statistical Analysis

We used pooled odds ratio (OR) with its corresponding 95% confidence interval (CI) to estimate the strength of the association between HG andH. pyloriinfection. Post hoc subgroup analyses were also performed to explain the heterogeneity in results. Subgroups were explored as follows: detection ofH. pyloriinfection (serumH. pylori IgG/IgM/IgA antibody by ELISA, stool antigen test, mucosal biopsy from endoscopy, orH. pylori genome by PCR), publication period (1996–2000, 2001–2005, 2006–2010, or 2011–2014), and region (Asia, North America, Europe, Africa, or Oceania).The heterogeneity of the studies included in this meta-analysis was assessed using theQ statistic test and the I
2 statistic test. The random-effects model was selected when P value < 0.1 or I
2 > 50%; otherwise, the fixed-effects model was selected. Possible publication bias was evaluated by visual inspection of funnel plots and application of Begg’s and Egger’s test [11–15]. P values of less than 0.05 from Egger’s test were considered statistically significant.All statistical analyses were done with STATA statistical software package version 12.0 (2000; STATA Corp., College Station, TX, USA);P
<
0.05 was identified as statistically significant.


## 3. Results

### 3.1. Literature Search

As shown in Figure1, after rigorous searching, we identified 104 citations. Of these, fifty-six irrelevant papers were excluded after screening the titles. In the remaining 48 articles, 16 studies included five studies without control group, two did not provide sufficient data, and 9 reviews or meta-analyses were discarded. Thus, a total of thirty-two studies included twenty-nine case-control studies and three cross-sectional studies published between 1998 and 2014 fulfilled our inclusion criteria and were included in the meta-analysis [3–6, 16–43].Figure 1
Flow chart of the literature searches for evaluatingHelicobacter pylori infection and hyperemesis gravidarum.


### 3.2. Characteristics of Included Studies

With respect to theH. pylori detection methods, serumH. pylori IgG/IgM/IgA antibody was detected by ELISA in twenty-nine, one, and one studies, respectively. However,H. pylori stool antigen (HpSA) was used in seven articles,H. pylori genome by PCR (Hp PCR DNA) tested in two studies, and biopsy and histological examination from endoscopy in one literature. Taking into account publication period, five studies were published from 1996 to 2000, twelve researches were from 2001 to 2005, eight studies were from 2006 to 2010, and seven articles were from 2011 to 2014. In addition, in terms of region, twenty studies were from Asian countries (Turkey, Iran, Japan, and China were grouped in Asia according to similarities in geographic position and racial traits), five from North America (USA, Canada, and Puerto Rico were grouped in North America according to similarities in geographic location and racial traits), three from Europe (Norway and Greece were grouped in Europe according to similarities in geographic position and racial traits), three from Africa, and one from Oceania. Apparently, all studies used hospital-based controls. All of the studies followed a standard definition of HG excluding subjects with differential diagnosis such as infections, gastrointestinal and endocrine diseases, or psychiatric illness.


### 3.3. Overall

Thirty-two articles published between 1998 and 2014 met the inclusion criteria and their characteristics were shown in Tables1 and 2 in detail. In total, thirteen studies found no association betweenH. pylori infection and the risk of HG [12, 18, 20, 26, 27, 32–34, 36, 38, 41–43]. However, nineteen researches suggestedH. pylori infection during pregnancy might be a risk factor for pregnant women with HG [3–6, 16, 17, 19, 21, 23–25, 28–31, 35, 37, 39, 40]. All included studies contained a total sample size of 4113 patients and contained 1851 HG cases and 2262 controls, with a totalH. pylori infection rate of 56.7% (2334/4113). Of the HG cases, 1289 (69.6%) wereH. pylori-positive; however, 1045 (46.2%) wereH. pylori-positive in control group. Since overall I
2 was 81.5%, we used the random-effects model for our analysis. As shown in Figure 2, the overall OR was 3.34 (95% CI: 2.32–4.81) and the overall effect Z value was 6.51 (P
<
0.0
01), which indicated that there was a powerful association betweenH. pylori infection and risk of HG.Table 1
Characteristics of studies onH. pylori infection in HG cases and controls.
First author, year
Study design
Country
Sample size
HG definition
Detection methodof H. pylori
Gestational age when included in the study
Sources of pregnant women
Frigo,  1998 [16]
Case-control
Austria
234
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by FEI
—
—
Perez-Perez,  1999 [18]
Case-control
USA
89
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum cagA by ELISA
—
—
Koćak,  1999 [17]
Case-control
Turkey
211
Vomiting >3 times/dayketonuria
Serum IgG antibodies by FEI
7–16 weeks
141 Primigravida 70 Multigravida
Hayakawa,  2000 [19]
Case-control
Japan
63
Nausea and vomiting in first trimester
Serum IgG antibodies by ELISA
The first trimester
—
Sahin,  2000 [20]
Case-control
Turkey
120
Prolonged severe vomitingdehydrationweight loss >5%ketonuria
Serum IgG antibodies by ELISA
—
—
Reymunde,  2001 [21]
Case-control
Puerto Rico
89
Daily nausea and vomiting in gestation weeks 6–16
Serum IgG antibodies not specified
6–16 weeks
—
Kazerooni,  2002 [24]
Case-control
Iran
107
Vomiting >3 times/dayweight loss >3 kg ketonuria
Serum IgG antibodies by ELISA
7–16 weeks
62 Primigravida45 Multigravida
Bagis,  2002 [23]
Case-control
Turkey
30
Severe HG in the first 16 weeks of pregnancy
Endoscopy with biopsy + histological examination
16 weeks
—
Erdem,  2002 [22]
Case-control
Turkey
86
Vomiting >4 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
—
—
Berker,  2003 [27]
Case-control
Turkey
240
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
10–14 weeks
55 Primigravida105 Multigravida
Jacobson,  2003 [26]
Case-control
Canada
206
Vomiting >3 times/dayweight lossketonuria
Serum IgG antibodies by ELISA
7–19 weeks
—
Salimi-Khayati,  2003 [25]
Case-control
Iran
108
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
6–16 weeks
93 Primigravida15 Multigravida
Karaca,  2004 [31]
Case-control
Turkey
146
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by FEI
—
—
Cevrioglu,  2004 [30]
Case-control
Turkey
124
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
The first 16 weeks
—
Xia,  2004 [29]
Case-control
China
172
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum specific IgG antibodies and CagA by ELISA
7–16 weeks
172 Multigravida
Jamal,  2004 [28]
Case-control
Iran
94
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
7–16 weeks
49 Primigravida45 Multigravida
Lee,  2005 [32]
Cross-sectional
USA
82
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
—
—
Karadeniz,  2006 [34]
Case-control
Turkey
60
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
8–14 weeks
—
Özcimen, 2006 [33]
Cross-sectional
Turkey
140
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
—
—
Tuncel, 2006 [35]
Case-control
Turkey
138
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
—
—
Hatziveis, 2007 [38]
Case-control
Greece
110
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
8–14 weeks
39 Primigravida71 Multigravida
Güney, 2007 [37]
Case-control
Turkey
60
Vomiting >4 times/dayweight loss >5%ketonuria
Serum IgG antibodies not specified
7–12 weeks
—
Aytac, 2007 [36]
Case-control
Turkey
107
Vomiting >3 times/dayweight loss >5%ketonuria
Stool antigen by ELISA
8–13 weeks
—
Sandven, 2008 [39]
Case-control
Norway
488
ICD-9 Code 643.1
Serum IgG antibodies by EIA
Mansour, 2009 [40]
Case-control
Egypt
100
Vomiting >3 times/dayweight lossketonuria
Serum IgG antibodies by ELISA
10–16 weeks
67 Primigravida33 Multigravida
Guven, 2011 [5]
Cross-sectional
Turkey
80
Vomiting >3 times/dayweight loss >5%ketonuriadehydration
Serum IgG antibodies by ELISA
7–12 weeks
—
Mansour, 2011 [4]
Case-control
Egypt
160
Vomiting >3 times/dayweight loss >3 kg ketonuria
Serum IgG antibodies by ELISA
10–16 weeks
—
Bezircioğlu, 2011 [3]
Case-control
Turkey
72
Vomiting >4 times/dayweight loss ≥3 kg ketonuria
Stool antigen by ELISA
10–14 weeks
—
Epstein, 2012 [41]
Case-control
USA
82
Met the diagnosis of hyperemesis
Serum IgG antibodies by ELISA
—
—
Vikanes, 2013 [43]
Case-control
Norway
170
Long-lasting nausea and vomiting, weight loss,electrolyte disturbances
Serum IgG antibodies and CagA and VacA by EIA
17th and 22nd
—
Güngören, 2013 [42]
Case-control
Turkey
140
Vomiting 3 times/dayweight loss ketone
Serum IgG antibodies by ELISA
Below the 20th week
—
Shaban, 2014 [6]
Case-control
Egypt
100
Vomiting >3 times/dayweight loss >5% or 3 kgketonuria
Serum IgG antibodies by membrane-based immunoassay
5–12 weeks
36 Primigravida64 Multigravida
HP:Helicobacter pylori; HG: hyperemesis gravidarum; FEI: fluorescent enzyme immunoassay; EIA: enzyme immunoassay; ELISA: enzyme-linked immunosorbent assay.Table 2
Statistical analysis of studies on the rate ofH. pylori infection in HG cases and non-HG controls.
First author, year
Number of cases
Number of controls
Number of cases with HP (+),n (%)
Number of controls with HP (+),n (%)
OR (95% CI)
Frigo,  1998 [16]
105
129
95  (90.5)
60  (46.5)
10.93  (5.22, 22.85)
Perez-Perez,  1999 [18]
42
47
8  (19.1)
12  (25.5)
0.69  (0.25, 1.89)
Koćak,  1999 [17]
95
116
87  (91.5)
52  (44.8)
13.38  (5.95, 30.13)
Hayakawa,  2000 [19]
34
29
18  (52.9)
6  (20.6)
4.31  (1.40, 13.25)
Sahin,  2000 [20]
60
60
37  (61.7)
32  (53.3)
1.41  (0.68, 2.91)
Reymunde,  2001 [21]
45
44
40  (89.0)
3  (7.0)
109.33  (24.49, 488.12)
Kazerooni,  2002 [24]
54
53
44  (81.5)
29  (54.7)
3.64  (1.52, 8.73)
Bagis,  2002 [23]
20
10
19  (95.0)
5  (50.0)
19.00  (1.79, 201.68)
Erdem,  2002 [22]
47
39
40  (85.1)
25  (64.1)
3.20  (1.14, 9.02)
Berker,  2003 [27]
80
80
56  (70.0)
49  (61.2)
1.48  (0.77, 2.85)
Jacobson,  2003 [26]
53
153
19  (35.7)
45  (29.7)
1.34  (0.69, 2.60)
Salimi-Khayati,  2003 [25]
54
54
48  (88.9)
22  (40.7)
11.64  (4.25, 31.87)
Karaca,  2004 [31]
56
90
46  (82.1)
58  (64.4)
2.54  (1.13, 5.70)
Cevrioglu,  2004 [30]
27
97
23  (85.2)
71  (73.2)
2.11  (0.66, 6.67)
Xia,  2004 [29]
72
100
64  (88.9)
45  (45.0)
9.78  (4.25, 22.51)
Jamal,  2004 [28]
39
55
26  (66.7)
23  (41.8)
2.78  (1.18, 6.54)
Lee,  2005 [32]
40
42
26 (65.0)
28  (66.7)
0.93  (0.37, 2.31)
Karadeniz,  2006 [34]
31
29
21  (67.7)
23  (79.3)
0.55  (0.17, 1.77)
Özcimen, 2006 [33]
70
70
35  (50.0)
33  (47.1)
1.12  (0.58, 2.18)
Tuncel, 2006 [35]
50
88
48  (96.0)
73  (82.9)
4.93  (1.08, 22.54)
Hatziveis, 2007 [38]
25
85
14  (56.0)
41  (48.2)
1.37  (0.56, 3.35)
Güney, 2007 [37]
25
20
20  (80.0)
10  (50.0)
4.00  (1.07, 14.90)
Aytac, 2007 [36]
52
55
22  (42.3)
22  (40.0)
1.10  (0.51, 2.38)
Sandven, 2008 [39]
244
244
105  (43.0)
58  (23.8)
2.42  (1.64, 3.57)
Mansour, 2009 [40]
50
50
42  (84.0)
18  (36.0)
9.33  (3.60, 24.17)
Guven, 2011 [5]
40
40
32  (80.0)
14  (35.0)
7.43  (2.70, 20.42)
Mansour, 2011 [4]
80
80
71  (88.8)
24  (30.0)
18.41  (7.93, 42.74)
Bezircioğlu, 2011 [3]
36
36
8  (22.2)
1  (2.8)
10.00  (1.18, 84.78)
Epstein, 2012 [41]
23
59
16  (69.6)
38  (64.4)
1.26  (0.45, 3.56)
Vikanes, 2013 [43]
62
108
38  (61.3)
67  (62.0)
0.97  (0.51, 1.84)
Güngören, 2013 [42]
90
50
75  (83.3)
30  (60.0)
3.33  (1.51, 7.36)
Shaban, 2014 [6]
50
50
46  (92.0)
28  (56.0)
9.04  (2.82, 28.95)
HG: hyperemesis gravidarum; OR: odds ratio; CI: confidence interval.Figure 2
Meta-analysis for the association between HG andHelicobacter pylori infection.


### 3.4. Subgroup Analysis

To evaluate the underlying confounding factors that may have impacted the overall results, we further conducted subgroup analyses based on detection ofH. pylori infection, publication period, and region, respectively. Since I
2 were 0 in subgroups of Hp PCR DNA test and Africa, we selected the fixed-effects model. In the remaining subgroups, I
2 were >50%, so the random-effects models were used. As shown in Table 3, ORs of serumH. pylori IgM/IgA antibody test by ELISA were 7.77 (95% CI: 0.43–140.84) and 1.32 (95% CI: 0.56–3.12), respectively, which suggested that there was no association betweenH. pylori and HG. However, serumH. pylori IgG antibody test by ELISA (OR = 3.32, 95% CI: 2.28–4.84), HpSA test (OR = 1.88, 95% CI: 1.33–2.65), and Hp PCR DNA test (OR = 5.87, 95% CI: 2.47–13.93) reflectedH. pylori infection was a risk factor of HG. In addition, method of histological examination from endoscopy also showed a positive correlation betweenH. pylori infection and HG (OR = 19.0, 95% CI: 1.79–201.68). With respect to publication period, studies from 1996 to 2000 (OR = 3.66, 95% CI: 1.17–11.48), 2001 to 2005 (OR = 3.89, 95% CI: 2.10–7.21), 2006 to 2010 (OR = 2.01, 95% CI: 1.15–3.49), and 2011 to 2014 (OR = 4.41, 95% CI: 1.72–11.29) all showed significantly high rates ofH. pylori infection in pregnant women with HG compared to those with normal pregnancy (Table 3). In the subgroup of region, shown in Table 3, compared to those studies in North America (OR = 2.33, 95% CI: 0.63–8.62) and Europe (OR = 1.55, 95% CI: 0.83–2.91), researches of Asia (OR = 3.27, 95% CI: 2.18–4.91), Africa (OR = 12.38, 95% CI: 7.12–21.54), and Oceania (OR = 10.93, 95% CI: 5.22–22.85) reflectedH. pylori was positively related to HG.Table 3
Subgroup analysis of the prevalence ofH. pyloriinfection in HG cases versus controls.
Subgroup
Number of studies
Cases with HP (+)
Controls with HP (+)
OR[95% CI]
P
Z
Tests of heterogeneity
Q
df
P
I
2 (%)
Region
Asia
20
769/1017
593/1121
3.27  [2.18,  4.91]
<0.001
5.71
68.04
19
<0.001
72.1
North America
5
109/203
28/345
2.33  [0.63,  8.62]
0.205
1.27
36.55
4
<0.001
89.1
Europe
3
157/331
166/437
1.55  [0.83,  2.91]
0.170
1.37
6.18
2
0.046
67.6
Africa
3
159/180
70/180
12.38 [7.12, 21.54]
<0.001
8.91
1.47
2
0.479
0
Oceania
1
95/105
60/129
3.34 [2.32, 4.81]
<0.001
6.35
0.00
0
—
—
Year
1996–2000
5
245/336
162/381
3.66  [1.17,  11.48]
0.026
2.23
35.41
4
<0.001
88.7
2001–2005
12
451/587
403/817
3.89  [2.10,  7.21]
<0.001
4.32
57.01
11
<0.001
80.7
2006–2010
8
307/547
278/641
2.01  [1.15,  3.49]
0.014
2.47
24.07
7
0.001
70.9
2011–2014
7
286/381
202/423
4.41 [1.72, 11.29]
0.002
3.09
39.71
6
<0.001
84.9
HP testing method
HpIgGAb
29
1240/1743
1017/2161
3.32 [2.28, 4.84]
<0.001
6.25
158.05
28
<0.001
82.3
HpSA
7
124/300
124/435
1.88 [1.33, 2.65]
0.0004
3.57
9.50
6
0.091
47.4
HpDNA PCR
2
45/124
10/79
5.87 [2.47, 13.93]
<0.001
4.02
0.63
1
0.43
0
HpIgAAb
1
13/27
40/97
1.32 [0.56, 3.12]
0.52
0.64
0.00
0
—
—
HpIgMAb
1
6/90
0/50
7.77 [0.43, 140.84]
0.17
1.39
0.00
0
—
—
histologically
1
19/20
5/10
19.00 [1.79, 201.68]
0.01
2.44
0.00
0
—
—
All studies
32
1289/1851
1045/1217
3.34  [2.32,  4.81]
<0.001
6.51
167.81
31
<0.001
81.5
HP:Helicobacter pylori; HG: hyperemesis gravidarum; OR: odds ratio; CI: confidence interval; df: degrees of freedom; HpIgGAb: H. pylori IgG antibodies; HpIgAAb: H. pylori IgA antibodies; HpIgMAb: H. pylori IgM antibodies; HpSA: H. pyloristool antigen; Hp DNA PCR: H. pylori genome by PCR.


### 3.5. Bias Diagnostics

Begg’s test was created for assessment of possible publication bias (Figure3). The P values for Egger’s tests were P
=
0.067 (P
>
0.05), indicating the absence of heterogeneity and implying that the results of the present meta-analysis were relatively stable and that the publication bias might exert little influence on the overall results.Figure 3
Publication bias tests for the overall data (H. pylori-positive versusH. pylori-negative).


## 3.1. Literature Search

As shown in Figure1, after rigorous searching, we identified 104 citations. Of these, fifty-six irrelevant papers were excluded after screening the titles. In the remaining 48 articles, 16 studies included five studies without control group, two did not provide sufficient data, and 9 reviews or meta-analyses were discarded. Thus, a total of thirty-two studies included twenty-nine case-control studies and three cross-sectional studies published between 1998 and 2014 fulfilled our inclusion criteria and were included in the meta-analysis [3–6, 16–43].Figure 1
Flow chart of the literature searches for evaluatingHelicobacter pylori infection and hyperemesis gravidarum.


## 3.2. Characteristics of Included Studies

With respect to theH. pylori detection methods, serumH. pylori IgG/IgM/IgA antibody was detected by ELISA in twenty-nine, one, and one studies, respectively. However,H. pylori stool antigen (HpSA) was used in seven articles,H. pylori genome by PCR (Hp PCR DNA) tested in two studies, and biopsy and histological examination from endoscopy in one literature. Taking into account publication period, five studies were published from 1996 to 2000, twelve researches were from 2001 to 2005, eight studies were from 2006 to 2010, and seven articles were from 2011 to 2014. In addition, in terms of region, twenty studies were from Asian countries (Turkey, Iran, Japan, and China were grouped in Asia according to similarities in geographic position and racial traits), five from North America (USA, Canada, and Puerto Rico were grouped in North America according to similarities in geographic location and racial traits), three from Europe (Norway and Greece were grouped in Europe according to similarities in geographic position and racial traits), three from Africa, and one from Oceania. Apparently, all studies used hospital-based controls. All of the studies followed a standard definition of HG excluding subjects with differential diagnosis such as infections, gastrointestinal and endocrine diseases, or psychiatric illness.


## 3.3. Overall

Thirty-two articles published between 1998 and 2014 met the inclusion criteria and their characteristics were shown in Tables1 and 2 in detail. In total, thirteen studies found no association betweenH. pylori infection and the risk of HG [12, 18, 20, 26, 27, 32–34, 36, 38, 41–43]. However, nineteen researches suggestedH. pylori infection during pregnancy might be a risk factor for pregnant women with HG [3–6, 16, 17, 19, 21, 23–25, 28–31, 35, 37, 39, 40]. All included studies contained a total sample size of 4113 patients and contained 1851 HG cases and 2262 controls, with a totalH. pylori infection rate of 56.7% (2334/4113). Of the HG cases, 1289 (69.6%) wereH. pylori-positive; however, 1045 (46.2%) wereH. pylori-positive in control group. Since overall I
2 was 81.5%, we used the random-effects model for our analysis. As shown in Figure 2, the overall OR was 3.34 (95% CI: 2.32–4.81) and the overall effect Z value was 6.51 (P
<
0.0
01), which indicated that there was a powerful association betweenH. pylori infection and risk of HG.Table 1
Characteristics of studies onH. pylori infection in HG cases and controls.
First author, year
Study design
Country
Sample size
HG definition
Detection methodof H. pylori
Gestational age when included in the study
Sources of pregnant women
Frigo,  1998 [16]
Case-control
Austria
234
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by FEI
—
—
Perez-Perez,  1999 [18]
Case-control
USA
89
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum cagA by ELISA
—
—
Koćak,  1999 [17]
Case-control
Turkey
211
Vomiting >3 times/dayketonuria
Serum IgG antibodies by FEI
7–16 weeks
141 Primigravida 70 Multigravida
Hayakawa,  2000 [19]
Case-control
Japan
63
Nausea and vomiting in first trimester
Serum IgG antibodies by ELISA
The first trimester
—
Sahin,  2000 [20]
Case-control
Turkey
120
Prolonged severe vomitingdehydrationweight loss >5%ketonuria
Serum IgG antibodies by ELISA
—
—
Reymunde,  2001 [21]
Case-control
Puerto Rico
89
Daily nausea and vomiting in gestation weeks 6–16
Serum IgG antibodies not specified
6–16 weeks
—
Kazerooni,  2002 [24]
Case-control
Iran
107
Vomiting >3 times/dayweight loss >3 kg ketonuria
Serum IgG antibodies by ELISA
7–16 weeks
62 Primigravida45 Multigravida
Bagis,  2002 [23]
Case-control
Turkey
30
Severe HG in the first 16 weeks of pregnancy
Endoscopy with biopsy + histological examination
16 weeks
—
Erdem,  2002 [22]
Case-control
Turkey
86
Vomiting >4 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
—
—
Berker,  2003 [27]
Case-control
Turkey
240
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
10–14 weeks
55 Primigravida105 Multigravida
Jacobson,  2003 [26]
Case-control
Canada
206
Vomiting >3 times/dayweight lossketonuria
Serum IgG antibodies by ELISA
7–19 weeks
—
Salimi-Khayati,  2003 [25]
Case-control
Iran
108
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
6–16 weeks
93 Primigravida15 Multigravida
Karaca,  2004 [31]
Case-control
Turkey
146
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by FEI
—
—
Cevrioglu,  2004 [30]
Case-control
Turkey
124
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
The first 16 weeks
—
Xia,  2004 [29]
Case-control
China
172
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum specific IgG antibodies and CagA by ELISA
7–16 weeks
172 Multigravida
Jamal,  2004 [28]
Case-control
Iran
94
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
7–16 weeks
49 Primigravida45 Multigravida
Lee,  2005 [32]
Cross-sectional
USA
82
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
—
—
Karadeniz,  2006 [34]
Case-control
Turkey
60
Vomiting >3 times/dayweight loss >5%ketonuria
Serum IgG antibodies by ELISA
8–14 weeks
—
Özcimen, 2006 [33]
Cross-sectional
Turkey
140
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
—
—
Tuncel, 2006 [35]
Case-control
Turkey
138
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
—
—
Hatziveis, 2007 [38]
Case-control
Greece
110
Vomiting >3 times/dayweight loss >3 kgketonuria
Serum IgG antibodies by ELISA
8–14 weeks
39 Primigravida71 Multigravida
Güney, 2007 [37]
Case-control
Turkey
60
Vomiting >4 times/dayweight loss >5%ketonuria
Serum IgG antibodies not specified
7–12 weeks
—
Aytac, 2007 [36]
Case-control
Turkey
107
Vomiting >3 times/dayweight loss >5%ketonuria
Stool antigen by ELISA
8–13 weeks
—
Sandven, 2008 [39]
Case-control
Norway
488
ICD-9 Code 643.1
Serum IgG antibodies by EIA
Mansour, 2009 [40]
Case-control
Egypt
100
Vomiting >3 times/dayweight lossketonuria
Serum IgG antibodies by ELISA
10–16 weeks
67 Primigravida33 Multigravida
Guven, 2011 [5]
Cross-sectional
Turkey
80
Vomiting >3 times/dayweight loss >5%ketonuriadehydration
Serum IgG antibodies by ELISA
7–12 weeks
—
Mansour, 2011 [4]
Case-control
Egypt
160
Vomiting >3 times/dayweight loss >3 kg ketonuria
Serum IgG antibodies by ELISA
10–16 weeks
—
Bezircioğlu, 2011 [3]
Case-control
Turkey
72
Vomiting >4 times/dayweight loss ≥3 kg ketonuria
Stool antigen by ELISA
10–14 weeks
—
Epstein, 2012 [41]
Case-control
USA
82
Met the diagnosis of hyperemesis
Serum IgG antibodies by ELISA
—
—
Vikanes, 2013 [43]
Case-control
Norway
170
Long-lasting nausea and vomiting, weight loss,electrolyte disturbances
Serum IgG antibodies and CagA and VacA by EIA
17th and 22nd
—
Güngören, 2013 [42]
Case-control
Turkey
140
Vomiting 3 times/dayweight loss ketone
Serum IgG antibodies by ELISA
Below the 20th week
—
Shaban, 2014 [6]
Case-control
Egypt
100
Vomiting >3 times/dayweight loss >5% or 3 kgketonuria
Serum IgG antibodies by membrane-based immunoassay
5–12 weeks
36 Primigravida64 Multigravida
HP:Helicobacter pylori; HG: hyperemesis gravidarum; FEI: fluorescent enzyme immunoassay; EIA: enzyme immunoassay; ELISA: enzyme-linked immunosorbent assay.Table 2
Statistical analysis of studies on the rate ofH. pylori infection in HG cases and non-HG controls.
First author, year
Number of cases
Number of controls
Number of cases with HP (+),n (%)
Number of controls with HP (+),n (%)
OR (95% CI)
Frigo,  1998 [16]
105
129
95  (90.5)
60  (46.5)
10.93  (5.22, 22.85)
Perez-Perez,  1999 [18]
42
47
8  (19.1)
12  (25.5)
0.69  (0.25, 1.89)
Koćak,  1999 [17]
95
116
87  (91.5)
52  (44.8)
13.38  (5.95, 30.13)
Hayakawa,  2000 [19]
34
29
18  (52.9)
6  (20.6)
4.31  (1.40, 13.25)
Sahin,  2000 [20]
60
60
37  (61.7)
32  (53.3)
1.41  (0.68, 2.91)
Reymunde,  2001 [21]
45
44
40  (89.0)
3  (7.0)
109.33  (24.49, 488.12)
Kazerooni,  2002 [24]
54
53
44  (81.5)
29  (54.7)
3.64  (1.52, 8.73)
Bagis,  2002 [23]
20
10
19  (95.0)
5  (50.0)
19.00  (1.79, 201.68)
Erdem,  2002 [22]
47
39
40  (85.1)
25  (64.1)
3.20  (1.14, 9.02)
Berker,  2003 [27]
80
80
56  (70.0)
49  (61.2)
1.48  (0.77, 2.85)
Jacobson,  2003 [26]
53
153
19  (35.7)
45  (29.7)
1.34  (0.69, 2.60)
Salimi-Khayati,  2003 [25]
54
54
48  (88.9)
22  (40.7)
11.64  (4.25, 31.87)
Karaca,  2004 [31]
56
90
46  (82.1)
58  (64.4)
2.54  (1.13, 5.70)
Cevrioglu,  2004 [30]
27
97
23  (85.2)
71  (73.2)
2.11  (0.66, 6.67)
Xia,  2004 [29]
72
100
64  (88.9)
45  (45.0)
9.78  (4.25, 22.51)
Jamal,  2004 [28]
39
55
26  (66.7)
23  (41.8)
2.78  (1.18, 6.54)
Lee,  2005 [32]
40
42
26 (65.0)
28  (66.7)
0.93  (0.37, 2.31)
Karadeniz,  2006 [34]
31
29
21  (67.7)
23  (79.3)
0.55  (0.17, 1.77)
Özcimen, 2006 [33]
70
70
35  (50.0)
33  (47.1)
1.12  (0.58, 2.18)
Tuncel, 2006 [35]
50
88
48  (96.0)
73  (82.9)
4.93  (1.08, 22.54)
Hatziveis, 2007 [38]
25
85
14  (56.0)
41  (48.2)
1.37  (0.56, 3.35)
Güney, 2007 [37]
25
20
20  (80.0)
10  (50.0)
4.00  (1.07, 14.90)
Aytac, 2007 [36]
52
55
22  (42.3)
22  (40.0)
1.10  (0.51, 2.38)
Sandven, 2008 [39]
244
244
105  (43.0)
58  (23.8)
2.42  (1.64, 3.57)
Mansour, 2009 [40]
50
50
42  (84.0)
18  (36.0)
9.33  (3.60, 24.17)
Guven, 2011 [5]
40
40
32  (80.0)
14  (35.0)
7.43  (2.70, 20.42)
Mansour, 2011 [4]
80
80
71  (88.8)
24  (30.0)
18.41  (7.93, 42.74)
Bezircioğlu, 2011 [3]
36
36
8  (22.2)
1  (2.8)
10.00  (1.18, 84.78)
Epstein, 2012 [41]
23
59
16  (69.6)
38  (64.4)
1.26  (0.45, 3.56)
Vikanes, 2013 [43]
62
108
38  (61.3)
67  (62.0)
0.97  (0.51, 1.84)
Güngören, 2013 [42]
90
50
75  (83.3)
30  (60.0)
3.33  (1.51, 7.36)
Shaban, 2014 [6]
50
50
46  (92.0)
28  (56.0)
9.04  (2.82, 28.95)
HG: hyperemesis gravidarum; OR: odds ratio; CI: confidence interval.Figure 2
Meta-analysis for the association between HG andHelicobacter pylori infection.


## 3.4. Subgroup Analysis

To evaluate the underlying confounding factors that may have impacted the overall results, we further conducted subgroup analyses based on detection ofH. pylori infection, publication period, and region, respectively. Since I
2 were 0 in subgroups of Hp PCR DNA test and Africa, we selected the fixed-effects model. In the remaining subgroups, I
2 were >50%, so the random-effects models were used. As shown in Table 3, ORs of serumH. pylori IgM/IgA antibody test by ELISA were 7.77 (95% CI: 0.43–140.84) and 1.32 (95% CI: 0.56–3.12), respectively, which suggested that there was no association betweenH. pylori and HG. However, serumH. pylori IgG antibody test by ELISA (OR = 3.32, 95% CI: 2.28–4.84), HpSA test (OR = 1.88, 95% CI: 1.33–2.65), and Hp PCR DNA test (OR = 5.87, 95% CI: 2.47–13.93) reflectedH. pylori infection was a risk factor of HG. In addition, method of histological examination from endoscopy also showed a positive correlation betweenH. pylori infection and HG (OR = 19.0, 95% CI: 1.79–201.68). With respect to publication period, studies from 1996 to 2000 (OR = 3.66, 95% CI: 1.17–11.48), 2001 to 2005 (OR = 3.89, 95% CI: 2.10–7.21), 2006 to 2010 (OR = 2.01, 95% CI: 1.15–3.49), and 2011 to 2014 (OR = 4.41, 95% CI: 1.72–11.29) all showed significantly high rates ofH. pylori infection in pregnant women with HG compared to those with normal pregnancy (Table 3). In the subgroup of region, shown in Table 3, compared to those studies in North America (OR = 2.33, 95% CI: 0.63–8.62) and Europe (OR = 1.55, 95% CI: 0.83–2.91), researches of Asia (OR = 3.27, 95% CI: 2.18–4.91), Africa (OR = 12.38, 95% CI: 7.12–21.54), and Oceania (OR = 10.93, 95% CI: 5.22–22.85) reflectedH. pylori was positively related to HG.Table 3
Subgroup analysis of the prevalence ofH. pyloriinfection in HG cases versus controls.
Subgroup
Number of studies
Cases with HP (+)
Controls with HP (+)
OR[95% CI]
P
Z
Tests of heterogeneity
Q
df
P
I
2 (%)
Region
Asia
20
769/1017
593/1121
3.27  [2.18,  4.91]
<0.001
5.71
68.04
19
<0.001
72.1
North America
5
109/203
28/345
2.33  [0.63,  8.62]
0.205
1.27
36.55
4
<0.001
89.1
Europe
3
157/331
166/437
1.55  [0.83,  2.91]
0.170
1.37
6.18
2
0.046
67.6
Africa
3
159/180
70/180
12.38 [7.12, 21.54]
<0.001
8.91
1.47
2
0.479
0
Oceania
1
95/105
60/129
3.34 [2.32, 4.81]
<0.001
6.35
0.00
0
—
—
Year
1996–2000
5
245/336
162/381
3.66  [1.17,  11.48]
0.026
2.23
35.41
4
<0.001
88.7
2001–2005
12
451/587
403/817
3.89  [2.10,  7.21]
<0.001
4.32
57.01
11
<0.001
80.7
2006–2010
8
307/547
278/641
2.01  [1.15,  3.49]
0.014
2.47
24.07
7
0.001
70.9
2011–2014
7
286/381
202/423
4.41 [1.72, 11.29]
0.002
3.09
39.71
6
<0.001
84.9
HP testing method
HpIgGAb
29
1240/1743
1017/2161
3.32 [2.28, 4.84]
<0.001
6.25
158.05
28
<0.001
82.3
HpSA
7
124/300
124/435
1.88 [1.33, 2.65]
0.0004
3.57
9.50
6
0.091
47.4
HpDNA PCR
2
45/124
10/79
5.87 [2.47, 13.93]
<0.001
4.02
0.63
1
0.43
0
HpIgAAb
1
13/27
40/97
1.32 [0.56, 3.12]
0.52
0.64
0.00
0
—
—
HpIgMAb
1
6/90
0/50
7.77 [0.43, 140.84]
0.17
1.39
0.00
0
—
—
histologically
1
19/20
5/10
19.00 [1.79, 201.68]
0.01
2.44
0.00
0
—
—
All studies
32
1289/1851
1045/1217
3.34  [2.32,  4.81]
<0.001
6.51
167.81
31
<0.001
81.5
HP:Helicobacter pylori; HG: hyperemesis gravidarum; OR: odds ratio; CI: confidence interval; df: degrees of freedom; HpIgGAb: H. pylori IgG antibodies; HpIgAAb: H. pylori IgA antibodies; HpIgMAb: H. pylori IgM antibodies; HpSA: H. pyloristool antigen; Hp DNA PCR: H. pylori genome by PCR.


## 3.5. Bias Diagnostics

Begg’s test was created for assessment of possible publication bias (Figure3). The P values for Egger’s tests were P
=
0.067 (P
>
0.05), indicating the absence of heterogeneity and implying that the results of the present meta-analysis were relatively stable and that the publication bias might exert little influence on the overall results.Figure 3
Publication bias tests for the overall data (H. pylori-positive versusH. pylori-negative).


## 4. Discussion

### 4.1. Main Findings

This updated meta-analysis suggests that exposure toH. pylori is associated with an increased risk of HG. The studies included in this meta-analysis, containing 1851 HG patients of which 1289 cases were confirmed withH. pylori infection, implied that the rate ofH. pylori infection was much greater in HG patients (1289/1851) than that in non-HG patients (1045/2262) after adjusting for confounding variables (P
<
0.001).Our meta-analysis contained 32 articles including 29 case-control studies and 3 cross-sectional articles, which contained comprehensive articles and added new primary studies. We enrolled much more patients with HG (1851) and controls (2262) than those in published studies to further confirm this relationship. We separated subgroups in detection ofH. pyloriinfection, publication period, and region to comprehensively evaluate the underlying confounding factors that may have impacted the overall results. As reported before, three previous articles reported similar meta-analysis results [44–46]. Golberg et al. [44] performed a meta-analysis of 14 studies and did subgroup analysis only on markers ofH. pylori infection, which suggested that the association might be possible if testing methods for activeH. pylori infection used nonserological methods. However, our meta-analysis showed that the serological method such asH. pylori IgG antibody test was relatively credible. Sandven et al. [45] included 25 case-control studies containing 1455 HG and 1970 controls and carried out subgroups analyses on matched design with nonmatched design and Turkish population with other population. We separated subgroup analyses of region according to Asia, North America, Europe, Africa, or Oceania as described above. Niemeijer et al. [46] performed a systematic review to summarize evidence on biomarkers of HG and their value in diagnosis and estimating disease severity and carried out a diagnostic meta-analysis of 19 studies onH. pylori IgG, which showed a sensitivity of 73% and a specificity of 55% in the diagnosis of HG as compared to controls without HG. Our study paid attention not only to the detection method ofH. pylori IgG, but also to the methods of Hp PCR DNA and HpSA. We also described other detection methods used in pregnant women.With respect to detection methods used in pregnant women, Hp PCR DNA test seemed much more efficient than ELISA test of serumH. pylori IgG antibody, and the latter was more reliable than HpSA test. Of note, Cevrioglu et al. [30] collected both serum and feces samples from pregnant women with HG to investigate specific antibodies forH. pylori(immunoglobulin-IgG, IgA) and HpSA, and only HpSA test suggested significant association betweenH. pylori infection and HG while serologic assessment failed to reflect the association (40% versus 12.4%, P
<
0.001). By using PCR with specimen of saliva, Güngören et al. [42] found a positive relationship between the symptoms of HG andH. pylori positivity, while test ofH. pylori IgG/IgM antibody failed to detect this association between the symptoms of HG andH. pylori positivity. From biopsies of the gastric antrum and corpus, Bagis et al. [23] found that, compared to controls, HG patients were detected with higherH. pylori density, degree of inflammation, andH. pylori activation, implying thatH. pylori density might be related to HG since the bacterium density of controls was lower. These results suggested that the degree of gastric complaints might be related to density ofH. pylori.In addition, two studies from New Zealand indicate that incidence of hyperemesis gravidarum differs according to women’s ethnic origin [47, 48]. Just as shown in our subgroup analysis of region, studies in North America and Europe suggested no association betweenH. pylori infection and risk of HG, while in Asia, Africa, and Oceania analysis indicatedH. pylori infection was a risk factor of HG, especially in Africa. Sandven et al. [39] also found this association betweenH. pylori infection and HG was much stronger in Africans as compared to non-Africans. This might be explained by ethnicity and low socioeconomic status.H. pylori-infected Africans possibly carry an aggressive variant of the bacterium and the host immune mechanisms might be a key to different responses toH. pylori in different populations and geographic areas. As well documented, the prevalence rate ofH. pylori infection is much higher in developing countries than that in developed countries [49–51]. As Eshraghian reviewed, the overall prevalence ofH. pylori infection in Iran and other Eastern Mediterranean Regional Office countries such as Egypt and Afghanistan, irrespective of time and age group, ranged from 30.6% to 82% and ranged from 22% to 87.6%, respectively. However theH. pyloriprevalence in North Africa was 76% [52]. The prevalence is high in developing countries, while pregnant women with HG in these countries have higher rate ofH. pyloriinfection. For example, it is 50%–70% in Turkey [53], more than 80% in Egypt [54]. The above studies all suggested thatH. pyloriinfection was a risk factor of HG. Strategies to improve sanitary facilities, educational status, and socioeconomic status should be implemented to minimizeH. pylori infection and come into the result of decline prevalence of HG.Our meta-analysis suggested thatH. pyloriinfection was a risk factor of HG. Frigo et al. suggested that theH. pylorimay contribute to its persistence beyond the normal time course [16]. It was once reported that HG was an oxidative stress condition induced by increasing reactive oxygen species (ROS) activity and decreasing antioxidant status [55]. Meanwhile,H. pylori colonizes gastric mucosa and generates ROS as well as downregulating levels of plasma antioxidants such as ascorbic acid [7], similar to Güney et al. [37] who found that, compared to the control, level of serum malondialdehyde (MDA) was significantly higher and activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CT), and glutathione peroxidase (GSH-Px) were significantly lower in the HG group (P
<
0.01). Therefore, they hypothesized that increased ROS activity or decreased antioxidant potential, possibly induced byH. pylori, might have a pathogenic role in HG. To date, however, the knowledge of howH. pylori causes HG is still very limited, and we assumed the following. Firstly, hormonal mechanisms, in the early phase of pregnancy, as a result of the elevated steroid and human chorionic gonadotropin (HCG) levels, accumulation of fluid, and a displacement of intracellular and extracellular volume occur which in turn leads to a shift in pH in the gastrointestinal tract during pregnancy [40, 56]. Secondly, emotional factors, the moods of pregnant women change frequently due to the changes of endocrine hormones that might increase women’s susceptibility to infection caused by altered cell-mediated immunity that causes changes of various classes of antibodies during different gestational periods [57, 58]. Thirdly,H. pylori infection might be one potential reason for HG. Dysmotility of gastrointestinal tract and prolonged gastric emptying and intestinal transit time induced by pregnancy might favor infectionofH. pylori [56, 58]. On the other side, host inflammation response to varies of virulence ofH. pyloristrains also different from each other. The virulence of the organism might be another factor creating a possible link betweenH. pyloriand the precipitation of HG. As we all know, cytotoxin-associated gene A product (CagA) and vacuolating cytotoxin A (VacA) are used as markers for genomic diversity ofH. pylori. In Western countries VacA, rather than CagA, was associated with more severe diseases, while in East Asian countries it is the opposite [59–61]. Similarly, as shown in Table 4, Xia et al. in Asia (OR = 13.96, 95% CI: 6.56–29.71) found that prevalence ofH. pyloriinfection with CagA was positively correlated with HG [29]. Nevertheless Perez-Perez et al. in USA [18] failed to find that CagA plays a role in HG. To date, Vikanes et al. [43] conducted the first case-control study to examine the relationship betweenH. pylori and HG by both CagA and VacA seropositivity in Norway and their results suggested that CagA and VacA seropositivity were not significantly associated with HG. So the role of CagA and VacA in the pathopoiesis of HG was still unclear, and no more studies were performed to explore this relationship. It suggested that study of CagA and VacA might be generalized and probably aim at the populations with high prevalence rate ofH. pyloriinfection.Table 4
The infection rate of CagA- or VacA-positiveH. pylori in HG cases and controls.
First author, year
Region
Number of cases
Number of controls
Number of cases with CagA- and/or VacA-positiveH. pylori, n (%)
Number of controls with CagA- and/or VacA-positiveH. pylori, n (%)
OR (95% CI)
Xia, 2004 [29]
Asia
72
100
50 (69.4%)
14 (14%)
13.96 (6.56, 29.71)
Vikanes, 2013 [43]
Europe
62
108
21 (33.9%)
44 (40.8)
0.75 (0.39, 1.43)
CagA: cytotoxin-associated gene A product; VacA: vacuolating cytotoxin A; HG: hyperemesis gravidarum; OR: odds ratio; CI: confidence interval.On the other hand, eradication ofH. pylori could relieve the symptoms of HG. Strachan et al. reported a case of eradication in a 38-year-old woman in her third pregnancy, who orally omeprazole 20 mg bid, metronidazole 400 mg bid, and amoxicillin 500 mg tid for 7 days in her 30 weeks of pregnancy. This led to prompt resolution of her vomiting and improvement of her reflux symptoms [62]. El Younis et al. also reported two cases in which first-trimester patients with severe HG required intravenous fluid replacement. Rapid improvement of the HG was observed with complete resolution of all symptomatology after using of erythromycin therapy orally, which possibly suggests a new therapeutic modality for similar patients [63]. On the other hand, omeprazole is not licensed for use in pregnancy and ought to be used with caution although experience from case-control and observational studies has not revealed any increase in congenital malformations or pregnancy complications [64]. Large-scale studies were not performed. However, the above case reports could verify that the eradication ofH. pylori might relieve the symptoms of HG.


### 4.2. Interpretation

This meta-analysis has some limitations to be acknowledged. Firstly, our meta-analysis only focused on papers published in the English language and might miss some eligible studies that were unpublished in other languages. Secondly, the articles identified were limited to those openly published up to March 2014, and it is possible that some related published or unpublished studies that might meet the inclusion criteria were missed. Finally, despite using a precise literature searching strategy to identify eligible studies, it is possible that a few studies meeting the inclusion criteria were not included, resulting in any inevitable bias, though the funnel plots and Egger’s tests failed to show any significant publication bias.


## 4.1. Main Findings

This updated meta-analysis suggests that exposure toH. pylori is associated with an increased risk of HG. The studies included in this meta-analysis, containing 1851 HG patients of which 1289 cases were confirmed withH. pylori infection, implied that the rate ofH. pylori infection was much greater in HG patients (1289/1851) than that in non-HG patients (1045/2262) after adjusting for confounding variables (P
<
0.001).Our meta-analysis contained 32 articles including 29 case-control studies and 3 cross-sectional articles, which contained comprehensive articles and added new primary studies. We enrolled much more patients with HG (1851) and controls (2262) than those in published studies to further confirm this relationship. We separated subgroups in detection ofH. pyloriinfection, publication period, and region to comprehensively evaluate the underlying confounding factors that may have impacted the overall results. As reported before, three previous articles reported similar meta-analysis results [44–46]. Golberg et al. [44] performed a meta-analysis of 14 studies and did subgroup analysis only on markers ofH. pylori infection, which suggested that the association might be possible if testing methods for activeH. pylori infection used nonserological methods. However, our meta-analysis showed that the serological method such asH. pylori IgG antibody test was relatively credible. Sandven et al. [45] included 25 case-control studies containing 1455 HG and 1970 controls and carried out subgroups analyses on matched design with nonmatched design and Turkish population with other population. We separated subgroup analyses of region according to Asia, North America, Europe, Africa, or Oceania as described above. Niemeijer et al. [46] performed a systematic review to summarize evidence on biomarkers of HG and their value in diagnosis and estimating disease severity and carried out a diagnostic meta-analysis of 19 studies onH. pylori IgG, which showed a sensitivity of 73% and a specificity of 55% in the diagnosis of HG as compared to controls without HG. Our study paid attention not only to the detection method ofH. pylori IgG, but also to the methods of Hp PCR DNA and HpSA. We also described other detection methods used in pregnant women.With respect to detection methods used in pregnant women, Hp PCR DNA test seemed much more efficient than ELISA test of serumH. pylori IgG antibody, and the latter was more reliable than HpSA test. Of note, Cevrioglu et al. [30] collected both serum and feces samples from pregnant women with HG to investigate specific antibodies forH. pylori(immunoglobulin-IgG, IgA) and HpSA, and only HpSA test suggested significant association betweenH. pylori infection and HG while serologic assessment failed to reflect the association (40% versus 12.4%, P
<
0.001). By using PCR with specimen of saliva, Güngören et al. [42] found a positive relationship between the symptoms of HG andH. pylori positivity, while test ofH. pylori IgG/IgM antibody failed to detect this association between the symptoms of HG andH. pylori positivity. From biopsies of the gastric antrum and corpus, Bagis et al. [23] found that, compared to controls, HG patients were detected with higherH. pylori density, degree of inflammation, andH. pylori activation, implying thatH. pylori density might be related to HG since the bacterium density of controls was lower. These results suggested that the degree of gastric complaints might be related to density ofH. pylori.In addition, two studies from New Zealand indicate that incidence of hyperemesis gravidarum differs according to women’s ethnic origin [47, 48]. Just as shown in our subgroup analysis of region, studies in North America and Europe suggested no association betweenH. pylori infection and risk of HG, while in Asia, Africa, and Oceania analysis indicatedH. pylori infection was a risk factor of HG, especially in Africa. Sandven et al. [39] also found this association betweenH. pylori infection and HG was much stronger in Africans as compared to non-Africans. This might be explained by ethnicity and low socioeconomic status.H. pylori-infected Africans possibly carry an aggressive variant of the bacterium and the host immune mechanisms might be a key to different responses toH. pylori in different populations and geographic areas. As well documented, the prevalence rate ofH. pylori infection is much higher in developing countries than that in developed countries [49–51]. As Eshraghian reviewed, the overall prevalence ofH. pylori infection in Iran and other Eastern Mediterranean Regional Office countries such as Egypt and Afghanistan, irrespective of time and age group, ranged from 30.6% to 82% and ranged from 22% to 87.6%, respectively. However theH. pyloriprevalence in North Africa was 76% [52]. The prevalence is high in developing countries, while pregnant women with HG in these countries have higher rate ofH. pyloriinfection. For example, it is 50%–70% in Turkey [53], more than 80% in Egypt [54]. The above studies all suggested thatH. pyloriinfection was a risk factor of HG. Strategies to improve sanitary facilities, educational status, and socioeconomic status should be implemented to minimizeH. pylori infection and come into the result of decline prevalence of HG.Our meta-analysis suggested thatH. pyloriinfection was a risk factor of HG. Frigo et al. suggested that theH. pylorimay contribute to its persistence beyond the normal time course [16]. It was once reported that HG was an oxidative stress condition induced by increasing reactive oxygen species (ROS) activity and decreasing antioxidant status [55]. Meanwhile,H. pylori colonizes gastric mucosa and generates ROS as well as downregulating levels of plasma antioxidants such as ascorbic acid [7], similar to Güney et al. [37] who found that, compared to the control, level of serum malondialdehyde (MDA) was significantly higher and activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CT), and glutathione peroxidase (GSH-Px) were significantly lower in the HG group (P
<
0.01). Therefore, they hypothesized that increased ROS activity or decreased antioxidant potential, possibly induced byH. pylori, might have a pathogenic role in HG. To date, however, the knowledge of howH. pylori causes HG is still very limited, and we assumed the following. Firstly, hormonal mechanisms, in the early phase of pregnancy, as a result of the elevated steroid and human chorionic gonadotropin (HCG) levels, accumulation of fluid, and a displacement of intracellular and extracellular volume occur which in turn leads to a shift in pH in the gastrointestinal tract during pregnancy [40, 56]. Secondly, emotional factors, the moods of pregnant women change frequently due to the changes of endocrine hormones that might increase women’s susceptibility to infection caused by altered cell-mediated immunity that causes changes of various classes of antibodies during different gestational periods [57, 58]. Thirdly,H. pylori infection might be one potential reason for HG. Dysmotility of gastrointestinal tract and prolonged gastric emptying and intestinal transit time induced by pregnancy might favor infectionofH. pylori [56, 58]. On the other side, host inflammation response to varies of virulence ofH. pyloristrains also different from each other. The virulence of the organism might be another factor creating a possible link betweenH. pyloriand the precipitation of HG. As we all know, cytotoxin-associated gene A product (CagA) and vacuolating cytotoxin A (VacA) are used as markers for genomic diversity ofH. pylori. In Western countries VacA, rather than CagA, was associated with more severe diseases, while in East Asian countries it is the opposite [59–61]. Similarly, as shown in Table 4, Xia et al. in Asia (OR = 13.96, 95% CI: 6.56–29.71) found that prevalence ofH. pyloriinfection with CagA was positively correlated with HG [29]. Nevertheless Perez-Perez et al. in USA [18] failed to find that CagA plays a role in HG. To date, Vikanes et al. [43] conducted the first case-control study to examine the relationship betweenH. pylori and HG by both CagA and VacA seropositivity in Norway and their results suggested that CagA and VacA seropositivity were not significantly associated with HG. So the role of CagA and VacA in the pathopoiesis of HG was still unclear, and no more studies were performed to explore this relationship. It suggested that study of CagA and VacA might be generalized and probably aim at the populations with high prevalence rate ofH. pyloriinfection.Table 4
The infection rate of CagA- or VacA-positiveH. pylori in HG cases and controls.
First author, year
Region
Number of cases
Number of controls
Number of cases with CagA- and/or VacA-positiveH. pylori, n (%)
Number of controls with CagA- and/or VacA-positiveH. pylori, n (%)
OR (95% CI)
Xia, 2004 [29]
Asia
72
100
50 (69.4%)
14 (14%)
13.96 (6.56, 29.71)
Vikanes, 2013 [43]
Europe
62
108
21 (33.9%)
44 (40.8)
0.75 (0.39, 1.43)
CagA: cytotoxin-associated gene A product; VacA: vacuolating cytotoxin A; HG: hyperemesis gravidarum; OR: odds ratio; CI: confidence interval.On the other hand, eradication ofH. pylori could relieve the symptoms of HG. Strachan et al. reported a case of eradication in a 38-year-old woman in her third pregnancy, who orally omeprazole 20 mg bid, metronidazole 400 mg bid, and amoxicillin 500 mg tid for 7 days in her 30 weeks of pregnancy. This led to prompt resolution of her vomiting and improvement of her reflux symptoms [62]. El Younis et al. also reported two cases in which first-trimester patients with severe HG required intravenous fluid replacement. Rapid improvement of the HG was observed with complete resolution of all symptomatology after using of erythromycin therapy orally, which possibly suggests a new therapeutic modality for similar patients [63]. On the other hand, omeprazole is not licensed for use in pregnancy and ought to be used with caution although experience from case-control and observational studies has not revealed any increase in congenital malformations or pregnancy complications [64]. Large-scale studies were not performed. However, the above case reports could verify that the eradication ofH. pylori might relieve the symptoms of HG.


## 4.2. Interpretation

This meta-analysis has some limitations to be acknowledged. Firstly, our meta-analysis only focused on papers published in the English language and might miss some eligible studies that were unpublished in other languages. Secondly, the articles identified were limited to those openly published up to March 2014, and it is possible that some related published or unpublished studies that might meet the inclusion criteria were missed. Finally, despite using a precise literature searching strategy to identify eligible studies, it is possible that a few studies meeting the inclusion criteria were not included, resulting in any inevitable bias, though the funnel plots and Egger’s tests failed to show any significant publication bias.


## 5. Conclusion

In conclusion, our meta-analysis suggested that there was a strong association betweenH. pylori infection and HG, allowing us to conclude thatH. pylorishould, therefore, be considered as one of the risk factors of HG. Screening forH. pylori should be added to the investigations for HG, especially in the developing countries. Appropriate therapeutic regimens for eradication ofH. pylori could be considered to relieve the symptoms of HG in some intractable cases.



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*Source: 278905-2015-03-16.xml*