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Effect of hyperemesis gravidarum on gestational diabetes mellitus screening
IJG-08496; No of Pages 3 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Effect of hyperemesis gravidarum on gestational diabetes mellitus screening Rena Ohara ⁎, Mana Obata-Yasuoka, Kanako Abe, Hiroya Yagi, Hiromi Hamada, Hiroyuki Yoshikawa Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
a r t i c l e
i n f o
Article history: Received 26 February 2015 Received in revised form 20 June 2015 Accepted 22 October 2015 Keywords: Gestational diabetes mellitus Hyperemesis gravidarum Screening
a b s t r a c t Objective: To clarify the effect of starvation due to hyperemesis gravidarum on the screening of gestational diabetes mellitus (GDM). Methods: A retrospective study was undertaken of pregnant women who delivered at Tsukuba University Hospital, Japan, between October 1, 2010, and September 30, 2013. GDM screening was performed in the first trimester using the random blood glucose test with a cutoff value of 5.2 mmol/L and in the second trimester using a 50-g glucose challenge test with a cutoff value of 7.8 mmol/L. If the screening was positive, a 75-g oral glucose tolerance test was performed for a definite diagnosis. Results: Among 2112 eligible women, 33 (1.6%) required hospitalization for hyperemesis; the remaining 2079 women formed the control group. In the first trimester, the positive GDM screening rate was significantly higher in the hyperemesis group than in the control group (13 [39.4%] vs 115 [5.5%]; P b 0.001). Additionally, the positive predictive value was significantly lower in the hyperemesis group (23.1% vs 73.9%; P b 0.001). In the second trimester, no significant differences were observed between groups. Conclusion: Hyperemesis gravidarum affects the positive GDM screening rate in the first trimester. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nausea and vomiting are observed in 50%–80% of pregnant women; approximately 1% experience severe nausea and vomiting during the first trimester and are diagnosed with hyperemesis gravidarum [1]. Although the hypothesized cause of hyperemesis is controversial and possibly multifactorial [2], a low body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) is thought to be the major cause. Indeed, Cedergren et al. [3] stated that hyperemesis gravidarum requiring hospitalization is related to maternal body constitution. Similarly, Fell et al. [4] and Rochelson et al. [5] indicated that a main risk factor for hyperemesis gravidarum is a low maternal BMI. Starvation as a result of hyperemesis can cause diabetes. During starvation, insulin secretion from β-cells in the pancreatic islets of Langerhans is reduced to maintain blood sugar levels [6]. Further, starvation and very-low-calorie diets may induce insulin resistance and overt diabetes mellitus [7]. By contrast, gestational diabetes mellitus (GDM) is one of the most frequently observed diseases in pregnant women, most commonly occurring in pregnant women who are obese, have a high BMI, or have a family history of abnormal sugar metabolism. GDM and perinatal ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 2-1-1 Tennodai, Tsukuba, Ibaraki, 305–8576 Japan. Tel./fax: +81 29 853 3073. E-mail address: [email protected] (R. Ohara).
prognosis are closely related and therefore maternal blood sugar levels should be controlled to prevent poor neonatal outcomes [8]. In Japan, GDM screening is performed in the first and second trimester for almost all pregnant women. First-trimester screening is performed using the random plasma glucose test because of its simplicity and cost–performance benefit [9]. However, there is no high-quality evidence regarding appropriate cutoff values or which screening method is preferable [10] and therefore, cutoff values and testing methods are determined at each facility. According to the Japanese Society of Obstetrics and Gynecology guidelines, the cutoff value in first-trimester screening should be a random plasma glucose value of 5.2 mmol/L or above [11]. If a woman screens positive for GDM, a definitive diagnosis must be obtained using a 75-g oral glucose tolerance test (OGTT). The aim of the present study was to assess the impact of hyperemesis gravidarum on GDM screening given the similar effect that hyperemesis and GDM have on the starvation state of cells.
2. Materials and methods In a retrospective study, pregnant women who delivered at Tsukuba University Hospital, Japan, between October 1, 2010, and September 30, 2013, were identified. Women diagnosed with diabetes mellitus before pregnancy were excluded. The study group consisted of women hospitalized for hyperemesis gravidarum during their pregnancy, whereas the control group included all other women who delivered within the specified period. The study design was approved by the institutional
http://dx.doi.org/10.1016/j.ijgo.2015.06.061 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Ohara R, et al, Effect of hyperemesis gravidarum on gestational diabetes mellitus screening, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.061
2
R. Ohara et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
review board of Tsukuba University Hospital ([H26-206]); informed consent requirements were waived given the study’s retrospective nature. Screening for GDM was performed twice during pregnancy. The initial screening was performed during the first trimester using the random plasma glucose test with a cutoff value of 5.2 mmol/L. Screening for GDM was performed for all women during their first prenatal visit, irrespective of the presence or absence of hyperemesis-associated symptoms. Among women with hyperemesis, screening for GDM was performed before recovery with serum glucose. The second screening was performed during the second trimester, from 24–27 weeks, using a 50-g glucose challenge test with a cutoff value of 7.8 mmol/L. When either of the two screening tests was positive, a definitive diagnosis was obtained with a 75-g OGTT, which was performed after recovery from hyperemesis. GDM was diagnosed on the basis of the universal criteria established by the International Association of Diabetes and Pregnancy Study Group: a plasma glucose level that met or exceeded the fasting cutoff value (5.1 mmol/L), the 1-h cutoff value (10.0 mmol/L), or the 2-h cutoff value (8.5 mmol/L). To be considered for hospitalization, women had to meet at least one of the following criteria: body weight loss of more than 5 kg, a urine ketone test result of more than 3 +, or an inability to drink any type of liquid. The delivery midwifery and medical records were retrospectively evaluated. The positive predictive value was calculated by dividing the number of patients diagnosed with GDM by the number of women who were screened as positive for GDM. Statistical χ2 comparisons were performed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA). P b 0.05 was considered statistically significant. 3. Results Among 2112 eligible women who delivered at the study center during the study period, 33 (1.6%) required hospitalization for hyperemesis and were included in the hyperemesis group; the remaining 2079 women were included in the control group. There were no differences in maternal age or BMI at delivery between the two groups (Table 1). Significantly more women in the hyperemesis group than in the control group had positive GDM screening during the first trimester (P b 0.001) (Table 2). However, the prevalence of GDM did not differ significantly (P = 0.32) (Table 2). The positive predictive value of GDM screening in the first trimester was significantly lower in the hyperemesis group (P b 0.001) (Table 2). In the second trimester, no significant differences were recorded in the rate of positive GDM screening, GDM prevalence, or the positive predictive value (Table 3). 4. Discussion The present results show that the GDM screening positive predictive value during the first trimester was significantly lower in the hyperemesis group than in the control group. Hyperemesis induces metabolic abnormalities and can be fatal in severe cases, in which dehydration or electrolyte abnormalities are typically treated with an intravenous drip. In the starvation state—such as that induced by hyperemesis—the cellular
Table 1 Characteristics of included patients.a Characteristic
Hyperemesis group (n = 33)
Control group (n = 2079)
P value
Age, y Parity Primipara Multipara BMI at delivery
31.1 ± 4.9
32.4 ± 5.4
0.26 0.31
21 (63.6) 12 (36.4) 24.3 ± 4.7
1142 (54.9) 937 (45.1) 25.9 ± 4.2
0.44
Abbreviation: BMI, body mass index, calculated as weight in kilograms divided by the square of height in meters. a Values are given as mean ± SD or number (percentage), unless indicated otherwise.
Table 2 Positive screening rate, prevalence of GDM, and positive predictive value of GDM screening in the first trimester.a Screening result
Hyperemesis group (n = 33)
Control group (n = 2079)
P value
Positive GDM screening GDM prevalence Positive predictive value, %
13 (39.4) 3 (9.1) 23.1
115 (5.5) 85 (4.1) 73.9
b0.001 0.32 b0.001
Abbreviation: GDM, gestational diabetes mellitus. a Values are given as number (percentage) unless indicated otherwise.
metabolic pathway changes from glycolysis to glycogenesis. During the starvation state in humans, fatty acids are obtained from fatty tissues to produce glucose via the tricarboxylic acid cycle. Through this process, ketones are also produced and used as an energy source. Zhou et al. [12] stated that long-term exposure to fatty acids and ketones inhibits β-cell functions in humans, thereby decreasing glucose tolerance. These findings have been corroborated by several studies reporting that increased levels of free fatty acids decrease glucose tolerance [13–15]. Thus, patients with hyperemesis gravidarum could be in a glucose-resistant state due to starvation, resulting in the observed increase in the positive GDM screening rate in the first trimester. Following amelioration of starvation, the positive predictive value for the hyperemesis group was equivalent to that of the control group in the second trimester. No difference in GDM prevalence between the hyperemesis and control groups was observed in the present study. Nevertheless, the 75-g OGTT for GDM diagnosis was performed following recovery from hyperemesis. It is therefore possible that improved hyperemesis led to normalization of the glucose metabolism, thereby obscuring any previous differences in the prevalence of GDM. However, symptoms related to hyperemesis were rare in the second trimester and therefore the influence of metabolic factors was negligible. Consequently, no differences in the positive GDM screening rate or GDM prevalence were detected. The International Association of Diabetes and Pregnancy Study Group recommends screening for overt diabetes in early pregnancy and favors the use of fasting glucose, random plasma glucose, or glycosylated hemoglobin values, for which tests are widely available in hospital laboratories [16]. However, the guidelines do not discuss appropriate cutoff values. In Japan, GDM screening is performed for most pregnant women and proves useful in the first trimester in detecting impaired glucose tolerance before pregnancy. Although differences in the prevalence of diabetes mellitus are observed according to race or ethnic origin, Jean et al. [17] reported that the prevalence of overt diabetes mellitus has increased worldwide, irrespective of these factors. Overt diabetes in pregnancy increases the risk of adverse pregnancy outcomes [18]; moreover, a relationship between overt diabetes and maternal complications, such as retinopathy or maternal hypertension, has been reported [19]. Despite these findings, few studies have assessed the effectiveness of early interventions for overt diabetes to improve prognosis, and therefore clarification is required. The positive GDM screening rate in the first trimester in the present study was much higher in the hyperemesis group than in the control
Table 3 Positive screening rate, prevalence of GDM, and positive predictive value of GDM screening in the second trimester.a Screening result
Hyperemesis group (n = 30)b
Control group (n = 1994)b
P value
Positive GDM screening GDM prevalence Positive predictive value, %
8 (26.7) 2 (6.7) 25.0
432 (21.7) 185 (9.3) 42.8
0.66 0.86 0.52
Abbreviation: GDM, gestational diabetes mellitus. a Values are given as number (percentage) unless indicated otherwise. b Analyses were performed after exclusion of GDM cases diagnosed in the first trimester.
Please cite this article as: Ohara R, et al, Effect of hyperemesis gravidarum on gestational diabetes mellitus screening, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.061
R. Ohara et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
group. As previously mentioned, this discrepancy could be potentially related to abnormal glucose metabolism in patients with hyperemesis. Therefore, to reduce medical costs, an appropriate GDM screening cutoff value in the first trimester is required, which has been discussed much less than the 75-g OGTT diagnostic criteria have. The present study has limitations. Given the lack of a method to quantify hyperemesis, the classification of hyperemesis might not have been strict enough and pregnant women with hyperemesis could have been included in the control group; this presents an ongoing issue regarding hyperemesis research. In conclusion, hyperemesis gravidarum affects the positive GDM screening rate in the first trimester, possibly due to related glucose metabolism abnormalities. An appropriate cutoff value should be developed for GDM screening of women with hyperemesis in the first trimester.
[7] [8]
[9]
[10] [11]
[12]
[13]
Conflicts of interest [14]
The authors have no conflicts of interest. References [1] Jarvis S, Nelson-Piercy C. Management of nausea and vomiting in pregnancy. BMJ 2011;342:d3606. [2] Helseth R, Ravlo M, Carlsen SM, Vanky EE. Androgens and hyperemesis gravidarum: a case–control study. Eur J Obstet Gynecol Reprod Biol 2014;175:167–71. [3] Cedergren M, Brynhildsen J, Josefsson A, Sydsjo A, Sydsjo G. Hyperemesis gravidarum that requires hospitalization and the use of antiemetic drugs in relation to maternal body composition. Am J Obstet Gynecol 2008;198(4):412.e1–5. [4] Fell DB, Dodds L, Joseph KS, Allen VM, Butler B. Risk factors for hyperemesis gravidarum requiring hospital admission during pregnancy. Obstet Gynecol 2006; 107(2 Pt 1):277–84. [5] Rochelson B, Vohra N, Darvishzadeh J, Pagano M. Low prepregnancy ideal weight: height ratio in women with hyperemesis gravidarum. J Reprod Med 2003;48(6): 422–4. [6] Gremlich S, Nolan C, Roduit R, Burcelin R, Peyot ML, Delghingaro-Augusto V, et al. Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-
[15] [16]
[17]
[18] [19]
3
activated receptor alpha transcriptional up-regulation of fatty acid oxidation. Endocrinology 2005;146(1):375–82. Koffler M, Kisch ES. Starvation diet and very-low-calorie diets may induce insulin resistance and overt diabetes mellitus. J Diabet Complicat 1996;10(2):109–12. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358(19):1991–2002. Sugiyama T, Kusaka H, Sagawa N, Toyoda N. The multicenter study report on the screening of gestational diabetes mellitus [in Japanese]. Tounyou-byou to Ninshin 2006;6:7–12. Benhalima K, Devlieger R, Van Assche A. Screening and management of gestational diabetes. Best Pract Res Clin Obstet Gynaecol 2015;29(3):339–49. Minakami H, Hiramatsu Y, Koresawa M, Fujii T, Hamada H, Iitsuka Y, et al. Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2011 edition. J Obstet Gynaecol Res 2011;37(9):1174–97. Zhou YP, Grill V. Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. J Clin Endocrinol Metab 1995;80(5): 1584–90. Duska F, Andel M, Kubena A, Macdonald IA. Effects of acute starvation on insulin resistance in obese patients with and without type 2 diabetes mellitus. Clin Nutr 2005; 24(6):1056–64. Fukuda M, Tahara Y, Yamamoto Y, Onishi T, Kumahara Y, Tanaka A, et al. Effects of very-low-calorie diet weight reduction on glucose tolerance, insulin secretion, and insulin resistance in obese non-insulin-dependent diabetics. Diabetes Res Clin Pract 1989;7(1):61–7. Bedoya FJ, Ramirez R, Goberna R. Glucose phosphorylating activities in the islets of Langerhans of the rat. Effect of fasting. Horm Metab Res 1984;16(Suppl. 1):11–5. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33(3): 676–82. Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999–2005. Diabetes Care 2008;31(5):899–904. Wong T, Ross GP, Jalaludin BB, Flack JR. The clinical significance of overt diabetes in pregnancy. Diabet Med 2013;30(4):468–74. Sugiyama T, Saito M, Nishigori H, Nagase S, Yaegashi N, Sagawa N, et al. Comparison of pregnancy outcomes between women with gestational diabetes and overt diabetes first diagnosed in pregnancy: a retrospective multi-institutional study in Japan. Diabetes Res Clin Pract 2014;103(1):20–5.
Please cite this article as: Ohara R, et al, Effect of hyperemesis gravidarum on gestational diabetes mellitus screening, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.061
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Effect of hyperemesis gravidarum on gestational diabetes mellitus screening Rena Ohara ⁎, Mana Obata-Yasuoka, Kanako Abe, Hiroya Yagi, Hiromi Hamada, Hiroyuki Yoshikawa Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
a r t i c l e
i n f o
Article history: Received 26 February 2015 Received in revised form 20 June 2015 Accepted 22 October 2015 Keywords: Gestational diabetes mellitus Hyperemesis gravidarum Screening
a b s t r a c t Objective: To clarify the effect of starvation due to hyperemesis gravidarum on the screening of gestational diabetes mellitus (GDM). Methods: A retrospective study was undertaken of pregnant women who delivered at Tsukuba University Hospital, Japan, between October 1, 2010, and September 30, 2013. GDM screening was performed in the first trimester using the random blood glucose test with a cutoff value of 5.2 mmol/L and in the second trimester using a 50-g glucose challenge test with a cutoff value of 7.8 mmol/L. If the screening was positive, a 75-g oral glucose tolerance test was performed for a definite diagnosis. Results: Among 2112 eligible women, 33 (1.6%) required hospitalization for hyperemesis; the remaining 2079 women formed the control group. In the first trimester, the positive GDM screening rate was significantly higher in the hyperemesis group than in the control group (13 [39.4%] vs 115 [5.5%]; P b 0.001). Additionally, the positive predictive value was significantly lower in the hyperemesis group (23.1% vs 73.9%; P b 0.001). In the second trimester, no significant differences were observed between groups. Conclusion: Hyperemesis gravidarum affects the positive GDM screening rate in the first trimester. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nausea and vomiting are observed in 50%–80% of pregnant women; approximately 1% experience severe nausea and vomiting during the first trimester and are diagnosed with hyperemesis gravidarum [1]. Although the hypothesized cause of hyperemesis is controversial and possibly multifactorial [2], a low body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) is thought to be the major cause. Indeed, Cedergren et al. [3] stated that hyperemesis gravidarum requiring hospitalization is related to maternal body constitution. Similarly, Fell et al. [4] and Rochelson et al. [5] indicated that a main risk factor for hyperemesis gravidarum is a low maternal BMI. Starvation as a result of hyperemesis can cause diabetes. During starvation, insulin secretion from β-cells in the pancreatic islets of Langerhans is reduced to maintain blood sugar levels [6]. Further, starvation and very-low-calorie diets may induce insulin resistance and overt diabetes mellitus [7]. By contrast, gestational diabetes mellitus (GDM) is one of the most frequently observed diseases in pregnant women, most commonly occurring in pregnant women who are obese, have a high BMI, or have a family history of abnormal sugar metabolism. GDM and perinatal ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tsukuba, 2-1-1 Tennodai, Tsukuba, Ibaraki, 305–8576 Japan. Tel./fax: +81 29 853 3073. E-mail address: [email protected] (R. Ohara).
prognosis are closely related and therefore maternal blood sugar levels should be controlled to prevent poor neonatal outcomes [8]. In Japan, GDM screening is performed in the first and second trimester for almost all pregnant women. First-trimester screening is performed using the random plasma glucose test because of its simplicity and cost–performance benefit [9]. However, there is no high-quality evidence regarding appropriate cutoff values or which screening method is preferable [10] and therefore, cutoff values and testing methods are determined at each facility. According to the Japanese Society of Obstetrics and Gynecology guidelines, the cutoff value in first-trimester screening should be a random plasma glucose value of 5.2 mmol/L or above [11]. If a woman screens positive for GDM, a definitive diagnosis must be obtained using a 75-g oral glucose tolerance test (OGTT). The aim of the present study was to assess the impact of hyperemesis gravidarum on GDM screening given the similar effect that hyperemesis and GDM have on the starvation state of cells.
2. Materials and methods In a retrospective study, pregnant women who delivered at Tsukuba University Hospital, Japan, between October 1, 2010, and September 30, 2013, were identified. Women diagnosed with diabetes mellitus before pregnancy were excluded. The study group consisted of women hospitalized for hyperemesis gravidarum during their pregnancy, whereas the control group included all other women who delivered within the specified period. The study design was approved by the institutional
http://dx.doi.org/10.1016/j.ijgo.2015.06.061 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Ohara R, et al, Effect of hyperemesis gravidarum on gestational diabetes mellitus screening, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.061
2
R. Ohara et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
review board of Tsukuba University Hospital ([H26-206]); informed consent requirements were waived given the study’s retrospective nature. Screening for GDM was performed twice during pregnancy. The initial screening was performed during the first trimester using the random plasma glucose test with a cutoff value of 5.2 mmol/L. Screening for GDM was performed for all women during their first prenatal visit, irrespective of the presence or absence of hyperemesis-associated symptoms. Among women with hyperemesis, screening for GDM was performed before recovery with serum glucose. The second screening was performed during the second trimester, from 24–27 weeks, using a 50-g glucose challenge test with a cutoff value of 7.8 mmol/L. When either of the two screening tests was positive, a definitive diagnosis was obtained with a 75-g OGTT, which was performed after recovery from hyperemesis. GDM was diagnosed on the basis of the universal criteria established by the International Association of Diabetes and Pregnancy Study Group: a plasma glucose level that met or exceeded the fasting cutoff value (5.1 mmol/L), the 1-h cutoff value (10.0 mmol/L), or the 2-h cutoff value (8.5 mmol/L). To be considered for hospitalization, women had to meet at least one of the following criteria: body weight loss of more than 5 kg, a urine ketone test result of more than 3 +, or an inability to drink any type of liquid. The delivery midwifery and medical records were retrospectively evaluated. The positive predictive value was calculated by dividing the number of patients diagnosed with GDM by the number of women who were screened as positive for GDM. Statistical χ2 comparisons were performed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA). P b 0.05 was considered statistically significant. 3. Results Among 2112 eligible women who delivered at the study center during the study period, 33 (1.6%) required hospitalization for hyperemesis and were included in the hyperemesis group; the remaining 2079 women were included in the control group. There were no differences in maternal age or BMI at delivery between the two groups (Table 1). Significantly more women in the hyperemesis group than in the control group had positive GDM screening during the first trimester (P b 0.001) (Table 2). However, the prevalence of GDM did not differ significantly (P = 0.32) (Table 2). The positive predictive value of GDM screening in the first trimester was significantly lower in the hyperemesis group (P b 0.001) (Table 2). In the second trimester, no significant differences were recorded in the rate of positive GDM screening, GDM prevalence, or the positive predictive value (Table 3). 4. Discussion The present results show that the GDM screening positive predictive value during the first trimester was significantly lower in the hyperemesis group than in the control group. Hyperemesis induces metabolic abnormalities and can be fatal in severe cases, in which dehydration or electrolyte abnormalities are typically treated with an intravenous drip. In the starvation state—such as that induced by hyperemesis—the cellular
Table 1 Characteristics of included patients.a Characteristic
Hyperemesis group (n = 33)
Control group (n = 2079)
P value
Age, y Parity Primipara Multipara BMI at delivery
31.1 ± 4.9
32.4 ± 5.4
0.26 0.31
21 (63.6) 12 (36.4) 24.3 ± 4.7
1142 (54.9) 937 (45.1) 25.9 ± 4.2
0.44
Abbreviation: BMI, body mass index, calculated as weight in kilograms divided by the square of height in meters. a Values are given as mean ± SD or number (percentage), unless indicated otherwise.
Table 2 Positive screening rate, prevalence of GDM, and positive predictive value of GDM screening in the first trimester.a Screening result
Hyperemesis group (n = 33)
Control group (n = 2079)
P value
Positive GDM screening GDM prevalence Positive predictive value, %
13 (39.4) 3 (9.1) 23.1
115 (5.5) 85 (4.1) 73.9
b0.001 0.32 b0.001
Abbreviation: GDM, gestational diabetes mellitus. a Values are given as number (percentage) unless indicated otherwise.
metabolic pathway changes from glycolysis to glycogenesis. During the starvation state in humans, fatty acids are obtained from fatty tissues to produce glucose via the tricarboxylic acid cycle. Through this process, ketones are also produced and used as an energy source. Zhou et al. [12] stated that long-term exposure to fatty acids and ketones inhibits β-cell functions in humans, thereby decreasing glucose tolerance. These findings have been corroborated by several studies reporting that increased levels of free fatty acids decrease glucose tolerance [13–15]. Thus, patients with hyperemesis gravidarum could be in a glucose-resistant state due to starvation, resulting in the observed increase in the positive GDM screening rate in the first trimester. Following amelioration of starvation, the positive predictive value for the hyperemesis group was equivalent to that of the control group in the second trimester. No difference in GDM prevalence between the hyperemesis and control groups was observed in the present study. Nevertheless, the 75-g OGTT for GDM diagnosis was performed following recovery from hyperemesis. It is therefore possible that improved hyperemesis led to normalization of the glucose metabolism, thereby obscuring any previous differences in the prevalence of GDM. However, symptoms related to hyperemesis were rare in the second trimester and therefore the influence of metabolic factors was negligible. Consequently, no differences in the positive GDM screening rate or GDM prevalence were detected. The International Association of Diabetes and Pregnancy Study Group recommends screening for overt diabetes in early pregnancy and favors the use of fasting glucose, random plasma glucose, or glycosylated hemoglobin values, for which tests are widely available in hospital laboratories [16]. However, the guidelines do not discuss appropriate cutoff values. In Japan, GDM screening is performed for most pregnant women and proves useful in the first trimester in detecting impaired glucose tolerance before pregnancy. Although differences in the prevalence of diabetes mellitus are observed according to race or ethnic origin, Jean et al. [17] reported that the prevalence of overt diabetes mellitus has increased worldwide, irrespective of these factors. Overt diabetes in pregnancy increases the risk of adverse pregnancy outcomes [18]; moreover, a relationship between overt diabetes and maternal complications, such as retinopathy or maternal hypertension, has been reported [19]. Despite these findings, few studies have assessed the effectiveness of early interventions for overt diabetes to improve prognosis, and therefore clarification is required. The positive GDM screening rate in the first trimester in the present study was much higher in the hyperemesis group than in the control
Table 3 Positive screening rate, prevalence of GDM, and positive predictive value of GDM screening in the second trimester.a Screening result
Hyperemesis group (n = 30)b
Control group (n = 1994)b
P value
Positive GDM screening GDM prevalence Positive predictive value, %
8 (26.7) 2 (6.7) 25.0
432 (21.7) 185 (9.3) 42.8
0.66 0.86 0.52
Abbreviation: GDM, gestational diabetes mellitus. a Values are given as number (percentage) unless indicated otherwise. b Analyses were performed after exclusion of GDM cases diagnosed in the first trimester.
Please cite this article as: Ohara R, et al, Effect of hyperemesis gravidarum on gestational diabetes mellitus screening, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.061
R. Ohara et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
group. As previously mentioned, this discrepancy could be potentially related to abnormal glucose metabolism in patients with hyperemesis. Therefore, to reduce medical costs, an appropriate GDM screening cutoff value in the first trimester is required, which has been discussed much less than the 75-g OGTT diagnostic criteria have. The present study has limitations. Given the lack of a method to quantify hyperemesis, the classification of hyperemesis might not have been strict enough and pregnant women with hyperemesis could have been included in the control group; this presents an ongoing issue regarding hyperemesis research. In conclusion, hyperemesis gravidarum affects the positive GDM screening rate in the first trimester, possibly due to related glucose metabolism abnormalities. An appropriate cutoff value should be developed for GDM screening of women with hyperemesis in the first trimester.
[7] [8]
[9]
[10] [11]
[12]
[13]
Conflicts of interest [14]
The authors have no conflicts of interest. References [1] Jarvis S, Nelson-Piercy C. Management of nausea and vomiting in pregnancy. BMJ 2011;342:d3606. [2] Helseth R, Ravlo M, Carlsen SM, Vanky EE. Androgens and hyperemesis gravidarum: a case–control study. Eur J Obstet Gynecol Reprod Biol 2014;175:167–71. [3] Cedergren M, Brynhildsen J, Josefsson A, Sydsjo A, Sydsjo G. Hyperemesis gravidarum that requires hospitalization and the use of antiemetic drugs in relation to maternal body composition. Am J Obstet Gynecol 2008;198(4):412.e1–5. [4] Fell DB, Dodds L, Joseph KS, Allen VM, Butler B. Risk factors for hyperemesis gravidarum requiring hospital admission during pregnancy. Obstet Gynecol 2006; 107(2 Pt 1):277–84. [5] Rochelson B, Vohra N, Darvishzadeh J, Pagano M. Low prepregnancy ideal weight: height ratio in women with hyperemesis gravidarum. J Reprod Med 2003;48(6): 422–4. [6] Gremlich S, Nolan C, Roduit R, Burcelin R, Peyot ML, Delghingaro-Augusto V, et al. Pancreatic islet adaptation to fasting is dependent on peroxisome proliferator-
[15] [16]
[17]
[18] [19]
3
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Please cite this article as: Ohara R, et al, Effect of hyperemesis gravidarum on gestational diabetes mellitus screening, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.06.061