Geburtshilfe und Frauenheilkunde, Inhaltsverzeichnis

CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2019; 79(04): 382-388
DOI: 10.1055/a-0830-1346

GebFra Science

Original Article

Georg Thieme Verlag KG Stuttgart · New York

Analysis of GDF15 and IGFBP7 in Hyperemesis Gravidarum Support Causality

Analyse von GDF-15 und IGFBP-7 bei Hyperemesis gravidarum unterstützt Kausalhypothese

Marlena S. Fejzo

¹Division of Hematology-Oncology, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, USA

²Department of Maternal-Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

,

Peter A. Fasching

³Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany

,

Michael O. Schneider

³Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany

,

Judith Schwitulla

³Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany

,

Matthias W. Beckmann

³Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany

,

Eva Schwenke

³Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany

,

Kimber W. MacGibbon

⁴Hyperemesis Education and Research Foundation, Damascus, OR, USA

,

Patrick M. Mullin

²Department of Maternal-Fetal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

› Institutsangaben

Abstract

Objective Hyperemesis gravidarum, severe nausea and vomiting in pregnancy, occurs in up to 2% of pregnancies and leads to significant weight loss, dehydration, electrolyte imbalance, and ketonuria. It is associated with both maternal and fetal morbidity. Familial aggregation studies and twin studies suggest a genetic component. In a recent GWAS, we showed that placentation, appetite, and cachexia genes GDF15 and IGFBP7 are linked to hyperemesis gravidarum (HG). The purpose of this study is to determine whether GDF15 and IGFBP7 are upregulated in HG patients.

Methods We compared serum levels of GDF15 and IGFBP7 at 12 and 24 weeksʼ gestation in women hospitalized for HG, and two control groups, women with nausea and vomiting of pregnancy (NVP), and women with no NVP.

Results We show GDF15 and IGFBP7 serum levels are significantly increased in women with HG at 12 weeksʼ gestation. Serum levels of hCG are not significantly different between cases and controls. At 24 weeks gestation, when symptoms have largely resolved, there is no difference in GDF15 and IGFBP7 serum levels between cases and controls.

Conclusion This study supports GDF15 and IGFBP7 in the pathogenesis of HG and may be useful for prediction and diagnosis. The GDF15-GFRAL brainstem-activated pathway was recently identified and therapies to treat conditions of abnormal appetite are under intense investigation. Based on our findings, HG should be included.

Zusammenfassung

Hyperemesis gravidarum – Übelkeit und übermäßiges Erbrechen in der Schwangerschaft – tritt in bis zu 2% aller Schwangerschaften auf und führt zu erheblichem Gewichtsverlust, Austrocknung, Elektrolytentgleisungen und Ketonurie. Sie ist mit mütterlicher sowie fetaler Morbidität assoziiert. Familiäre Aggregationsstudien und Zwillingsstudien deuten auf eine genetische Komponente hin. In einer kürzlich publizierten, genomweiten Assoziationsstudie konnten wir zeigen, dass es einen Zusammenhang zwischen den Plazentations-, Appetit- und Kachexie-Genen GDF-15 und IGFBP-7 und Hyperemesis gravidarum (HG) gibt. Ziel dieser Studie war es, zu prüfen, ob GDF-15 und IGFBP-7 in HG-Patientinnen hochreguliert sind.

Methoden Wir verglichen die GDF-15- und IGFBP-7-Spiegel in SSW 12 und 24 von Frauen, die wegen HG ins Krankenhaus eingewiesen wurden, mit den GDF-15- und IGFBP7-Spiegeln von 2 Kontrollgruppen (Frauen mit normaler Übelkeit und Erbrechen in der Schwangerschaft und Frauen ohne Übelkeit und Erbrechen in der Schwangerschaft).

Ergebnisse Die GDF-15- und IGFBP-7-Spiegel von Frauen mit HG waren in SSW 12 signifikant erhöht. Dagegen unterschied sich der hCG-Serumspiegel nicht wesentlich zwischen Fällen und Kontrollen. In SSW 24 hatten sich die Symptome weitgehend gelegt, und es gab keine Unterschiede in den GDF-15- und IGFBP-7-Spiegeln zwischen Fällen und Kontrollen.

Schlussfolgerung Diese Studie unterstützt die Hypothese, dass GDF-15 und IGFBP-7 eine Rolle bei der Pathogenese von HG spielen und dass sie bei der Vorhersage und Diagnose nützlich sein könnten. Der GDF-15-GFRAL-Hirnstamm-aktivierte Signalweg wurde vor Kurzem identifiziert, und es wird intensiv nach Therapien zur Behandlung von abnormen Essgelüsten geforscht. Vor dem Hintergrund unserer Ergebnisse sollte HG ebenfalls einbezogen werden.

Key words

Key words

hyperemesis gravidarum - nausea and vomiting of pregnancy - GDF15 - IGFBP7 - GFRAL

Schlüsselwörter

Schlüsselwörter

Hyperemesis gravidarum - Übelkeit und Erbrechen in der Schwangerschaft - GDF-15 - IGFBP-7 - GFRAL

References
1 Clark SM, Costantine MM, Hankins GD. Review of NVP and HG and Early Pharmacotherapeutic Intervention. Obstet Gynecol Int 2012; 2012: 252676
2 Verberg MF, Gillott DJ, Al-Fardan N. et al. Hyperemesis gravidarum, a literature review. Hum Reprod Update 2005; 11: 527-539
3 Kallen B. Hyperemesis during pregnancy and delivery outcome: a registry study. Eur J Obstet Gynecol Reprod Biol 1987; 26: 291-302
4 Jiang HG, Elixhauser A, Nicholas J, Steiner C, Reyes C, Brierman AS. Care of Women in US Hospitals, 2000: HCUP Fact Book No. 3, No. 02-0044. Rockville, MD: Agency for Healthcare Research and Quality; 2002
5 Chiossi G, Neri I, Cavazutti M. et al. Hyperemesis gravidarum complicated by Wernickeʼs encephalopathy: background, case report and review of the literature. Obstet Gynecol Surv 2006; 61: 255-268
6 Hill JB, Yost NP, Wendel jr. GD. Acute renal failure in association with severe hyperemesis gravidarum. Obstet Gynecol 2002; 100: 1119-1121
7 Adams RH, Gordon J, Combes B. Hyperemesis gravidarum. I. Evidence of hepatic dysfunction. Obstet Gynecol 1968; 31: 659-664
8 Liang SG, Ooka F, Santo A. et al. Pneumomediastinum following esophageal rupture associated with hyperemesis gravidarum. J Obstet Gynaecol Res 2002; 28: 172-175
9 Christodoulou J, Mullin PM, Romero R. et al. Posttraumatic Stress Symptoms (PTSS) following Hyperemesis Gravidarum (HG). J Matern Fetal Neonatal Med 2011; 24: 1307-1311
10 Fejzo MS, Magtira A, Schoenberg FP. et al. Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 2013; 170: 71-76
11 Fejzo MS, Magtira A, Schoenberg FP. et al. Neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 2015; 189: 79-84
12 Dypvik J, Pereira AL, Tanbo TG. et al. Maternal human chorionic gonadotrophin concentrations in very early pregnancy and risk of hyperemesis gravidarum: A retrospective cohort study of 4372 pregnancies after in vitro fertilization. Eur J Obstet Gynecol Reprod Biol 2018; 221: 12-16
13 Fejzo MS, Sazonova OV, Sathirapongsasuti F. et al. 23andMe Research Team. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nat Commun 2018; 9: 1178
14 Moore AG, Brown DA, Fairlie WD. et al. The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 2000; 85: 4781-4788
15 Liu ZK, Wang RC, Han BC. et al. A Novel Role of IGFBP7 in Mouse Uterus: Regulating Uterine Receptivity through Th1/Th2 Lymphocyte Balance and Decidualization. PLoS One 2012; 7: e45224
16 Tsai VW, Macia L, Johnen H. et al. TGF-b Superfamily Cytokine MIC-1/GDF15 Is a Physiological Appetite and Body Weight Regulator. PLoS One 2013; 8: e55174
17 Bader R, Sarraf-Zadeh L, Peters M. et al. The IGFBP7 homolog Imp-L2 promotes insulin signaling in distinct neurons of the Drosophila brain. J Cell Sci 2013; 126: 2571-2576
18 Lerner L, Tao J, Liu Q. et al. MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J Cachexia Sarcopenia Muscle 2016; 7: 467-482
19 Loncar G, Omersa D, Cvetinovic N. et al. Emerging Biomarkers in Heart Failure and Cardiac Cachexia. Int J Mol Sci 2014; 15: 23878-23896
20 Hsu JY, Crawley S, Chen M. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 2017; 550: 255-259
21 Marjono AB, Brown DA, Horton KE. et al. Macrophage inhibitory cytokine-1 in gestational tissues and maternal serum in normal and pre-eclamptic pregnancy. Placenta 2003; 24: 100-106
22 Xiong Y, Walker K, Min X. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci Transl Med 2017; 9: pii:eaan8732
23 Petry CJ, Ong KK, Burling KA. et al. Associations of vomiting and antiemetic use in pregnancy with levels of circulating GDF15 early in the second trimester: A nested case-control study. Wellcome Open Res 2018; 3: 123
24 Hsu LA, Wu S, Juang JJ. et al. Growth Differentiation Factor 15 May Predict Mortality of Peripheral and Coronary Artery Diseases and Correlate with Their Risk Factors. Mediators Inflamm 2017; 2017: 9398401 doi:10.1155/2017/9398401
25 Tong S, Marjono B, Brown DA. et al. Serum concentrations of macrophage inhibitory cytokine 1 (MIC1) as a predictor of miscarriage. Lancet 2004; 363: 129-130
26 Lerner L, Hayes TG, Tao N. et al. Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. J Cachexia Sarcopenia Muscle 2015; 6: 317-324
27 Fejzo MS, Arzy D, Tian R. et al. Evidence GDF15 Plays a Role in Familial and Recurrent Hyperemesis Gravidarum. Geburtsh Frauenheilk 2018; 78: 866-870
28 Tempfer C, Horn LC, Ackermann S. et al. Gestational and Non-gestational Trophoblastic Disease. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 032/049, December 2015). Geburtsh Frauenheilk 2016; 76: 134-144
29 Sherman PW, Flaxman SM. Nausea and vomiting of pregnancy in an evolutionary perspective. Am J Obstet Gynecol 2002; 186 (5 Suppl. Understanding): S190-S197
30 Huxley RR. Nausea and vomiting in early pregnancy: its role in placental development. Obstet Gynecol 2000; 95: 779-782

Zusatzmaterial

Supporting Information