Hyperemesis gravidarum; GDF15; GFRAL; PUQE-24; nausea and vomiting of pregnancy; ELISA; Iraq
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Durar Kamil Jabbar
Department of Basic Sciences, College of Dentistry, University of Al-Qadisiyah, Al-Diwaniyah, Iraq.
durar.kamil@qu.edu.iq
Abstract
Background: Hyperemesis gravidarum (HG) is the severe end of nausea and vomiting in pregnancy. Growth differentiation factor 15 (GDF15), released by the placenta, acts on the brainstem emesis centre via the GFRAL receptor. Recent evidence from European cohorts places GDF15 at the centre of HG pathophysiology, yet no Iraqi data have been reported.Objective: To compare serum GDF15 between Iraqi women with HG and pregnant controls, and to explore its association with symptom severity.Methods: In this case–control study at Al-Diwaniyah Teaching Hospital, 80 women with HG (Windsor definition) and 80 pregnant controls at 7–14 weeks’ gestation were enrolled. Severity was graded with the PUQE-24 instrument. Serum GDF15 was measured by sandwich ELISA. Groups were compared with the Mann–Whitney U test; Spearman correlation between GDF15 and PUQE-24 within HG was computed with a bootstrap confidence interval; and multivariable models of ln(GDF15) used HC3-robust standard errors.Results: Median serum GDF15 was 14.15 ng/mL (Q1–Q3 10.64–16.60) in HG and 10.57 ng/mL (7.53–13.25) in controls (p < 0.001). The adjusted GDF15 ratio for HG versus controls was 1.373 (95% CI 1.218–1.547; p < 0.001). Within HG, Spearman's ρ between GDF15 and PUQE-24 was 0.235 (bootstrap CI −0.004 to 0.462; p = 0.036). Each PUQE-24 point corresponded to a GDF15 ratio of 1.058 (95% CI 1.003–1.116; p = 0.040). Geometric mean GDF15 rose from 9.99 ng/mL in controls through 12.38 in moderate HG to 14.99 ng/mL in severe HG (Kruskal–Wallis p < 0.001).Conclusion: Serum GDF15 was significantly higher in Iraqi women with HG than in controls, with a weak positive trend with symptom severity that did not reach significance by the bootstrap CI criterion. These findings support the GDF15–GFRAL model and further investigation of GDF15 as a severity marker in this population.
Keywords:
Hyperemesis gravidarum, GDF15, GFRAL, PUQE-24, nausea and vomiting of pregnancy, ELISA, Iraq
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References
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3. Nana M, Painter R, Williamson C, Nelson-Piercy C. Hyperemesis gravidarum. Lancet. 2026;407(10523):78–89.
4. Nurmi M, Rautava P, Gissler M, Vahlberg T, Polo-Kantola P. Readmissions due to hyperemesis gravidarum: a nation-wide Finnish register study. Arch Gynecol Obstet. 2022;306(5):1519–1529.
5. Mitchell-Jones N, Lawson K, Bobdiwala S, Farren JA, Tobias A, Bourne T, et al. Association between hyperemesis gravidarum and psychological symptoms, psychosocial outcomes and infant bonding: a two-point prospective case–control multicentre survey study in an inner city setting. BMJ Open. 2020;10(10):e039715.
6. Nana M, Tydeman F, Bevan G, Boulding H, Kavanagh K, Dean C, et al. Hyperemesis gravidarum is associated with increased rates of termination of pregnancy and suicidal ideation: results from a survey completed by > 5,000 participants. Am J Obstet Gynecol. 2024;230(3):362.e1–362.e10.
7. Nijsten K, van der Minnen LM, Dean C, Bais JMJ, Ris-Stalpers C, van Eekelen R, et al. Depression, anxiety, and post-traumatic stress disorder symptoms after hyperemesis gravidarum: a prospective cohort study. J Matern Fetal Neonatal Med. 2022;35(25):10003–10010.
8. Moberg T, Van der Veeken L, Persad E, Hansson SR, Bruschettini M. Placenta-associated adverse pregnancy outcomes in women experiencing mild or severe hyperemesis gravidarum – a systematic review and meta-analysis. BMC Pregnancy Childbirth. 2023;23(1):815.
9. Fiorentini M, Nedu B, Dapoto F, Brunelli E, Pilu G, Youssef A. When time is brain: a systematic review about Wernicke encephalopathy as a dramatic consequence of thiamin deficiency in hyperemesis gravidarum. J Matern Fetal Neonatal Med. 2025;38(1):2470988.
10. Liu C, Zhao G, Qiao D, Wang L, He Y, Zhao M, et al. Emerging progress in nausea and vomiting of pregnancy and hyperemesis gravidarum: challenges and opportunities. Front Med (Lausanne). 2022;8:809270.
11. Fejzo MS. Hyperemesis gravidarum theories dispelled by recent research: a paradigm change for better care and outcomes. Trends Mol Med. 2024;30(6):530–540.
12. Fejzo MS, MacGibbon KW, First O, Quan C, Mullin PM. Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum. BJOG. 2022;129(11):1845–1852.
13. Fejzo M, Wang X, Tan Q, Zöllner J, Pujol-Gualdo N, Laisk T, et al. Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting. Nat Genet. 2026;58(4):810–820.
14. Lockhart SM, Saudek V, O'Rahilly S. GDF15: a hormone conveying somatic distress to the brain. Endocr Rev. 2020;41(4):bnaa007.
15. Breit SN, Brown DA, Tsai VW. The GDF15-GFRAL pathway in health and metabolic disease: friend or foe? Annu Rev Physiol. 2021;83:127–151.
16. Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol. 2021;17(10):592–607.
17. Borner T, Pataro AM, De Jonghe BC. Central mechanisms of emesis: a role for GDF15. Neurogastroenterol Motil. 2025;37(3):e14886.
18. Andersson-Hall U, Svedin P, Mallard C, Blennow K, Zetterberg H, Holmäng A. Growth differentiation factor 15 increases in both cerebrospinal fluid and serum during pregnancy. PLoS One. 2021;16(5):e0250718.
19. Klein AB, Ranea-Robles P, Nicolaisen TS, Gil C, Johann K, Prats Quesada J, et al. Cross-species comparison of pregnancy-induced GDF15. Am J Physiol Endocrinol Metab. 2023;325(4):E303–E309.
20. Fejzo M, Rocha N, Cimino I, Lockhart SM, Petry CJ, Kay RG, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625(7996):760–767.
21. Svenningsen JS, Ostenfeld A, Petersen JF, Svenningsen MS, Hillig T, Gillum MP, et al. Early pregnancy GDF15 trajectories and their association with normal gestation, pregnancy loss, and hyperemesis gravidarum. EBioMedicine. 2026;131:106428.
22. Meran NM, Hussein RM. Maternal serum tumor necrosis factor level in women with hyperemesis gravidarum. J Fac Med Baghdad. 2025;67(2):143–148.
23. Alkhateeb SMJ, Salman AF, Ali EA, Al-Jedda WA, Alwan AF. Growth differentiation factor-15 and erythroferrone are reliable predictors of iron status among Iraqi pregnant women with anemia: a case-control study. Hematology. 2024;29(1):2376064.
24. Abd FN, Abd Ali RA. Clinical and diagnostic value of GDF-15 and β-hCG in first trimester pregnancy with threatened miscarriage and the short-term impact of hormonal support: a prospective study. J Reprod Immunol. 2025;168:104396.
25. Karusheva Y, Ratcliff M, Mörseburg A, Barker P, Melvin A, Sattar N, et al. The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels. Clin Chem. 2024;70(7):986–995.
26. Koren G, Boskovic R, Hard M, Maltepe C, Navioz Y, Einarson A. Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system for nausea and vomiting of pregnancy. Am J Obstet Gynecol. 2002;186(5 Suppl):S228–S231.
27. Ebrahimi N, Maltepe C, Garcia-Bournissen F, Koren G. Nausea and vomiting of pregnancy: using the 24-hour Pregnancy-Unique Quantification of Emesis (PUQE-24) scale. J Obstet Gynaecol Can. 2009;31(9):803–807.
28. Aslancan Bayram R, Cömert EH, Ayanoğlu E, Yücel B. Validation of Pregnancy Unique Quantification of Emesis and Nausea (PUQE) score in a Turkish population. Anat J Obstet Gynecol Res. 2025;2(2):58–63.
29. Koot MH, Grooten IJ, van der Post JAM, Bais JMJ, Ris-Stalpers C, Leeflang MMG, et al. Determinants of disease course and severity in hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 2020;245:162–167.
30. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human participants. JAMA. 2025;333(1):71–74.
31. Rousselet GA, Pernet CR, Wilcox RR. The percentile bootstrap: a primer with step-by-step instructions in R. Adv Methods Pract Psychol Sci. 2021;4(1):2515245920911881.
32. West RM. Best practice in statistics: the use of log transformation. Ann Clin Biochem. 2022;59(3):162–165.
33. Mansournia MA, Nazemipour M, Naimi AI, Collins GS, Campbell MJ. Reflection on modern methods: demystifying robust standard errors for epidemiologists. Int J Epidemiol. 2021;50(1):346–351.
34. Ghanem HB, Hammoudeh SM, Abulfaraj M, Elsherbini DMA, Hussein SE, Algader JI, et al. Prevalence of hyperemesis gravidarum and its associated electrolyte and hematologic disturbances in pregnant women at a tertiary hospital in Saudi Arabia. Cureus. 2024;16(2):e53684.
35. Worede A, Deress T, Wondifraw H, Fetene G, Berie A. Electrolyte imbalance and liver function test abnormalities among pregnant women with hyperemesis gravidarum at Wag-himra zone public hospitals, northeast Ethiopia. BMC Pregnancy Childbirth. 2023;23(1):710.
36. Welsh P, Kimenai DM, Marioni RE, Hayward C, Campbell A, Porteous D, et al. Reference ranges for GDF-15, and risk factors associated with GDF-15, in a large general population cohort. Clin Chem Lab Med. 2022;60(11):1820–1829.
37. Koot MH, Grooten IJ, van der Post JAM, Bais JMJ, Ris-Stalpers C, Naaktgeboren CA, et al. Ketonuria is not associated with hyperemesis gravidarum disease severity. Eur J Obstet Gynecol Reprod Biol. 2020;254:315–320.
38. Nijsten K, Koot MH, van der Post JAM, Bais JMJ, Ris-Stalpers C, Naaktgeboren C, et al. Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum: a prospective cohort study. Acta Obstet Gynecol Scand. 2021;100(8):1419–1429.
39. Farshbaf-Khalili A, Salehi-Pourmehr H, Najafipour F, Alamdari NM, Pourzeinali S, Ainehchi N. Is hyperemesis gravidarum associated with transient hyperthyroidism? A systematic review and meta-analysis. Taiwan J Obstet Gynecol. 2023;62(2):205–225.
40. MacGibbon KW, Kim S, Mullin PM, Fejzo MS. HyperEmesis Level Prediction (HELP score) identifies patients with indicators of severe disease: a validation study. Geburtshilfe Frauenheilkd. 2021;81(10):1106–1114.
41. Chrysafi P, Valenzuela-Vallejo L, Stefanakis K, Kelesidis T, Connelly MA, Mantzoros CS. Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans. Nat Commun. 2024;15(1):5190.
42. Andersson-Hall U, Joelsson L, Svedin P, Mallard C, Holmäng A. Growth-differentiation-factor 15 levels in obese and healthy pregnancies: relation to insulin resistance and insulin secretory function. Clin Endocrinol (Oxf). 2021;95(1):92–100.
43. Høgh S, Borgsted C, Hegaard HK, Renault KM, Ekelund K, Bruzzone SEP, et al. Growth differentiation factor 15 during pregnancy and postpartum as captured in blood, cerebrospinal fluid and placenta. J Reprod Immunol. 2024;161:104187.
44. Kından A, Üçok BS. Association between PUQE-based severity of hyperemesis gravidarum and systemic inflammatory indices. BMC Pregnancy Childbirth. 2026;26(1):446.
45. van der Minnen LM, Vendelbo JH, Pedersen LH, Painter RC. Preconception metformin and hyperemesis gravidarum in Denmark: clinical implications of growth differentiation factor 15's etiological role. BJOG. 2024;131(13):1843–1849.
46. Sillis L, Whaites Heinonen E, Ceulemans M, Johnson D, Luo Y, Chambers CD. Metformin for the prevention of hyperemesis gravidarum: an observational cohort study. BJOG. 2025;132(12):1772–1778.
47. Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444–448.
48. Groarke JD, Crawford J, Collins SM, Lubaczewski S, Roeland EJ, Naito T, et al. Ponsegromab for the treatment of cancer cachexia. N Engl J Med. 2024;391(24):2291–2303.
49. Gurtan AM, Khalid S, Koch C, Khan MZ, Lamarche LB, Splawski I, et al. Identification and characterization of human GDF15 knockouts. Nat Metab. 2024;6(10):1913–1921.
50. Alshaikh ABA, Al-kuraishy HM, Kafy S, Albar M, Sebghatallah A, Shokr MM, et al. Hyperemesis gravidarum revisited: from GDF15 biology to precision multimodal therapy. Naunyn Schmiedebergs Arch Pharmacol. 2026;399(9):12953–12966.
2. Nijsten K, Dean C, van der Minnen LM, Bais JMJ, Ris-Stalpers C, van Eekelen R, et al. Recurrence, postponing pregnancy, and termination rates after hyperemesis gravidarum: follow up of the MOTHER study. Acta Obstet Gynecol Scand. 2022;101(9):964–974.
3. Nana M, Painter R, Williamson C, Nelson-Piercy C. Hyperemesis gravidarum. Lancet. 2026;407(10523):78–89.
4. Nurmi M, Rautava P, Gissler M, Vahlberg T, Polo-Kantola P. Readmissions due to hyperemesis gravidarum: a nation-wide Finnish register study. Arch Gynecol Obstet. 2022;306(5):1519–1529.
5. Mitchell-Jones N, Lawson K, Bobdiwala S, Farren JA, Tobias A, Bourne T, et al. Association between hyperemesis gravidarum and psychological symptoms, psychosocial outcomes and infant bonding: a two-point prospective case–control multicentre survey study in an inner city setting. BMJ Open. 2020;10(10):e039715.
6. Nana M, Tydeman F, Bevan G, Boulding H, Kavanagh K, Dean C, et al. Hyperemesis gravidarum is associated with increased rates of termination of pregnancy and suicidal ideation: results from a survey completed by > 5,000 participants. Am J Obstet Gynecol. 2024;230(3):362.e1–362.e10.
7. Nijsten K, van der Minnen LM, Dean C, Bais JMJ, Ris-Stalpers C, van Eekelen R, et al. Depression, anxiety, and post-traumatic stress disorder symptoms after hyperemesis gravidarum: a prospective cohort study. J Matern Fetal Neonatal Med. 2022;35(25):10003–10010.
8. Moberg T, Van der Veeken L, Persad E, Hansson SR, Bruschettini M. Placenta-associated adverse pregnancy outcomes in women experiencing mild or severe hyperemesis gravidarum – a systematic review and meta-analysis. BMC Pregnancy Childbirth. 2023;23(1):815.
9. Fiorentini M, Nedu B, Dapoto F, Brunelli E, Pilu G, Youssef A. When time is brain: a systematic review about Wernicke encephalopathy as a dramatic consequence of thiamin deficiency in hyperemesis gravidarum. J Matern Fetal Neonatal Med. 2025;38(1):2470988.
10. Liu C, Zhao G, Qiao D, Wang L, He Y, Zhao M, et al. Emerging progress in nausea and vomiting of pregnancy and hyperemesis gravidarum: challenges and opportunities. Front Med (Lausanne). 2022;8:809270.
11. Fejzo MS. Hyperemesis gravidarum theories dispelled by recent research: a paradigm change for better care and outcomes. Trends Mol Med. 2024;30(6):530–540.
12. Fejzo MS, MacGibbon KW, First O, Quan C, Mullin PM. Whole-exome sequencing uncovers new variants in GDF15 associated with hyperemesis gravidarum. BJOG. 2022;129(11):1845–1852.
13. Fejzo M, Wang X, Tan Q, Zöllner J, Pujol-Gualdo N, Laisk T, et al. Multi-ancestry genome-wide association study of severe pregnancy nausea and vomiting. Nat Genet. 2026;58(4):810–820.
14. Lockhart SM, Saudek V, O'Rahilly S. GDF15: a hormone conveying somatic distress to the brain. Endocr Rev. 2020;41(4):bnaa007.
15. Breit SN, Brown DA, Tsai VW. The GDF15-GFRAL pathway in health and metabolic disease: friend or foe? Annu Rev Physiol. 2021;83:127–151.
16. Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol. 2021;17(10):592–607.
17. Borner T, Pataro AM, De Jonghe BC. Central mechanisms of emesis: a role for GDF15. Neurogastroenterol Motil. 2025;37(3):e14886.
18. Andersson-Hall U, Svedin P, Mallard C, Blennow K, Zetterberg H, Holmäng A. Growth differentiation factor 15 increases in both cerebrospinal fluid and serum during pregnancy. PLoS One. 2021;16(5):e0250718.
19. Klein AB, Ranea-Robles P, Nicolaisen TS, Gil C, Johann K, Prats Quesada J, et al. Cross-species comparison of pregnancy-induced GDF15. Am J Physiol Endocrinol Metab. 2023;325(4):E303–E309.
20. Fejzo M, Rocha N, Cimino I, Lockhart SM, Petry CJ, Kay RG, et al. GDF15 linked to maternal risk of nausea and vomiting during pregnancy. Nature. 2024;625(7996):760–767.
21. Svenningsen JS, Ostenfeld A, Petersen JF, Svenningsen MS, Hillig T, Gillum MP, et al. Early pregnancy GDF15 trajectories and their association with normal gestation, pregnancy loss, and hyperemesis gravidarum. EBioMedicine. 2026;131:106428.
22. Meran NM, Hussein RM. Maternal serum tumor necrosis factor level in women with hyperemesis gravidarum. J Fac Med Baghdad. 2025;67(2):143–148.
23. Alkhateeb SMJ, Salman AF, Ali EA, Al-Jedda WA, Alwan AF. Growth differentiation factor-15 and erythroferrone are reliable predictors of iron status among Iraqi pregnant women with anemia: a case-control study. Hematology. 2024;29(1):2376064.
24. Abd FN, Abd Ali RA. Clinical and diagnostic value of GDF-15 and β-hCG in first trimester pregnancy with threatened miscarriage and the short-term impact of hormonal support: a prospective study. J Reprod Immunol. 2025;168:104396.
25. Karusheva Y, Ratcliff M, Mörseburg A, Barker P, Melvin A, Sattar N, et al. The common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels. Clin Chem. 2024;70(7):986–995.
26. Koren G, Boskovic R, Hard M, Maltepe C, Navioz Y, Einarson A. Motherisk-PUQE (pregnancy-unique quantification of emesis and nausea) scoring system for nausea and vomiting of pregnancy. Am J Obstet Gynecol. 2002;186(5 Suppl):S228–S231.
27. Ebrahimi N, Maltepe C, Garcia-Bournissen F, Koren G. Nausea and vomiting of pregnancy: using the 24-hour Pregnancy-Unique Quantification of Emesis (PUQE-24) scale. J Obstet Gynaecol Can. 2009;31(9):803–807.
28. Aslancan Bayram R, Cömert EH, Ayanoğlu E, Yücel B. Validation of Pregnancy Unique Quantification of Emesis and Nausea (PUQE) score in a Turkish population. Anat J Obstet Gynecol Res. 2025;2(2):58–63.
29. Koot MH, Grooten IJ, van der Post JAM, Bais JMJ, Ris-Stalpers C, Leeflang MMG, et al. Determinants of disease course and severity in hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol. 2020;245:162–167.
30. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human participants. JAMA. 2025;333(1):71–74.
31. Rousselet GA, Pernet CR, Wilcox RR. The percentile bootstrap: a primer with step-by-step instructions in R. Adv Methods Pract Psychol Sci. 2021;4(1):2515245920911881.
32. West RM. Best practice in statistics: the use of log transformation. Ann Clin Biochem. 2022;59(3):162–165.
33. Mansournia MA, Nazemipour M, Naimi AI, Collins GS, Campbell MJ. Reflection on modern methods: demystifying robust standard errors for epidemiologists. Int J Epidemiol. 2021;50(1):346–351.
34. Ghanem HB, Hammoudeh SM, Abulfaraj M, Elsherbini DMA, Hussein SE, Algader JI, et al. Prevalence of hyperemesis gravidarum and its associated electrolyte and hematologic disturbances in pregnant women at a tertiary hospital in Saudi Arabia. Cureus. 2024;16(2):e53684.
35. Worede A, Deress T, Wondifraw H, Fetene G, Berie A. Electrolyte imbalance and liver function test abnormalities among pregnant women with hyperemesis gravidarum at Wag-himra zone public hospitals, northeast Ethiopia. BMC Pregnancy Childbirth. 2023;23(1):710.
36. Welsh P, Kimenai DM, Marioni RE, Hayward C, Campbell A, Porteous D, et al. Reference ranges for GDF-15, and risk factors associated with GDF-15, in a large general population cohort. Clin Chem Lab Med. 2022;60(11):1820–1829.
37. Koot MH, Grooten IJ, van der Post JAM, Bais JMJ, Ris-Stalpers C, Naaktgeboren CA, et al. Ketonuria is not associated with hyperemesis gravidarum disease severity. Eur J Obstet Gynecol Reprod Biol. 2020;254:315–320.
38. Nijsten K, Koot MH, van der Post JAM, Bais JMJ, Ris-Stalpers C, Naaktgeboren C, et al. Thyroid-stimulating hormone and free thyroxine fail to predict the severity and clinical course of hyperemesis gravidarum: a prospective cohort study. Acta Obstet Gynecol Scand. 2021;100(8):1419–1429.
39. Farshbaf-Khalili A, Salehi-Pourmehr H, Najafipour F, Alamdari NM, Pourzeinali S, Ainehchi N. Is hyperemesis gravidarum associated with transient hyperthyroidism? A systematic review and meta-analysis. Taiwan J Obstet Gynecol. 2023;62(2):205–225.
40. MacGibbon KW, Kim S, Mullin PM, Fejzo MS. HyperEmesis Level Prediction (HELP score) identifies patients with indicators of severe disease: a validation study. Geburtshilfe Frauenheilkd. 2021;81(10):1106–1114.
41. Chrysafi P, Valenzuela-Vallejo L, Stefanakis K, Kelesidis T, Connelly MA, Mantzoros CS. Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans. Nat Commun. 2024;15(1):5190.
42. Andersson-Hall U, Joelsson L, Svedin P, Mallard C, Holmäng A. Growth-differentiation-factor 15 levels in obese and healthy pregnancies: relation to insulin resistance and insulin secretory function. Clin Endocrinol (Oxf). 2021;95(1):92–100.
43. Høgh S, Borgsted C, Hegaard HK, Renault KM, Ekelund K, Bruzzone SEP, et al. Growth differentiation factor 15 during pregnancy and postpartum as captured in blood, cerebrospinal fluid and placenta. J Reprod Immunol. 2024;161:104187.
44. Kından A, Üçok BS. Association between PUQE-based severity of hyperemesis gravidarum and systemic inflammatory indices. BMC Pregnancy Childbirth. 2026;26(1):446.
45. van der Minnen LM, Vendelbo JH, Pedersen LH, Painter RC. Preconception metformin and hyperemesis gravidarum in Denmark: clinical implications of growth differentiation factor 15's etiological role. BJOG. 2024;131(13):1843–1849.
46. Sillis L, Whaites Heinonen E, Ceulemans M, Johnson D, Luo Y, Chambers CD. Metformin for the prevention of hyperemesis gravidarum: an observational cohort study. BJOG. 2025;132(12):1772–1778.
47. Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444–448.
48. Groarke JD, Crawford J, Collins SM, Lubaczewski S, Roeland EJ, Naito T, et al. Ponsegromab for the treatment of cancer cachexia. N Engl J Med. 2024;391(24):2291–2303.
49. Gurtan AM, Khalid S, Koch C, Khan MZ, Lamarche LB, Splawski I, et al. Identification and characterization of human GDF15 knockouts. Nat Metab. 2024;6(10):1913–1921.
50. Alshaikh ABA, Al-kuraishy HM, Kafy S, Albar M, Sebghatallah A, Shokr MM, et al. Hyperemesis gravidarum revisited: from GDF15 biology to precision multimodal therapy. Naunyn Schmiedebergs Arch Pharmacol. 2026;399(9):12953–12966.
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Jabbar DK. Hyperemesis gravidarum; GDF15; GFRAL; PUQE-24; nausea and vomiting of pregnancy; ELISA; Iraq. Am J Med Nat Sci [Internet]. 2026Oct.3 [cited 2026Oct.11];7(2):39-8. Available from: https://www.ajmns.com/index.php/journal/article/view/39
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