Gebeliğin intrahepatik kolestazında hastalığın şiddeti ve tedaviye yanıtın perinatal sonuçlara etkisi

Öz

Amaç: Gebeliğin intrahepatik kolestazı (GİHK) ile komplike olan gebeliklerde, serum safra asiti (SA) düzeyleri ve ursodeoksikolik asit (UDKA) tedavisine verilen cevabın perinatal sonuçlar üzerine etkisini araştırmaktır. Gereçler ve Yöntem: Bu çalışmada Ocak 2013 ile Ocak 2018 tarihleri arasında üçüncü basamak bir merkezde GİHK nedeniyle takip edilen gebelikler retrospektif olarak analiz edildi. GİHK şiddeti, serum SA seviyelerine göre hafif (10–40 μmol/L), orta (40-80 μ mol/L) ve şiddetli (>80 μ mol/L) olarak gruplandırıldı. GİHK’nın şiddeti ve UDKA tedavisine verilen olumlu veya olumsuz yanıtın perinatal sonuçlar üzerine etkisi araştırıldı. Bulgular: GİHK tanısı koyulan toplamda 200 gebe çalışmaya dahil edildi. Hastaların %65 (n=130)’inde hafif GİHK, %20 (n=40)’sinde orta şiddetli GİHK ve %15 (n=30)’inde şiddetli GİHK saptandı. GİHK tanısıyla takip edilen hastaların 4 (%2.0)’ünde ölü doğum gerçekleşti. Şiddetli GİHK hastalarında spontan preterm doğum oranı, orta ve hafif GİHK hastalarına kıyasla anlamlı olarak daha yüksekti (p=0.001). Şiddetli GİHK hastalarında ve UDKA tedavisine yanıt vermeyen hastalarda, ortalama doğum haftası, ortalama doğum ağırlığı, 1. ve 5. dakika Apgar skorları daha düşük, amniyosta mekonyum varlığı, yenidoğan yoğun bakım ünitesi ihtiyacı ve ölü doğum oranları daha yüksekti. Sonuç: GİHK ile komplike olan gebelikler fetal ve neonatal olumsuz sonuçlar açısından artmış riske sahiptir. Maternal serum SA düzeyleri hastalığın siddeti ve olumsuz perinatal sonuçlarla ilişkilidir. Bununla birlikte, UDKA tedavisine verilen klinik cevap, fetal ve neonatal sonuçları öngörmede etkili olabilir.

Anahtar Kelimeler

• Gebeliğin intrahepatik kolestazı
• gebelik kolestazı
• kolestaz
• yenidoğan sonuçları
• ursodeoksikolik asit.

The effect of disease severity and response to treatment on perinatal outcomes in intrahepatic cholestasis of pregnancy

Öz

Aim: To investigate the effects of serum bile acid (BA) levels and response to ursodeoxycholic acid (UDCA) treatment on perinatal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP). Materials and Method: In this retrospective study, pregnancies followed for GIHC at a tertiary center between January 2013 and January 2018 were analyzed. ICP severity was classified according to serum BA levels as mild (10–40 μmol/L), moderate (40-80 μ mol/L) and severe (>80 μ mol/L). The effects of the severity of ICP and the positive or negative response to UDCA treatment on perinatal outcomes were investigated. Results: A total of 200 pregnant women diagnosed with ICP were included in the study. Mild ICP was detected in 65% (n=130) of the patients, moderate ICP in 20% (n=40) and severe ICP in 15% (n=30). Stillbirth occurred in 4 (2.0%) of the patients. Spontaneous preterm birth rate was significantly higher in patients with severe ICP compared with patients with moderate and mild ICP (p=0.001). Mean gestational age, mean birth weight, 1st and 5th minute Apgar scores were lower, and the presence of meconium in the amniotic fluid, need for neonatal intensive care unit and stillbirth rates were higher in patients with severe ICP and patients who did not respond to UDCA treatment. Conclusion: Pregnancies complicated by ICP have an increased risk for adverse fetal and neonatal outcomes. Maternal serum BA levels are associated with disease severity and adverse perinatal outcomes. The clinical response to UDCA treatment may be effective in predicting fetal and neonatal outcomes.

Anahtar Kelimeler

• Cholestasis
• cholestasis of pregnancy
• intrahepatic cholestasis of pregnancy
• neonatal outcomes
• ursodeoxycholic acid.

Kaynakça

1. Saleh MM, Abdo KR. Intrahepatic cholestasis of pregnancy: review of the literature and evaluation of current evidence. J Womens Health. 2007;16:833-41.
2. Reyes H. Review: intrahepatic cholestasis. A puzzling disorder of pregnancy. J Gastroenterol Hepatol. 1997; 12:211-6.
3. Holzbach RT, Sivak DA, Braun WE. Familial recurrent intrahepatic cholestasis of pregnancy. A genetic study providing evidence for transmission of a sex-limited, dominant trait. Gastroenterology. 1983;85:175- 9
4. Arrese M, Macias RI, Briz O, Perez MJ, Marin JJ. Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Expert Rev Mol Med. 2008;10:e9.
5. Gitlin N. Liver disease in pregnancy. In: Millward-SadlerGH, Wright R, Arthur MJP (eds). Wright’s liver and biliary disease. 3rd ed. London: WB Saunders Company Ltd, 1992;1155-69.
6. Heikkinen J. Serum bile acids in early diagnosis of intrahepatic cholestasis of pregnancy. Obstet Gynecol. 1983;61:581-7
7. Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol. 2006; 26:527-32
8. Lee RH, Kwok KM, Ingles S, Wilson ML, Mullin P, Incerpi M, et al. Pregnancy outcomes during an era of aggressive management for intrahepatic cholestasis of pregnancy. Am J Perinatol. 2008;25:341-5.

9. Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort. PLoS One. 2012;7:e28343.
10. Gorelik J, Shevchuk A, de Swiet M, Lab M, Korchev Y, Williamson C. Comparison of the arrhythmogenic effects of tauro- and glycoconjugates of cholic acid in an in vitro study of rat cardiomyocytes. BJOG 2004;111:867-70
11. Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. Eur J Obstet Gynecol Reprod Biol. 1991;42:211-5
12. Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL, Glasinovic JC. Bile acids increase response and expression of human myometrial oxytocin receptor. Am J Obstet Gynecol 2003;189:577-82
13. Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006; 3: 318-28.
14. Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU. Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology. 2008;47:544-51.
15. Bacq Y. Liver diseases unique to pregnancy: A 2010 update. Clin Res Hepatol Gastroentero.2011;35:182-93.
16. Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014;124(1):120-33.
17. Gabzdyl EM, Schlaeger JM. Intrahepatic cholestasis of pregnancy: a criticalclinical review. J Perinat Neonatal Nurs. 2015;29(1):41-50.
18. Pata Ö, Vardareli E, Özcan A. Intrahepatic cholestasis of pregnancy: Correlation of preterm delivery with bile acids. Turk J Gastroenterol 2011;22: 602-5
19. Brouwers L, Koster MP, Page-Christiaens GC, Kemperman H, Boon J, Evers IM, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. Am J Obstet Gynecol. 2015;212:100.e1-7.
20. Chappell LC, Bell JL, Smith A, Linsell L, Juszczak E, Dixon PH, et al. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet. 2019;394:849-60.
21. Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020;7:CD000493.