Альманах клинической медицины. 2018; 46: 282-288
Тяжелая преэклампсия и мутация в гене HNF4A (MODY1): клиническое описание
https://doi.org/10.18786/2072-0505-2018-46-3-282-288Аннотация
Преэклампсия – акушерское осложнение, которое становится одной из важнейших причин материнской и перинатальной заболеваемости и смертности. Частота преэклампсии при сахарном диабете в 3–5 раз превышает популяционную. Для профилактики преэклампсии используют гепарин, поскольку в эксперименте показана важная его роль в процессе инвазии и дифференцировке трофобласта, а также влиянии на выработку проангиогенных факторов. В статье описано клиническое наблюдение, позволяющее расширить представления о патогенезе преэклампсии и возможностях ее профилактики. У пациентки 30 лет, ранее не имевшей серьезных соматических заболеваний, две предыдущие беременности протекали на фоне тяжелой преэклампсии с ранним началом (артериальная гипертензия, массивная протеинурия, тромбоцитопения, почечно-печеночная недостаточность). Оба ребенка родились глубоко недоношенными (24–25 недель) и погибли. Наследственность: сахарный диабет 2-го типа у бабушки по линии матери. Глюкоза венозной плазмы натощак в ранние сроки обеих беременностей составила 3,8–4,6 ммоль/л (норма < 5,1 ммоль/л). Глюкозотолерантный тест, который по протоколу проводится в 24–28 недель, не проводился. При планировании 3-й беременности индекс массы тела 29 кг/м2, нормальные показатели артериального давления и почечной функции, отсутствие протеинурии, нет данных за антифосфолипидный синдром. В 1-м триместре глюкоза венозной плазмы натощак 4,4 ммоль/л. С ранних сроков беременности получала низкомолекулярный гепарин, с 15 недель начата гипотензивная терапия по поводу гестационной артериальной гипертензии. Манифестный диабет выявлен на 24–25-й неделе на основании глюкозотолерантного теста (4,96–10,42–11,46 ммоль/л). На фоне диеты постпрандиальная гликемия до 8,9 ммоль/л, в связи с чем с 25 недель гестации начата базис-болюсная инсулинотерапия (0,4 ЕД/кг), достигнута компенсация диабета. В 16 недель sFlt1/PlGF = 44 (высокий риск развития преэклампсии). При молекулярно-генетическом исследовании выявлена мутация в гене HNF4A, ассоциированная с сахарным диабетом MODY1. С 34 недель развилась умеренная преэклампсия и задержка роста плода. Родоразрешена путем планового кесарева сечения на 38-й неделе, здоровый мальчик 2300 г, 48 см. После родов диабет компенсирован на диете. У ребенка определена аналогичная мутация. Таким образом, нельзя исключить генетически детерминированную взаимосвязь осложнений предыдущих беременностей и манифестного сахарного диабета, выявленного в настоящую беременность. Обнаружение у беременной MODY1 требует максимально ранней инициации инсулинотерапии для предотвращения макросомии плода и неонатальных гипогликемических состояний, а также профилактики преэклампсии. Причиной успешного завершения данной беременности можно считать назначение гепарина в ранние сроки, что позволило добиться полноценной имплантации и плацентации, а также своевременной компенсации диабета.
Список литературы
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Almanac of Clinical Medicine. 2018; 46: 282-288
Severe preeclampsia and gene mutation HNF4A (MODY1): а case report
https://doi.org/10.18786/2072-0505-2018-46-3-282-288Abstract
Preeclampsia is an obstetric complication that is becoming a major cause of maternal and perinatal morbidity and mortality. The rate of preeclampsia in diabetes mellitus is 3 to 5-fold higher than in the population. Heparin is used for prevention of preeclampsia due to its experimentally shown important role in the trophoblast invasion and differentiation, as well as its influence on the production of proangiogenic factors. The paper gives a clinical case report that broadens our understanding on the preeclampsia pathophysiology and possibilities of its prevention. A 30-year old patient with no past history of serious physical illnesses had her two previous pregnancies with severe preeclampsia of early onset (arterial hypertension, massive proteinuria, thrombocytopenia, renal and hepatic insufficiency). Both babies were born extremely preterm (24 to 25 weeks of gestation) and died. Her hereditary background included type 2 diabetes in her maternal grandmother. At early terms of both pregnancies she had her fasting venous plasma glucose of 3.8 to 4.6 mmol/L (normal, < 5.1 mmol/L). Oral glucose tolerance test which had to be performed at 24 to 28 weeks of gestation, according to the protocol, was not performed. While planning for the third pregnancy, her body mass index was 29 kg/m2, with normal values of the blood pressure and renal function, no proteinuria and no evidence of the anti-phospholipid syndrome. In the 1st trimester, she had her fasting venous plasma glucose of 4.4 mmol/L. From the early term of her pregnancy, the patient was administered low molecular weight heparin; from the week 15, she was started with antihypertensive medications due to gestational arterial hypertension. Manifest diabetes was diagnosed at week 24 to 25 based on the results of the oral glucose tolerance test (4.96–10.42–11.46 mmol/L). With diet treatment, she had her postprandial glycaemia of up to 8.9 mmol/L, causing the initiation of basal-bolus insulin therapy from week 25 of gestation (0.4 U/kg), with achievement of good glucose control. At week 16, she had her sFlt1/PlGF level of 44 (high risk of preeclampsia). Molecular genetic assessment identified a HNF4A gene mutation, associated with MODY1. From week 34, she had moderate preeclampsia and fetal growth delay. An elective cesarean section was performed at week 38, with a healthy boy of 2300 g and 48 cm. After delivery, her diabetes was controlled by diet. The baby had an identical mutation. Thus, one cannot exclude a genetically determined link between complications of previous pregnancies and manifest diabetes diagnosed during the current pregnancy. Diagnosis of MODY1 in a pregnant patient would require the earliest initiation insulin treatment to prevent fetal macrosomia and neonatal hypoglycemia, as well as to prevent preeclampsia. The reason of successful outcome of this pregnancy could be related to heparin administration at the early terms of pregnancy that allowed for appropriate implantation and placenta formation, as well as for timely good glucose control.
References
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2. Cerdeira AS, Karumanchi SA. Angiogenic proteins as aid in the diagnosis and prediction of preeclampsia. Scand J Clin Lab Invest Suppl. 2010;242:73–8. doi: 10.3109/00365513.2010.493400.
3. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7): 672–83. doi: 10.1056/NEJMoa031884.
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5. Mañé L, Flores-Le Roux JA, Benaiges D, Rodríguez M, Marcelo I, Chillarón JJ, Pedro-Botet J, Llauradó G, Gortazar L, Carreras R, Payà A. Role of First-Trimester HbA1c as a Predictor of Adverse Obstetric Outcomes in a Multiethnic Cohort. J Clin Endocrinol Metab. 2017;102(2): 390–7. doi: 10.1210/jc.2016-2581.
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12. Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Hattersley AT. Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers. Diabetes Care. 2002;25(12): 2287–91. doi: 10.2337/diacare.25.12.2287.
13. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118. doi: 10.1371/journal.pmed.0040118.
14. Gris JC, Chauleur C, Molinari N, Marès P, Fabbro-Peray P, Quéré I, Lefrant JY, Haddad B, Dauzat M. Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia. The pilot randomised controlled NOH-PE trial. Thromb Haemost. 2011;106(6): 1053–61. doi: 10.1160/TH11-05-0340.
15. Urban G, Vergani P, Tironi R, Ceruti P, Vertemati E, Sala F, Pogliani E, Triche EW, Lockwood CJ, Paidas MJ. Antithrombotic prophylaxis inmultiparous women with preeclampsia or intrauterine growth retardation in an antecedent pregnancy. Int J Fertil Womens Med. 2007;52(2–3): 59–67.
16. Rodger MA, Carrier M, Le Gal G, Martinelli I, Perna A, Rey E, de Vries JI, Gris JC; Low-Molecular-Weight Heparin for Placenta-Mediated Pregnancy Complications Study Group. Meta-analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood. 2014;123(6): 822–8. doi: 10.1182/blood-2013-01-478958.
17. de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014;(7):CD004734. doi: 10.1002/14651858.CD004734.pub4.
18. Dusse LM, Alpoim PN, Lwaleed BA, de Sousa LP, Carvalho MD, Gomes KB. Is there a link between endothelial dysfunction, coagulation activation and nitric oxide synthesis in preeclampsia? Clin Chim Acta. 2013;415:226–9. doi: 10.1016/j.cca.2012.10.006.
19. Quaranta M, Erez O, Mastrolia SA, Koifman A, Leron E, Eshkoli T, Mazor M, Holcberg G. The physiologic and therapeutic role of heparin in implantation and placentation. Peer J. 2015;3:e691. doi: 10.7717/peerj.691.
20. Fiedler K, Würfel W. Effectivity of heparin in assisted reproduction. Eur J Med Res. 2004;9(4): 207–14.
21. Sobel ML, Kingdom J, Drewlo S. Angiogenic response of placental villi to heparin. Obstet Gynecol. 2011;117(6): 1375–83. doi: 10.1097/AOG.0b013e31821b5384.
22. Yinon Y, Ben Meir E, Margolis L, Lipitz S, Schiff E, Mazaki-Tovi S, Simchen MJ. Low molecular weight heparin therapy during pregnancy is associated with elevated circulatory levels of placental growth factor. Placenta. 2015;36(2): 121–4. doi: 10.1016/j.placenta.2014.12.008.
