Thesis is devoted to contemporary issue of modern obstetrics, i.e. reduction of obstetric and perinatal complications in women with pre-existing type 1 diabetes mellitus (T1DM) through development and implementation of complex of preventive and treatment measures based on the study of polymorphic variants of genes and correction of vascular disorders and which is aimed at preeclampsia (PE) prevention and treatment.
In order to achieve the established goal, we studied clinical parameters, prevalence of polymorphic variants of studied genes, as well as existed gene-gene and gene-environment interactions, correlated with PE development in T1DM, its severity/ terms of onset, as well as parameters of antihypertensive therapy efficacy in 76 patients with T1DM and superimposed PE and in 60 diabetic women without PE. It was found that in T1DM patients PE developed in the presence of the following factors: pre-existing diabetic nephropathy (DN), BMI>24 kg/m2 and ID– or DD–genotype of ACE gene. The best gene-gene interaction model included three loci – ACE_ID/PON1_C108T/eNOS_G894T. The study of different combinations of polymorphic variants of genes within the above-mentioned model, as well as investigation of other genes and clinical factors disclosed significant predictors of PE development in different subpopulations of pregnant women with pre-existing T1DM.
The following risk factors were found to be the main contributors to mild PE development. Combinaton of ACE_II/PON1_CC genotypes provides protective effect on PE development, while ACE_ID/PON1_CT combination is associated with development of mild PE. In heterozygous carriers of PON1 108CT genotype clinical parameters exert modifying effect: when this genotype is combined with DN, or duration of diabetes<8,5 years, or BMI<23,8 kg/m2 mild PE develops; in the presence of the same genotype moderate/severe PE develops when duration of diabetes is >13,5 years and the value of BMI>25,17 kg/m2.
That were long duration of diabetes; presence of vascular complications (in particular, angiopathy of lower extremities and DN) and ID-genotype of ACE gene which influenced early-onset (<32 weeks) PE development in pregnant women with pre-existing DM1. The most significant genotype combinations associated with early-onset PE development were as follows: ACE(ID)/AT2R1(1166AA); ACE(ID)/eNOS(4b/4b); ACE(ID)/eNOS(894GG). Genetic factor influenced the development of late-onset PE to a much lesser extent; only one statistically significant combination of genotypes was detected to be associated with PE debut after 32 weeks of pregnancy – ACE(ID)/MGP(138TC).
The strong involvement of ACE and MGP gene polymorphisms in PE development may be explained by their impact on maternal central hemodynamics parameters during the first trimester of pregnancy. For instance, as compared to II– and ID-genotypes, DD-genotype of ACE gene was associated with the lowest values of stroke volume and stroke index. Whilst 83Ala/Ala genotype of MGP gene Thr83Ala polymorphism correlated with minimal values of circulating blood volume (and, as a result, with more pronounced hypovolemia). Thus, the above-mentioned polymorphic variants of genes are involved in formation of pathogenic pattern of central hemodynamics, which, in its turn, predispose to early-onset PE formation.
Pharmacogenetic study revealed unfavorable allele-dose dependent impact of causative D-allele of ACE(I/D) gene, Ala-allele of MGP (Thr83Ala) gene and T–allele of PON1 (C108T) gene on efficacy of antihypertensive therapy. The latter necessitated earlier prescription of first- and second-line (combination) therapy, required more time to achieve appropriate therapeutic effect and showed higher pre- and post-treatment levels of systolic and diastolic blood pressure.
Data obtained in the study let us develop the optimized complex of preventive and treatment measures, as well as to revise approaches to antihypertensive therapy in pregnant women with pre-existing DM1 at high risk for PE development based on individual profile of polymorphic variants of genes. The suggested approach allowed to reduce the prevalence of different complications of pregnancy (early gestosis - by 21,0%; miscarriage - by 34,8%; preterm labour – by 19,6%; fetal distress – by 17,5%; polyhydramnios – by 25,4%; PE – by 27%; early-onset PE – by 13,3% and moderate/severe PE – by 26,7%) and to lower the rates of perinatal morbidity (respiratory distress syndrome – by 18,5%, fetal macrosomia – by 22,1%; IUGR – by 14,4%; episodes of hypoglycemia – by 31,5%). Thus, the proposed complex should be recommended for a wider use within perinatal care facilities.
