Гомоцистеинемия и неразвивающаяся беременность

[Dr.Vad]

На заметку коллегам и пациентам а также на их суд хотелось бы вынести весьма интересную на мой взгляд статью в оригинале о варианте лечения выкидышей на ранних сроках беремменнности. Конечно, понимаю что, определение гомоцистеинемии или генетических дефектов в MTHFR "доступно повсеместно", но подкупает простота и относительная безопасность лечения, может для кого-то это будет одним из последних шансов оказаться в числе счастливых матерей...

Fertility and Sterility Volume 75, Issue 4 , April 2001, p. 823-825

Vitamin supplementation and pregnancy outcome in women with recurrent early pregnancy loss and hyperhomocysteinemia

Isabelle Quéré M.D., Ph.D.a, Eric Mercierb, Hélène Bellet M.D.c, Charles Janbon M.D.a, Pierre Marès M.D.d and Jean-Christophe Gris M.D., Ph.D., , b

a Service de Médecine B et Médecine Vasculaire,a CHU, Montpellier, France
b Consultations et Laboratoire d'Hématologie et Immunologie,b CHU, Nîmes, et Faculté de Pharmacie, Montpellier, France
c Laboratoire de Biochimie,c CHU, Montpellier, France
d Departement de Gynécologie et Obstétrique,d CHU, Nîmes, France


Mild to moderate hyperhomocysteinemia seems to be related to negative pregnancy outcome: in northern Europe, an association with embryo toxicity leading to spontaneous abortion, or with vascular toxicity leading to placental infarction, has been described by investigators. We recently confirmed the prevalence of hyperhomocysteinemia in women from our region in Mediterranean France. As folic acid and vitamin B6 can normalize fasting total homocysteinemia, we performed a pilot noncontrolled evaluation of vitamin supplementation in women with hyperhomocysteinemia and unexplained recurrent early pregnancy loss.
Twenty-five consecutive hyperhomocysteinemic patients, ages 20–37 years, who had no biological children were studied, each patient having 3–5 episodes between the eighth and sixteenth week of amenorrhea, in the absence of any folate supplementation during pregnancy. The usual etiologies were ruled out; however, these previous pregnancies had not been systematically karyotyped and pathologic changes in the placentas had not been investigated. Laboratory tests revealed the absence of constitutional or acquired predisposition to thrombosis (normal antithrombin and protein C and S levels; negative antiphospholipid antibodies; and absence of factor V or II Leiden mutations) but showed a significant sex- and age-adjusted fasting total hyperhomocysteinemia (laboratory normal values for premenopausal women <12 mol/L) in two consecutive blood samples. The 25 patients were homozygous for the 5,10 methylene tetrahydrofolate reductase (MTHFR) C677T allele. Plasma creatinine (<110 mol/L) and vitamin B12 (>150 pmol/L) concentrations were normal; six patients had plasma folate concentrations lower than 5 nmol/L, and 13 had red blood cell folate contents lower than 350 nmol/L (165–310 nmol/L).
We first tested the effect of a 1-month high-dose folic acid, 15 mg daily, and vitamin B6, 750 mg daily, treatment on homocysteine plasma concentrations. This work had been approved by our local Institutional Ethics Committee, and agreement was obtained from the institutional review board. Informed consent was obtained from all patients. A folic acid and vitamin B6 association was chosen because of a first successful pregnancy in our index patient and because the vitamin B6 status of our patients was unknown. Preference was given to high doses in the absence of any consensus dose treatment. Most of the patients normalized their homocysteinemia; in this case, the same treatment was continued throughout the next pregnancy.
Twenty-two patients initiated a pregnancy during the 3-month period after the normalization of their homocysteinemia. Twenty patients were still pregnant after the sixteenth week of amenorrhea. No additional treatment was given. None of them developed gravidic hypertension, preeclampsia, elevated liver enzymes, low platelet syndrome, or abruptio placentae. All 20 pregnancies were successful with no evidence of any malformation. In the mothers, no abnormal bleeding was observed during delivery and they did not develop any clinically obvious thromboembolic complication. Premature birth occurred in four cases, with a nonsevere fetal growth retardation in two cases; postnatal evolution was good. Analysis of the placenta showed no evidence of abnormal vascular damage or tissue infarct.
Three months after pregnancy, the mothers' treatment was reduced by discontinuing vitamin B6 and by lowering daily folic acid doses to 5 mg. At present, nine of the women have subsequently become pregnant. The simplified vitamin supplementation was continued during pregnancies, leading to nine normal births.
The clinical association between hyperhomocysteinemia and recurrent unexplained miscarriages, despite the absence of a proven direct link, raises the question of what is the most adequate, available treatment that can be proposed to such patients. It has previously been shown that a 0.5 mg folic acid daily supplementation administered for 2 months in women with a history of unexplained recurrent miscarriage causes, in general, substantially reduced homocysteine concentrations: this effect was more distinct in women homozygous for the C677T mutation of the MTHFR gene. All our patients were homozygous for that mutation.
Fetal losses occurring between the eighth and sixteenth week of amenorrhea are mainly thought to depend on reduced chorionic vascularization, a fact which has been described in hyperhomocysteinemia; this point had not been evaluated in our patients during previous pregnancies. We thus cannot firmly establish that hyperhomocysteinemia was the cause of the patients' previous losses. We can only show that the single abnormal trait found during the investigations was a vitamin supplementation–responsive mild hyperhomocysteinemia, which was frequently associated, as supplementation was maintained, with a first successful pregnancy.
Our general purpose is not to discuss the hyperhomocysteinemia-mediated recurrent early pregnancy losses concept any further. Homocysteinemia is regulated by a complex metabolism in which vitamin B6 and folate are involved. These two vitamins may have, in themselves, some impact on embryonic and fetal growth. Evaluation of the vitamin B6 status of patients cannot be routinely performed; total plasma and/or red blood cell folates are very poorly related to levels of active folates (intracellular methylfolates). However, homocysteinemia increases in the case of vitamin B6 or intracellular methylfolates deficiency. In France, in the absence of neural tube defect antecedents, vitamin supplementation is not systematically prescribed and is not paid for by social funds. Therefore, we propose hyperhomocysteinemia as a marker for a subgroup of women more prone to experience a favorable pregnancy outcome when taking vitamin supplementation. New technologies for the routine testing of vitamin B6 and intracellular methylfolates will probably improve the understanding of homocysteine-related pregnancy outcome.
The clinical association between hyperhomocysteinemia and recurrent unexplained miscarriages, despite the absence of a proven direct link, raises the question of what is the most adequate, available treatment that can be proposed to such patients. It has previously been shown that a 0.5 mg folic acid daily supplementation administered for 2 months in women with a history of unexplained recurrent miscarriage causes, in general, substantially reduced homocysteine concentrations: this effect was more distinct in women homozygous for the C677T mutation of the MTHFR gene. All our patients were homozygous for that mutation.
Fetal losses occurring between the eighth and sixteenth week of amenorrhea are mainly thought to depend on reduced chorionic vascularization, a fact which has been described in hyperhomocysteinemia; this point had not been evaluated in our patients during previous pregnancies. We thus cannot firmly establish that hyperhomocysteinemia was the cause of the patients' previous losses. We can only show that the single abnormal trait found during the investigations was a vitamin supplementation–responsive mild hyperhomocysteinemia, which was frequently associated, as supplementation was maintained, with a first successful pregnancy.
Our general purpose is not to discuss the hyperhomocysteinemia-mediated recurrent early pregnancy losses concept any further. Homocysteinemia is regulated by a complex metabolism in which vitamin B6 and folate are involved. These two vitamins may have, in themselves, some impact on embryonic and fetal growth. Evaluation of the vitamin B6 status of patients cannot be routinely performed; total plasma and/or red blood cell folates are very poorly related to levels of active folates (intracellular methylfolates). However, homocysteinemia increases in the case of vitamin B6 or intracellular methylfolates deficiency. In France, in the absence of neural tube defect antecedents, vitamin supplementation is not systematically prescribed and is not paid for by social funds. Therefore, we propose hyperhomocysteinemia as a marker for a subgroup of women more prone to experience a favorable pregnancy outcome when taking vitamin supplementation. New technologies for the routine testing of vitamin B6 and intracellular methylfolates will probably improve the understanding of homocysteine-related pregnancy outcome.

[Dr.Vad]

Очередной опус французских коллег, оцененный настолько высоко, что удостоился публикации в журнале BLOOD:

Blood First Edition Paper, prepublished online January 22, 2004.
Submitted December 12, 2003
Accepted January 20, 2004

Low molecular weight heparin versus low-dose aspirinin women with one fetal loss and a constitutional thrombophilic disorder

Jean-Christophe GRIS*, Eric MERCIER, Isabelle QUERE, Geraldine LAVIGNE-LISSALDE, Eva COCHERY-NOUVELLON, Mederic HOFFET, Sylvie RIPART-NEVEU, Marie-Laure TAILLAND, Michel DAUZAT, and Pierre MARES
Hematology Laboratory, University Hospital, Nimes, France; Hematology Laboratory, University of Montpellier 1, Montpellier, France; Equipe d'Acceuil 2992, University of Montpellier 1, Nimes, France
Hematology Laboratory, University Hospital, Nimes, France
Equipe d'Acceuil 2992, University of Montpellier 1, Nimes, France
Hematology Laboratory, University Hospital, Nimes, France; Hematology Laboratory, University of Montpellier 1, Montpellier, France
Department of Gynecology and Obstetrics, University Hospital, Nimes, France


* Corresponding author; email: [Ссылки доступны только зарегистрированным пользователям ].


The prospective evaluation of the effect of thromboprophylaxis in women with one unexplained pregnancy loss from the 10th week of amenorrhoea was performed: 160 patients, with heterozygous factor V Leiden mutation, prothrombin G20210A mutation, or protein S deficiency, were given 5 mg folic acid daily before conception, to be continued during pregnancy, and low-dose aspirin, 100 mg daily or low-molecular weight heparin enoxaparin, 40mg, were taken from the 8th week. Twenty three of the 80 patients treated with low-dose aspirin and 69 of the 80 patients treated with enoxaparin had a normal live birth (OR 15.5, 95%CI 7-34, p<0.0001). Enoxaparin was superior to low-dose aspirin in each subgroup defined according to the underlying constitutional thrombophilic disorder. An associated protein Z deficiency, and/or positive anti-protein Z antibodies, were associated with poorer outcomes. The neonate weight was higher in the women successfully treated with enoxaparin and neonates small for gestational age were more frequent in patients treated with low-dose aspirin. No significant side-effects of the treatments could be evidenced in patients or newborns. As there is no argument to prove that low-dose aspirin may had been deleterious, these results support enoxaparin use during such at-risk pregnancies.