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

      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 (
      • Steegers-Theunissen R.P.M
      • Boers G.H.J
      • Trijbels J.M.F
      • Eskes T.K.A.B
      Hyperhomocysteinemia and recurrent abortion or abruptio placentae.
      ). We recently confirmed the prevalence of hyperhomocysteinemia in women from our region in Mediterranean France (
      • Quéré I
      • Bellet H
      • Hoffet M
      • Janbon C
      • Marès P
      • Gris J.C
      A woman with five consecutive fetal deaths case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages.
      ). 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 (Table 1) , 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 μmol/L; (
      • Quéré I
      • Bellet H
      • Hoffet M
      • Janbon C
      • Marès P
      • Gris J.C
      A woman with five consecutive fetal deaths case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages.
      )) in two consecutive blood samples. The 25 patients were homozygous for the 5,10 methylene tetrahydrofolate reductase (MTHFR) C677T allele. Plasma creatinine (<110 μmol/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).
      TABLE 1Effect of a high-dose 1-month induction treatment with 15 mg daily of folic acid and 750 mg daily of vitamin B6 on homocysteine plasma concentrations and obstetrical events under maintenance vitamin therapy in 17 childless women with unexplained recurrent miscarriages and initial hyperhomocysteinemia.
      NA, not applicable.
      ,
      Quéré. Homocysteine, early fetal loss and treatment.Fertil Steril 2001.
      Patient no. (n = 25)Age (y)No. of previous miscarriagesHCY level (μmol/L)Pregnancy while receiving high-dose vitamin therapyNew pregnancy while receiving low-dose vitamin therapy
      5 mg of folic acid daily.
      Before treatmentAfter treatmentPositive pregnancy testNo. of weeks of amenorrhea
      No. of weeks of amenorrhea reached by an evolutive pregnancy.
      Live birthPremature
      No. in parentheses represents the no. of weeks of amenorrhea at the moment of delivery.
      birth
      Positive pregnancy testNormal living birth
      816
      1253266++++NA
      2253225++++NA
      3253255++
      4343133++++++
      5303198
      6253185++++NA
      7333197+++++ (36)++
      8243258++++NA
      9273387
      10273266++++NA
      11263249++++++
      12233267++++++
      16203235+++++ (36)++
      17243289++++++
      18293254++++NA
      19344239++++NA
      20334284+++++ (33)NA
      21294258++
      223242911++++NA
      23354258+++++ (35)NA
      24274227++++++
      25254195++++++
      26375207++++NA
      273055115NA
      28285349++++++
      Total22222020499
      legend NA, not applicable.
      a No. of weeks of amenorrhea reached by an evolutive pregnancy.
      b No. in parentheses represents the no. of weeks of amenorrhea at the moment of delivery.
      c 5 mg of folic acid daily.
      legend Quéré. Homocysteine, early fetal loss and treatment.Fertil Steril 2001.
      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 (
      • Quéré I
      • Bellet H
      • Hoffet M
      • Janbon C
      • Marès P
      • Gris J.C
      A woman with five consecutive fetal deaths case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages.
      ) 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 (Table 1); 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 (Table 1). 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 (
      • Nelen W.L
      • Blom H.J
      • Thomas C.M
      • Steegers E.A
      • Boers G.H
      • Eskes T.K
      Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages.
      ). 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.

      References

        • Steegers-Theunissen R.P.M
        • Boers G.H.J
        • Trijbels J.M.F
        • Eskes T.K.A.B
        Hyperhomocysteinemia and recurrent abortion or abruptio placentae.
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        • Quéré I
        • Bellet H
        • Hoffet M
        • Janbon C
        • Marès P
        • Gris J.C
        A woman with five consecutive fetal deaths.
        Fertil Steril. 1998; 69: 152-154
        • Nelen W.L
        • Blom H.J
        • Thomas C.M
        • Steegers E.A
        • Boers G.H
        • Eskes T.K
        Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages.
        J Nutr. 1998; 128: 1336-1341