Clinical Review

Inherited thrombophilia and adverse pregnancy outcomes: What the evidence shows

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References

Several other studies have addressed the use of preconception aspirin (81 mg per day) and postconception unfractionated heparin among women with a history of habitual miscarriage. In 1 investigation involving 149 women whose recurrent miscarriages were due to a variety of procoagulant defects as well as factor V Leiden, fewer than 1% failed such therapy.25 Among a smaller population (n=34), treatment with postconception heparin resulted in decreased fetal loss, although the drug had no effect on other obstetric complications.26 In addition, among women with a combination of infertility, miscarriage, and thrombophilia, who experienced an 85% historical rate of early-pregnancy loss, that rate declined to 15% when either preconception enoxaparin (history of infertility) or post-conception enoxaparin (miscarriage alone) was administered.27

Folic acid supplementation and preeclamptic toxemia. Among all individuals—pregnant or not—folate supplementation significantly lowers homocysteine levels. Efficacy is greatest at the highest pretreatment homocysteine levels and least at the lowest pretreatment levels.28

Decreases in homocysteine levels are seen with 0.5 mg to 5 mg folic acid daily plus vitamin B6. No additional benefit is obtained with supplemental vitamin B12. Folate appears most beneficial in lowering homocysteine in the presence of MTHFR polymorphisms, as such individuals have higher homocysteine levels at given folate deficiencies than individuals without this polymorphism.29

Based on these observations, folic acid supplements have been examined for their role in preeclampsia and intrauterine growth retardation (IUGR).30 In 1 study, women with a history of preeclampsia; hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome; or eclampsia (n=181) and IUGR (n=26) were identified following delivery. Assessment in the nonpregnant state—by measurement of both fasting and post–methionine-load levels—indicated positive results (above the 97.5 percentile in healthy premenopausal females) in 17.7% of preeclamptic toxemia cases and 19.2% of IUGR cases.

Of this group, 27 women proceeded to daily supplementation with folate (5 mg) and vitamin B6 (250 mg) for a minimum of 10 weeks and achieved significantly decreased homocysteine levels (TABLE 2). (Interestingly, analysis by fasting levels alone would have missed more than 50% of the hyperhomocysteinemic women; their latent metabolic insufficiencies were documented only following load to the enzymatic system with methionine.) The supplementation protocol was continued preconception in 14 eligible women (11 had been hospitalized for preeclamptic toxemia and 3 had a history of IUGR), with a baby aspirin added daily at 10 to 12 weeks. Although the recurrence rate (64%) was unaltered from the expected, disease onset occurred later in pregnancy, resulting in infants delivered at significantly later gestational ages with better birth weights. These results anticipate reduced neonatal mortality and morbidity (TABLE 3).

TABLE 2

Folate supplementation decreases homocysteine levels in women*30

TIME OF ASSESSMENTMEAN FASTING HOMOCYSTEINE (UMOL/L)95% CIMEAN POST-LOAD HOMOCYSTEINE (UMOL/L)95% CI
Presupplementation16.613.0–20.168.560.8–76.2
Postsupplementation6.15.6–6.729.325.6–33.0
CI=confidence interval
*All subjects had a history of preeclampsia.

TABLE 3

Folic acid supplementation in women with a history of severe preeclampsia30

TIME OF ASSESSMENTGESTATIONAL AGE AT DELIVERY (WEEKS)BIRTH WEIGHT (G)
Presupplementation29.5±3.71,088±570
Postsupplementation36.7±2.22,867±648

Summary

With rapid expansion of human genome sequencing and low-cost assays for the detection of DNA sequence changes, the panel of suspect polymorphisms will likely increase. Randomized, controlled studies are needed to optimize the treatment choices.

Dr. Wilkins-Haug reports no affiliations or financial arrangements with any of the manufacturers of products mentioned in this article.

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