CONTROVERSIES IN OB/GYN

Do thrombophilias cause early first-trimester miscarriages?

By Henry Roqué, MD

No. Large studies do not support an association.

In selected populations the inherited thrombophilias—factor V Leiden (FV) gene mutation, the prothrombin gene mutation G20210A, and homozygotes for the thermolabile variant of methylenetetrahydrofolate reductase—have prevalences of 5%, 2%, and 11%, respectively. Maternal thrombophilias clearly have been associated with second- and third-trimester adverse pregnancy outcomes. Placental infarction is the lesion most commonly noted in these pregnancies. Slow flow rates and large surface areas (over 100 m²) place the intervillous space at high risk for infarction.

First-trimester losses, on the other hand, have not been consistently associated with maternal thrombophilia. In part, this may be because of difficulties in evaluating first-trimester losses. The first problem is potential bias toward early pregnancy identification in patients who previously had an adverse pregnancy outcome. Estimates indicate that although 40% of conceptions are lost, only 15% of these cases are clinically recognized. Patients who have previously lost a pregnancy, however, may be anxious and perform sensitive home pregnancy tests at the first suggestion of pregnancy. The result may be identification of more early pregnancy losses by women with reproductive histories suggestive of thrombophilia. Comparisons of such a group with a general obstetric population, then, could very well suggest a falsely inflated prevalence of early pregnancy losses.

The second problem is the lack of physiologic uniformity of the first trimester. Division of pregnancy into three equal trimesters is convenient, but bears little relevance to fetal physiologic alterations. Rather than viewing the first trimester as uniform, it may be prudent to divide it into oxygen-poor embryonic and oxygen-rich fetal periods.

The role of intervillous circulation

Before patent intervillous circulation develops at 8 to 10 weeks' gestation, the fetus thrives in a relatively hypoxic environment. Using Doppler velocimetry, Jaffe and colleagues reported no noticeable blood flow within the intervillous space before the end of the first trimester.¹ Ex vivo examination of hysterectomy specimens has demonstrated obstruction of blood flow in the intervillous space by trophoblastic plugs until the end of the first trimester.¹ Consistent with this, Rodesch and colleagues found that at 8 to 10 weeks, the placental pO₂ is 18 mm Hg and increases to 60 mm Hg by 12 to 13 weeks.² Finally, coincident with this increase in oxygenation, there is a dramatic increase in superoxide dismutase.³ Oxygen is the final electron acceptor from the electron transport chain, producing the superoxide anion. This highly reactive oxygen intermediate is rapidly converted by superoxide dismutase to much-less-damaging hydrogen peroxide. Taken together, these findings suggest that a comparatively hypoxic environment may not only permit but may be required for embryonic development.

Testing the hypothesis

We hypothesized that maternal thrombophilias would not be associated with pregnancy wastage until the intervillous circulation was patent. We chose to examine a cohort of nearly 500 women referred for a history of recurrent pregnancy loss, preeclampsia, intrauterine fetal demise, intrauterine growth restriction, and abruption. We compared early first-trimester losses in women with and without inherited or acquired thrombophilia.

We noted an inverse relationship between the prevalence of maternal thrombophilia and number of losses at less than 10 weeks.⁴ Conversely, we noted a trend toward increasing prevalence of maternal thrombophilia with increasing losses between 10 to 14 weeks.⁴ Similarly, in smaller studies, Kutteh and colleagues and Nowak-Gottl and colleagues each independently reported no association between recurrent first-trimester pregnancy loss and maternal thrombophilia.^5,6

In our cohort, maternal thrombophilia paradoxically appeared protective of recurrent losses at less than 10 weeks. Consistent with this finding, Gopel and colleagues reported increased success with IVF in heterozygotes for the FV gene mutation, compared to those without the mutation (90% vs. 49%, P<0.05).⁷

Taken together, these findings support the hypothesis that early pregnancy requires an oxygen-depleted environment, and that augmentation of the trophoblastic blockade of the intervillous space in the early first trimester may help a pregnancy to progress.

It has been estimated that roughly 60% of early first-trimester losses are caused by aneuploidy. We therefore postulated that if maternal thrombophilias caused first-trimester loss, maternal thrombophilia would be significantly more prevalent in women who experienced only euploid first-trimester losses than in women who experienced only aneuploid first-trimester losses. We identified 48 patients who experienced only aneuploid first-trimester losses and compared them to 44 patients who experienced only euploid losses. There was no difference in the prevalence of maternal thrombophilia between these groups (euploid losses 18.2% vs. aneuploid losses 22.9%).⁴

Conclusion

Early first-trimester losses do not appear to be positively associated with maternal thrombophilia, a finding consistent with placental physiologic alterations. Patients with isolated or recurrent first-trimester losses who present for evaluation are an emotionally vulnerable population. Depending on patient ethnicity, testing may result in positives, which inevitably culminate in use of unproven therapies.

REFERENCES

1. Jaffe R. Investigation of abnormal first-trimester gestations by color Doppler imaging. J Clin Ultrasound. 1993;21:521-526.

2. Rodesch F, Simon P, Donner C, et al. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol. 1992;80:283-285.

3. Watson AL, Skepper JN, Jauniaux E, et al. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab. 1998;83:1697-1705.

4. Roqué H, Paidas M, Rebarber A, et al. There is no association between maternal thrombophilia and recurrent first-trimester loss. Am J Obstet Gynecol. 2001;184:S15. Abstract nr0031.

5. Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril. 1999;71:1048-1053.

6. Nowak-Gottl U, Sonntag B, Junker R, et al. Evaluation of lipoprotein(a) and genetic prothrombotic risk factors in patients with recurrent foetal loss. Thromb Haemost. 2000;83:350-351.

7. Gopel W, Ludwig M, Junge AK, et al. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet. 2001;358:1238-1239.

Dr. Roqué is Assistant Professor of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Conn.

Reader Response Form

Do thrombophilias cause early first-trimester miscarriages?

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Henry Roque. Do thrombophilias cause early first-trimester miscarriages? Contemporary Ob/Gyn Mar. 1, 2004;49:51-59.