HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Many, A. Articles by Kupferminc, M. J. Search for Related Content PubMed PubMed Citation Articles by Many, A. Articles by Kupferminc, M. J.

Third-Trimester Unexplained Intrauterine Fetal Death Is Associated With Inherited Thrombophilia

From the Lis Maternity Hospital and Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.

Address reprint requests to: Michael J. Kupferminc, MD, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv, 64239, Israel; E-mail: tmcobgyn{at}tasmc.health.gov.il.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
OBJECTIVE: To determine the risk of thrombophilias in women with unexplained intrauterine fetal deaths (IUFD).

METHODS: All women with IUFD at 27 weeks’ gestation or greater were initially assessed during a period of 26 months. Subjects with multiple pregnancies, congenital anomalies, intrauterine infection, chorioamnionitis, immune hydrops, diabetes mellitus, previous thromboembolism, and severe hypertensive disease were excluded. The remaining 40 women with unexplained IUFD (study group) were matched for age and ethnicity with 80 healthy women who had at least one normal pregnancy (control group). All participants were tested at least 2 months after delivery for mutations of factor V Leiden, prothrombin gene, methylenetetrahydrofolate reductase, and for deficiencies of protein S, protein C, and antithrombin III. They were also tested and found to be negative for anticardiolipin antibodies.

RESULTS: The gestational age at delivery and birth weight were significantly lower in the study group. The prevalence of inherited thrombophilias was 42.5% in the study group compared with 15% in the control group (odds ratio 2.8, 95% confidence interval 1.5, 5.3, P = .001). The prothrombin mutation and protein S deficiency rates were significantly higher in the study group (odds ratio 2.3, 95% confidence interval 1.3, 4.0, and odds ratio 3.2, 95% confidence interval 2.4, 4.1, respectively).

CONCLUSION: Third-trimester IUFD is significantly associated with thrombophilias. These findings suggest that thrombophilia work-ups should be part of IUFD investigations and may have therapeutic and prognostic implications in future pregnancies.

Thrombophilic conditions are abnormalities of the coagulation system, which can be either inherited or acquired. Unexplained late intrauterine fetal death (IUFD) is an unexpected devastating complication in an otherwise normal pregnancy and remains an unresolved problem in obstetrics. Third-trimester fetal death is not common in developed countries, with an incidence of 0.5–0.2%.^1–3 There are several known causes for IUFD, among them major congenital anomalies, hydrops fetalis, severe maternal hypertensive disease, maternal diabetes mellitus, intrauterine infection, as well as some other less common etiologies. Nevertheless, after excluding all known etiologies, the primary cause of late fetal death very often remains unexplained.¹

Placental changes related to hypercoagulability are detected in many cases of IUFD. These changes include infarcts, thrombosis, and obliteration of blood vessels. An association between thrombophilia and "unexplained fetal demise" has been recently reported.^4–6 However, the number of studies is very few, the definition of IUFD varies, and cases of severe hypertensive disorders are usually included. In the present study, we wanted to assess the risk of thrombophilias in women with "unexplained" third-trimester fetal death after excluding severe hypertensive disorders.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
All women with IUFD diagnosed at 27 weeks’ gestation or greater at our institution during a period of 26 months (1997–1999) were assessed and initially considered for study enrollment. Subjects with multiple pregnancies, major congenital anomalies, intrauterine infection, chorioamnionitis, immune hydrops, or diabetes mellitus were then excluded. Other exclusion criteria were women with severe hypertensive disorders⁷ (n = 6) or previous thromboembolism (n = 0). During this period, we had 18,503 deliveries. Thus, the rate of IUFD at 27 weeks’ gestation or greater, which had been investigated in the present study, was 0.36% (66 cases). Twenty-six women were excluded because of multiple pregnancies (n = 8), hypertension (n = 6), listeriosis (n = 2), chorioamnionitis (n = 2), congenital anomalies (n = 5), immune hydrops (n = 2), and diabetes mellitus (n = 1). Each of the remaining 40 women with unexplained IUFD was matched for age and ethnicity (ie, Ashkenazi or non-Ashkenazi) with two healthy women who had at least one uneventful pregnancy and who delivered during the study period (control group, n = 80). Each woman who had been identified as having an unexplained IUFD was matched with the next two suitable women to give birth in our institution.

All the 120 women in the study and control groups were assessed for the presence of thrombophilia at least 8 weeks postpartum. The thrombophilia work-up included factor V Leiden mutation,⁸ homozygosity for a cytosinethymine mutation at nucleotide 677 in the methylenetetrahydrofolate reductase gene,⁹ prothrombin mutation,¹⁰ protein C deficiency, protein S deficiency, and antithrombin III deficiency. They were also tested and found to be negative for anticardiolipin antibodies. Thrombophilia assays were performed as previously described.¹¹ The study was approved by our institutional review board, and informed consent was obtained from all the participating women.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The gestational week at delivery and the birth weight were significantly lower in the study group compared with the control group (Table 1). There were 18 and 40 primiparous women in the study and control groups, respectively. The frequency of inherited thrombophilias was 42.5% in the study group compared with 15% in the control group (odds ratio 2.8, 95% confidence interval 1.5, 5.3, P = .001) (Table 2). All factor V Leiden and prothrombin mutations were heterozygote. One woman in the study group and none in the control group had multiple thrombophilias, methylenetetrahydrofolate reductase, and prothrombin mutation, and she was counted only once. The incidence of the prothrombin mutation and protein S deficiency was significantly higher in the study group. The incidence of factor V Leiden was not significantly different between the groups (Table 2).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The findings in this study demonstrated the presence of thrombophilia in 42.5% of cases in women with pregnancies complicated by unexplained IUFD at 27 weeks’ gestation or greater. Several recent reports have shown an association between IUFD and maternal thrombophilias.^4–6 They, however, included pregnancies complicated by severe hypertensive disorders in the evaluation, despite the fact that IUFD might be attributed to maternal hypertensive disease and its complications. Severe hypertensive disorder is associated with thrombophilia,¹² and IUFD is sometimes a complication of severe hypertensive disorder. We excluded these women in the current study. We found that the incidence of the prothrombin mutation was significantly higher in women with IUFD. This finding was also described in the recent study by Martinelli et al.⁴ Protein S deficiency was also more prevalent in our study group, a finding also reported by Preston et al⁶ in women with stillbirth at greater than 28 weeks’ gestation.

The factor V Leiden incidence was higher in the study group, but it did not reach statistical significance. This finding is in contrast to those of Martinelli et al,⁴ our previous findings,¹¹ and those of Gris et al,⁵ but in agreement with the findings of Preston et al.⁶ This difference between the studies may derive from lack of power in our study or from a different study design because we included only women at 27 weeks’ gestation or greater and excluded women with severe hypertensive disorders. Martinelli et al⁴ had shown that the incidence of factor V Leiden and the prothrombin mutations were significantly higher in women with an IUFD at 20 weeks’ gestation or greater. They found an incidence of 16% of either factor V Leiden or the prothrombin mutation in the study group compared with 6% in the control group. In our study, the incidence was 20% of either factor V Leiden or prothrombin mutation in the women with IUFD and 7.7% in the control group.

The gestational ages and birth weights were lower in the IUFD group. This was a result of the study design, where only uneventful term pregnancies were included in the control group. We did not find any difference in the gestational age or birth weight between women with IUFD with and without thrombophilia. It had been previously shown that women with severe preeclampsia and thrombophilia had lower gestational age at delivery and lower birth weight of the newborn compared with women without thrombophilia.¹¹ It should be noted, however, that most of the inherited thrombophilias had been described in the last few years and that there might be additional undiscovered thrombophilic women in the study group.

In the group of women with IUFD, 50% of multiparous women with thrombophilia but only 16% of multiparous women without thrombophilia experienced a previous major pregnancy complication. These previous complications included intrauterine growth retardation, preeclampsia, and placental abruption. This finding emphasizes the importance of carrying out a thrombophilia work-up in every woman with adverse pregnancy outcome because of the relatively high rate of recurrence. The type of complication may change in a subsequent pregnancy (ie, IUFD in the present pregnancy and intra-uterine growth retardation in a subsequent one).

Abnormal placental findings related to hypercoagulation have been recently reported in IUFD.⁴ In addition, our group recently described higher single and multiple placental infarcts in placentas of women with adverse pregnancy outcome and thrombophilia compared with placentas of women with adverse pregnancy outcome without thrombophilia.¹³ Dizon-Townson et al¹⁴ found a ten-fold increase of placental infarcts of more than 10% in placentas of spontaneous miscarriage when factor V Leiden was identified. It is suggested that one of the mechanisms of association between thrombophilia and IUFD is through abnormal placental perfusion and hemostasis. In the current study, however, we do not address the issue of placental findings in women with unexplained IUFD. Another limitation of this study is the lack of fetal genetic data, given that fetal thrombophilia may also have an impact on outcome of pregnancy.

In conclusion, we found an association between thrombophilias and third-trimester unexplained IUFD. We believe that a work-up for thrombophilias should be included in the evaluation of women experiencing third-trimester IUFD. Further studies should be focused on the treatment of these women in future pregnancies with the aim of reducing recurrent pregnancy complications.

	Footnotes

 
The authors would like to dedicate this paper to one of the coauthors, Professor Amiram Eldor, Head of our Hematology Institute and a world-renowned leader in the field of thrombosis, who died in an airplane crash in Switzerland on November 25, 2001.

PII S0029-7844(02)01938-5

Received August 8, 2001. Received in revised form December 3, 2001. Accepted December 26, 2001.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Yudkin PL, Wood L, Redman CW. Risk of unexplained stillbirth at different gestational ages. Lancet 1987;1: 1192–4.[Medline]

2. Naeye RL. Causes of perinatal mortality in the US collaborative perinatal project. JAMA 1977;238:228–32.[Abstract]

3. Ogunyemi D, Jackson U, Buyske S, Risk A. Clinical and pathologic correlates of stillbirths in a single institution. Acta Obstet Gynecol Scand 1998;77:722–8.[Medline]

4. Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000;343: 1015–8.[Abstract/Free Full Text]

5. Gris JC, Quere I, Monpeyroux F, Mercier E, Ripart-Neveu S, Tailand M, et al. Case control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent. Thromb Haemost 1999;81:891–9.[Medline]

6. Preston FE, Rosendaal FR, Walker ID, Briet E, Berntop E, Conard J, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996;348:913–6.[Medline]

7. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. ACOG technical bulletin no. 219. Washington, DC: American College of Obstetricians and Gynecologists, 1996.

8. Brenner B, Zivlin A, Lanir N, Greengard JS, Griffin JH, Seligsohn U. Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of previously described homozygous protein C deficient newborn with massive thrombosis. Blood 1996;88: 877–80.[Abstract/Free Full Text]

9. Frosst P, Bloom HJ, Milos R. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10: 111–3.[Medline]

10. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3' — untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–703.[Abstract/Free Full Text]

11. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9–13.[Abstract/Free Full Text]

12. Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000; 96:45–9.[Abstract/Free Full Text]

13. Many A, Schreiber L, Rosner S, Lessing JB, Eldor A, Kupferminc MJ. Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia. Obstet Gynecol 2001;98:1041–4.[Abstract/Free Full Text]

14. Dizon-Townson DS, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1997;177:402–5.[Medline]

This article has been cited by other articles:

				S. M. Bates, I. A. Greer, I. Pabinger, S. Sofaer, and J. Hirsh Venous Thromboembolism, Thrombophilia, Antithrombotic Therapy, and Pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 844S - 886S. [Abstract] [Full Text] [PDF]

				A. G. Eller, D. W. Branch, and J. L. B. Byrne Stillbirth at Term Obstet. Gynecol., August 1, 2006; 108(2): 442 - 447. [Full Text] [PDF]

				A. Huber, C. Grimm, S. Jirecek, R. Zeillinger, K. Heim, P. Husslein, and L. Hefler An lnterleukin-6 Gene Promoter Polymorphism and Unexplained Late Intrauterine Fetal Death: A Multicenter Study Reproductive Sciences, January 1, 2005; 12(1): 33 - 36. [Abstract] [PDF]

				C. J. Glueck, P. Wang, N. Goldenberg, and L. Sieve Pregnancy Loss, Polycystic Ovary Syndrome, Thrombophilia, Hypofibrinolysis, Enoxaparin, Metformin Clinical and Applied Thrombosis/Hemostasis, October 1, 2004; 10(4): 323 - 334. [Abstract] [PDF]

				B. S. Donahue Factor V Leiden and Perioperative Risk Anesth. Analg., June 1, 2004; 98(6): 1623 - 1634. [Abstract] [Full Text] [PDF]

				L. Hefler, S. Jirecek, K. Heim, C. Grimm, G. Antensteiner, R. Zeillinger, P. Husslein, and C. Tempfer Genetic Polymorphisms Associated With Thrombophilia and Vascular Disease in Women With Unexplained Late Intrauterine Fetal Death: A Multicenter Study Reproductive Sciences, January 1, 2004; 11(1): 42 - 44. [Abstract] [PDF]

				Late Unexplained Intrauterine Fetal Demise Linked with Thrombophilias Journal Watch (General), May 31, 2002; 2002(531): 7 - 7. [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Many, A. Articles by Kupferminc, M. J. Search for Related Content PubMed PubMed Citation Articles by Many, A. Articles by Kupferminc, M. J.