Once again, we are happy to discuss this matter fur-ther with Kalter.

Arnon Wiznitzer, MDAssociate Professor of Obstetrics and Gynecology, Director, Division ofMaternal-Fetal Medicine, Ben Gurion University/Soroka MedicalCenter, Beer Sheeva, Israel

E. Albert Reece, MDThe Abraham Roth Professor and Chairman, Professor of Obstetrics andGynecology and of Internal Medicine, Director, Division of Maternal-Fetal Medicine, Temple University School of Medicine, OutpatientBuilding, 7th Floor, 3401 N Broad St, Philadelphia, PA 19140

ANNOTATED BIBLIOGRAPHY

1. Akashi M, Akazawa S, Akazawa M, Trocino R, Itashimoto M,Maeda Y, et al. Effects of insulin and myo-inositol on embryogrowth and development during early organogenesis in strepto-zotocin-induced diabetic rats. Diabetes 1991;40:1574-9. Rat embryos were examined on the 11th gestational day for evi-dence of growth restriction and presence of neural lesions.

2. Goldman AS, Baker L, Piddington R, Marx B, Herold R, Egler J.Hyperglycemia-induced teratogenesis is mediated by a func-tional deficiency of arachidonic acid. Proc Natl Acad Sci U S A1985;82:8227-31. These investigators demonstrated the protective effects ofarachidonic acid against neural tube fusion defects in diabeticpregnant rats at days 9 to 12 of gestation.

3. Eriksson UJ. Importance of genetic predisposition and maternalenvironment for the occurrence of congenital malformations inoffspring of diabetic rats. Teratology 1988;37:365-74. These investigators examined rat embryos for malformations,including severe malrotation, abnormally open neural tube, orheart hypertrophy, on day 11 of gestation.

4. Cagliero E, Forsberg H, Sals R, Lorenzi M, Eriksson UJ.Maternal diabetes induces increased expression of extracellularmatrix components in rat embryos. Diabetes 1993;42:975-80.Investigators examined rat embryos at days 11 and 12 of gesta-tion to determine crown-rump length, somite number, and mal-formations, including delayed closure of a single neural poreand severe malrotation with open neural pore.

5. Sussman I, Matschinsky FM. Diabetes affects sorbitol and myo-inositol levels of neuroectodermal tissue during embryogenesisin rat. Diabetes 1988;37:974-8l. Investigators measured the myoinositol content of neuroecto-dermal neural tissue in embryos 10 and 12 days old (time coin-cident with normal neural tube fusion).

6. Shuey DL, Sadler TW, Lauder JM. Serotonin as a regulator ofcraniofacial morphogenesis: site specific malformations follow-ing exposure to serotonin uptake inhibitors. Teratology1992;46:367-78. The critical period of sertraline exposure occurred on days 10to 11, and developmental anomalies were evaluated.

7. Hod M, Star S, Passonneau J, Unterman TG, Freinkel N.Glucose-induced dysmorphogenesis in the cultured rat concep-tus; prevention by supplementation with myo-inositol. Isr J MedSci 1990;20:641-4. Growth restriction and dysmorphogenesis in the rat conceptusare accompanied by diminished tissue myoinositol after culturefrom day 9.5 to day 11.5 of development in the presence of in-creased amounts of glucose.

6/8/101135

Unusual cases of severe thrombotic episodes dur-ing the peripartum periodTo the Editors: We read with interest the findings ofGrandone et al concerning the potential role of geneticmutation in the development of venous thromboem-

bolism during pregnancy (Grandone E, Margaglione M,Colaizzo D, D’Andrea G, Cappucci G, Brancaccio V, DiMinno G. Genetic susceptibility to pregnancy-related ve-nous thromboembolism: Roles of factor V Leiden, pro-thrombin G20210A, and methylenetetrahydrofolate re-ductase C677T mutations. Am J Obstet Gynecol1998;179:1324-8). In 1998, our hospital obstetrics servicerecorded 2800 deliveries; both patients with preeclamp-sia and those diagnosed with thrombotic complicationsare screened for factor V Leiden and methylenetetrahy-drofolate reductase (MTHFR C677T) mutations with thepolymerase chain reaction–restriction fragment lengthpolymorphism technique. In a study of 140 obstetric pa-tients seen at our institution, 18.8% of those experienc-ing preeclampsia were found to be positive for factor VLeiden mutation.1

Whereas the frequency of thrombotic episodes inpregnant carriers of factor V Leiden has not yet beenstudied in detail, we recently documented 3 unusualcases of severe thrombotic episodes during the peripar-tum period. All patients were determined by polymerasechain reaction–restriction fragment length polymor-phism to be carriers of factor V Leiden mutation, and inaddition they were heterozygotic for MTHFR C677T mu-tation. Patient 1 was a 26-year-old woman with no indica-tions of preeclampsia, who was delivered of a dysmaturefemale neonate via cesarean during gestastional week 36.On the fifth postoperative day the patient experiencedtonic-clonic convulsions with subsequent motor aphasiaand left hemiplegia. Magnetic resonance imaging an-giography revealed thrombosis of the sagittal and lefttransverse sinus of dura mater. In patient 2, a 32-year-oldprimiparous woman, preeclampsia developed during the36th gestational week. After delivery via cesarean, she ex-perienced eclamptic seizures accompanied by HELLP(hemolysis, elevated liver enzyme levels, and low plateletcount) syndrome. She died the next day, and autopsy re-vealed cerebral hemorrhage as the cause of death.Patient 3, a 27-year-old primiparous woman, began tohave clinical symptoms of HELLP syndrome during week28 of gestation. Three days after delivery by cesarean, se-vere vertigo developed, accompanied by tinnitus. A diag-nosis of vertebrobasilar circulation failure was made withthe use of brain stem auditory evoked potentials andelectronystagmography.

Although we describe only 3 cases here, the severity ofthese cases suggests a potentially beneficial role in appro-priately screening pregnant women at risk for factor VLeiden and MTHFR C677T mutations. By initiation ofprophylactic therapy when indicated, severe complica-tions may be minimized or avoided entirely. We echo thecall of Kupferminc et al2 and Sibai et al3 for further in-vestigation into the risk of thromboembolism in preg-nant carriers of these mutations, as well as additionalevaluation of the safety and efficacy of existing prophy-lactic methods.

Zoltan Ban, MD, Janos Rigo, Jr, MD, and Balint Nagy,PhD

1st Department of Obstetrics and Gynecology, Semmelweis UniversityMedical School, Baross u. 27, 1088 Budapest, Hungary

1040 Letters October 1999Am J Obstet Gynecol

REFERENCES

1. Nagy B, Toth T, Rigo J Jr, Karadi I, Romics L, Papp Z. Detectionof factor V Leiden mutation in severe pre-eclamptic Hungarianwomen. Clin Genet 1998;53:478-81.

2. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, JaffaA, et al. Increased frequency of genetic thrombophilia inwomen with complications of pregnancy. N Engl J Med1999;340:9-13.

3. Sibai BM. Thrombophilias and adverse outcomes of preg-nancy—what should a clinician do? N Engl J Med 1999;340:50-2.

6/8/100639

ReplyTo the Editors: An increasing number of data has been pro-duced in recent years about the association between in-herited causes of thrombophilia and obstetric complica-tions. All of these were case-control studies; this kind ofstudy is usually retrospective and does not provideprospective evaluations of pregnancy (maternal andfetal) outcomes in women with one or more mutationsversus women without. To date, the selection criteriaused for the case-control studies evaluating the presenceof factor V Leiden, the prothrombin A20210 allele, andthe TT MTHFR genotype in women with preeclampsiaare quite different. Moreover, Kupferminc et al1 consid-ered women with different types of obstetric complica-tions.

A study we have conducted in women with gestationalhypertension2 showed the presence of an association be-tween factor V Leiden and prothrombin A20210 muta-tions and the occurrence of gestational hypertension re-gardless of proteinuria. A logistic regression analysis,performed to evaluate the impact of potential confound-ing variables (ie, parity), showed that both the mutationsand nulliparity are independently associated with gesta-tional hypertension.

In our series we registered 4 deep venous thromboses:One of them occurred in a patient with proteinuria car-rying the prothrombin A20210 gene variant. Kupfermincet al did not observe thrombosis in their patients.

The low incidence of venous thrombosis in our casesand those of Kupferminc et al may be explained by ashort exposure time to risk factors, the mean age of thewomen being lower than the mean age observed in seriesof women with venous thrombosis. Because women withobstetric complications are younger than patients in-cluded in thrombosis series and are more frequently car-riers of inherited thrombophilic abnormalities, it couldbe hypothesized that the presence of obstetric complica-tions is predictive for the occurrence of venous throm-boembolism.

The observations of Ban et al are interesting, and it isconceivable that a pharmacologic treatment of obstetriccomplications could be beneficial. We are now studying aseries of pregnant women carrying one or more of thesegenetic variants; some of these are parous women with ahistory of uneventful pregnancies in the absence ofthrombotic events, whereas others had a history of still-birth, gestational hypertension with or without protein-

uria, or venous thrombosis. Prospective evaluations of fe-tomaternal outcomes are possible, and a randomized,controlled trial, establishing whether pharmacologictreatment or prophylaxis of obstetric complications canameliorate the outcomes, could be designed. Moreover,such studies could answer the question whether it is con-ceivable to treat women (or which subgroup of women)at risk for obstetric abnormality.

Elvira Grandone, MD, Maurizio Margaglione, MD, andGiovanni Di Minno, MD

Arteriosclerosis and Thrombosis Unit, I.R.C.C.S. ì Casa Sollievo dellaSofferenzaî, S. Giovanni Rotondo (FG), 71013 Italy

REFERENCES

1. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, JaffaA, et al. Increased frequency of genetic thrombophilia inwomen with complications of pregnancy. N Engl J Med1999;340:9-13.

2. Grandone E, Margaglione M, Colaizzo D, Cappucci G,Scianname N, Montanaro S, et al. Prothrombotic genetic riskfactors and the occurrence of gestational hypertension with orwithout proteinuria. Thromb Haemost 1999;81:349-52.

6/8/100640

The clinical significance of intermittent sinusoidalfetal heart rateTo the Editors: The cases reported by Kang and Boehm(Kang AH, Boehm FH. The clinical significance of inter-mittent sinusoidal fetal heart rate. Am J Obstet Gynecol1999;180:151-2) were most interesting. Among a reviewof an unknown number of cases with bad outcomes, thesinusoidal pattern was found (intermittently) in 12 cases.

It is very easy to reach false conclusions about an asso-ciation between 2 events in any retrospective review ofcases. This is especially true when no controls are in-cluded. For example, I feel confident that a review of thebad outcomes in my own institution would show a mater-nal leukocyte count >5000/mm3 in nearly all cases. Thisdoes not mean that there is any association between badoutcome and leukocyte count >5000/mm3.

It is well known that the sinusoidal pattern occurs atleast intermittently in 4% to 5% of fetuses who are moni-tored for at least 10 minutes during labor.1 The outcomein such cases is nearly uniformly good.1-3

The first sentence of the article states the following:“Since the original description of sinusoidal fetal heartrate (FHR), its definition and significance have been de-bated.”

The debate continues.Charles Egley, MD

Director of Maternal and Fetal Medicine, Methodist Medical Center ofIllinois, 221 NE Glen Oak, Peoria, IL 61636

REFERENCES

1. Egley CC, Bowes WA Jr, Wagner D. Sinusoidal fetal heart ratepattern during labor. Am J Perinatol 1991;8:197-20.

2. Johnson TRB Jr, Compton AA, Rotmensch J, Work BA Jr,Johnson JWC. Significance of the sinusoidal fetal heart rate pat-tern. Am J Obstet Gynecol 1981;139:446-53.

Volume 181, Number 4 Letters 1041Am J Obstet Gynecol