Michael J. Kupferminc

Severe preeclampsia and high frequency of genetic thrombophilic mutations

Objective To determine whether severe preeclampsia is associated with genetic thrombophilic mutations or other types of thrombophilia. Methods A case-control study compared 63 consecutive women with severe preeclampsia evaluated at our institution between November 1997 and April 1999 with 126 control women matched for age and ethnicity. All of these women were tested several months after delivery for mutations of factor V Leiden, methylenetetrahydrofolate reductase, and prothrombin gene; for deficiencies of protein C, protein S, and antithrombin-III; and for the presence of anticardiolipin antibodies. Results Thirty-five study women (56%) had a thrombophilic mutation compared with 24 control women (19%), P < .001. Seven other study women (11%) had other thrombophilias, compared with one control woman (0.8%), P < .01. Within the study group, women with thrombophilia delivered at an earlier gestational age, and their neonates birth weights were lower compared with those of women without thrombophilia. Conclusion Because thrombophilia was found in 67% of women with severe preeclampsia, we suggest that women who have severe preeclampsia should be tested for thrombophilia.

Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias.

OBJECTIVEnTo evaluate the benefit of combined low-molecular-weight (LMW) heparin and aspirin for prophylaxis in women carriers of thrombophilia who had previously suffered from severe obstetric complications.nnnMETHODSnThe 33 studied women had an earlier pregnancy complicated by severe preeclampsia, abruptio placentae, intrauterine growth retardation, or intrauterine fetal death. All were subsequently diagnosed as carrying inherited thrombophilias. In their subsequent pregnancy, prophylactic therapy consisting of LMW heparin 40 mg/day (Enoxaparin, Rhone-Poulenc-Rorer, France) and aspirin was administered. Patients who were found to be homozygotes for the methylenetetrahydrofolate reductase mutation also received folic acid supplementation throughout their pregnancy.nnnRESULTSnLow-molecular-weight heparin was well tolerated and none of the women or the newborns developed any hemorrhagic complications. Only three (9.1%) of the women developed pregnancy complications. The mean gestational age and the mean birth weight at delivery in the previously complicated pregnancies were 32.1 +/- 5.0 weeks and 1175 +/- 590 g, respectively, compared to 37.6 +/- 2.3 weeks and 2719 +/- 526 g, respectively, in the treated pregnancies (p < 0.001).nnnCONCLUSIONSnThis uncontrolled trial suggests that patients with obstetric complications and an inherited thrombophilia may benefit from treatment with combined LMW heparin and aspirin in subsequent pregnancies. However, this needs to be verified by controlled trials before considering clinical application.

Genetic hypofibrinolysis in complicated pregnancies

Objective To assess the hypofibrinolytic 4G/4G mutation of the plasminogen activator inhibitor (PAI-1) gene as a possible factor contributing to severe preeclampsia, abruptio placentae, fetal growth restriction, and stillbirth. Methods We compared 94 women from a previous report who had obstetric complications to 95 controls with normal pregnancies matched for ethnic background and age. We collected blood and extracted DNA after delivery. All subjects had been tested for thrombophilic mutations factor V Leiden, C677T mutation in the methylenetetrahydrofolate reductase gene, and the G20210A mutation in the prothrombin gene. In the present study we tested for the hypofibrinolytic 4G/4G mutation in the PAI-1 gene. Results Women who had obstetric complications were more likely than controls to be 4G/4G homozygotes, 32% (30 of 94) women versus 19% (18 of 95) controls, odds ratio (OR) and 95% confidence intervals (CI) 2.0 (1.02, 3.9). Mutations in the PAI-1 gene were independently associated with obstetric complications (OR 1.56, 95% CI 1.005, 2.43). Heterozygosity for the factor V Leiden mutation was more common in the 30 women who had PAI-1 4G/4G than in the 18 4G/4G controls (33% versus 0%, Fisher P = .008). Seventy-six percent of women had some form of thrombophilia or hypofibrinolysis compared with 37% of controls (Fisher P < .001). Conclusions Women with severe preeclampsia, abruptio placentae, fetal growth restriction, and stillbirth had increased incidence of the hypofibrinolytic 4G/4G mutation of the PAI-1 gene that is frequently associated with the thrombophilic factor V Leiden mutation, further predisposing them to thrombosis.

Neurodevelopmental and Cognitive Assessment of Children Born Growth Restricted to Mothers with and Without Preeclampsia

We examined neurological and intellectual outcome of growth‐restricted newborns of pregnancies complicated with preeclampsia and without preeclampsia. Seventy‐five consecutive growth restricted newborns (<5th percentile) were prospectively followed up at 6 months intervals. Newborns with major congenital malformations and newborns with evident intrauterine viral infection were excluded. At 3 years of age all children had detailed neurological examination and intellectual examination using the Mean developmental index (Stanford Binnet‐IQ). Eleven children were born to mother with preeclampsia (ACOG criteria), and 64 were born to mothers without a definite diagnosis of preeclampsia. Gestational age was 34.7 weeks in the preeclamptic group and 37 weeks in the non‐preeclamptic group. After adjustment for gestational age, there was no significant difference in the neurological exam score between groups, but the IQ was 85.5 in the preeclamptic group and 96.9 in the non‐preeclamptic group (p<0.03). We conclude that newborns born growth restricted after pregnancies complicated by preeclampsia have a lower IQ at the age of 3 years compared to growth‐restricted babies without preeclampsia.

The Significance of Clinical Signs and Blood Indices for the Diagnosis of Appendicitis during Pregnancy

Objective: To evaluate the significance of clinical signs and blood indices for the diagnosis of appendicitis during pregnancy. Sample: Of the 40,112 women delivering at our institution (January 1995 to June 2002), 38 women (0.094%) were operated due to the suspicion of appendicitis during pregnancy. Methods: Body temperature, clinical examination, white blood cell counts and lag time from arrival to operation were obtained for each patient. All women were operated with the clinical diagnosis of appendicitis, and their appendices were removed and examined by a pathologist. Results: Inflammatory appendix was discovered in 19 (0.047%) of the pregnancies with subsequent deliveries while a normal appendix was found in 19 of the 38 (50%) appendices removed. The group with normal appendix did not significantly differ from women with inflamed appendix with regard to gestational age at presentation, signs of peritoneal irritation, body temperature, leukocyte count, time elapsed between arrival and surgery, gestational age at delivery and birth weight. Conclusions: The accurate diagnosis of appendicitis during pregnancy is a difficult task requiring a very high level of suspicion and clinical skills and not merely relying upon laboratory and classic signs.

Management of severe postpartum hemorrhage by intrauterine irrigation with prostaglandin E2

Continuous intrauterine irrigation with minute amounts of prostaglandin E2 was used in 22 patients with severe postpartum hemorrhage unmanageable by conventional therapy. Twenty-one women were treated because of uterine atonic hemorrhage and one because of late postpartum hemorrhage from subinvolution. A quick tetanic contraction of the uterine muscle with dramatic and sustained hemostasis was achieved in all patients. The therapeutic response was continuous and uninterrupted regardless of the predisposing factors for the hemorrhage or the hemodynamic condition of the patients. No side effects were observed.