Donna Dizon-Townson

The factor V Leiden mutation may predispose women to severe preeclampsia

OBJECTIVE A recent study showed that resistance to activated protein C may underlie some cases of severe preeclampsia. A common missense mutation in the factor V gene, the Leiden mutation, is the most frequent genetic cause of resistance to activated protein C. Our objective was to determine whether this mutation is more prevalent in patients with severe preeclampsia than in normotensive controls. STUDY DESIGN Deoxyribonucleic acid was extracted from whole blood of 158 gravid women meeting criteria of The American College of Obstetricians and Gynecologists for severe preeclampsia and 403 normotensive gravid women. The polymerase chain reaction was used to amplify exon 10 of the factor V gene, followed by allele-specific restriction with Mnl 1 for mutation detection. Results were analyzed with a chi(2) contingency table. RESULTS No patients were homozygous for the Leiden mutation. Fourteen of 158 women with severe preeclampsia (8.9%) were heterozygous for the Leiden mutation compared with 17 of 403 normotensive gravid controls (4.2%). The difference in frequency between women with severe preeclampsia and normotensive controls was statistically significant, chi(2) 4.686, p = 0.03. CONCLUSIONS Our data suggest that carriers of the factor V Leiden mutation are at increased risk for severe preeclampsia. Deoxyribonucleic acid analysis for the factor V Leiden mutation could serve as one component of a genetic screening profile for preeclampsia and other adverse pregnancy outcomes. Women who carry this mutation are at increased risk for deep venous thrombosis. Carriers of this common thrombophilic mutation may be identified so that adequate counseling regarding future contraceptive usage and effective thromboembolic prophylaxis during pregnancy and surgical procedures may be offered.

The factor V Leiden mutation is not a common cause of recurrent miscarriage

Some investigators suggest that placental thrombosis and infarction can cause recurrent miscarriage. We have shown that the common missense mutation in the factor V gene, the Leiden mutation, which renders factor Va resistant to cleavage inactivation by activated protein C, predisposes to placental thrombosis and spontaneous miscarriage. Our objective was to determine the frequency of the Leiden mutation in a population with well-characterized idiopathic recurrent miscarriage. DNA was extracted from whole blood of 40 couples with a history of idiopathic recurrent miscarriage and 25 couples with a history of proven fertility (seven or more live births). The polymerase chain reaction was used to amplify exon 10 of the factor V gene followed by allele-specific restriction with Mnl1 for mutation detection. Results were analyzed with a chi 2 contingency table. None of the 40 women with idiopathic recurrent miscarriage carried the mutation and only one of their reproductive partners was heterozygous for the mutation. Similarly, none of the control women carried the mutation, and only one of the 25 control male partners was heterozygous for the mutation. In our referral population, the factor V Leiden mutation which predisposes to thrombosis is not a common cause of recurrent miscarriage.

A molecular variant of angiotensinogen is associated with idiopathic intrauterine growth restriction.

OBJECTIVE Intrauterine growth restriction has been associated with failed maternal physiologic changes such as abnormal spiral artery remodeling and reduced maternal blood volume. A polymorphism of angiotensinogen Thr235 has been considered a risk factor for preeclampsia. We genotyped maternal and fetal deoxyribonucleic acid (DNA) for angiotensinogen Thr235 to estimate whether the polymorphism is also a risk factor for intrauterine growth restriction. METHODS We examined maternal blood DNA in 174 patients with intrauterine growth restriction and 60 patients with both preeclampsia and intrauterine growth restriction. The control group comprised 400 consecutive cases of women with term pregnancies and infants with birth weight between the fifth and 95th percentiles. We also examined 162 DNA samples from fetal blood with intrauterine growth restriction for the Thr235 polymorphism, and 240 normal fetuses were used as the control group. The angiotensinogen genotype was determined using mutagenically separated polymerase chain reaction. The products were size fractionated on an agarose gel. Angiotensinogen genotypes were divided into three groups: MM (homozygous for angiotensinogen Met235 allele), TT (homozygous for angiotensinogen Thr235 allele), and MT (heterozygous). RESULTS Maternal genotyping revealed a significantly higher Thr235 allele frequency in intrauterine growth restriction (.60) and preeclampsia/intrauterine growth restriction (.63) than in the control group (.36) (P < .001). Fetal genotyping revealed a Thr235 allele frequency of .59 in intrauterine growth restriction fetuses, as compared with the control group (.38) (P < .001). CONCLUSION Maternal and fetal angiotensinogen Thr235 genotypes are associated with an increased risk of intrauterine growth restriction in our study population. The angiotensinogen Thr235 allele may predispose women to deliver growth-restricted fetuses.

LABETALOL DECREASES CEREBRAL PERFUSION PRESSURE WITHOUT NEGATIVELY AFFECTING CEREBRAL BLOOD FLOW IN HYPERTENSIVE GRAVIDAS

Objective: To research the cerebral hemodynamic effects of labetalol in pregnant women with hypertension. Design: Prospective observational study. Setting: Tertiary Care Medical Center. Population: Pregnant patients with hypertension. Methods: Transcranial Doppler (TCD) ultrasound was used to measure the blood velocity in the middle cerebral arteries (MCA) of eight pregnant patients with hypertension, before and after the administration of a 200 mg oral dose of labetalol. Five patients had severe preeclampsia, and three had chronic hypertension with superimposed preeclampsia. MCA blood velocity and systemic blood pressure were measured simultaneously at the baseline, and at 60 and 180 min after labetalol. Selected cerebral hemodynamic parameters were compared with normative curves. Values outside of the 5th and 95th percentiles were regarded as abnormal. Main outcome measures: Cerebral perfusion pressure (CPP), resistance area product (RAP), and cerebral flow index (CFI). Results: Patient age, gestational age, and parity were similar to those of the normal women from whom the normative data were obtained. Women with hypertension had higher baseline CPP, MAP, and RAP than normal pregnant women, but their CFI was within the normal range. Labetalol reduced the CPP, as well as the systolic, diastolic, and mean BP significantly at 60 and 180 min without significantly affecting the heart rate, MCA velocities, RAP, or CFI. Conclusions: Labetalol effectively reduces CPP, without affecting cerebral perfusion, primarily by a decrease in systemic blood pressure. This makes it an ideal agent for blood pressure control in severely hypertensive pregnant women.

Avascular Villi, Increased Syncytial Knots, and Hypervascular Villi Are Associated with Pregnancies Complicated by Factor V Leiden Mutation

There is controversy about whether pathologic abnormalities are associated with pregnancies complicated by factor V Leiden (FVL) mutation. The purpose of this study was to evaluate 105 placentas delivered to mothers heterozygous for FVL mutation to determine if there are pathologic changes suggestive of hypoxia or thrombosis, which correlate with mutation status. We examined placentas obtained as part of a prospective study of 5188 pregnancies analyzed for the presence of FVL mutation in either the mother or the infant. One hundred five placentas from mothers heterozygous for the mutation were compared with 225 controls matched for maternal age, race, and geographic site. Of the 330 pregnancies, 50 infants were FVL mutation heterozygotes. Maternal FVL heterozygote status was associated with more frequent increased numbers of syncytial knots (13% vs 4%); the difference remained significant after controlling for hypertension, preeclampsia, small-for-gestational-age infants, and delivery prior to 35 weeks of gestation (odds ratio 3.6, 95% confidence interval 1.5−8.7, P = 0.004). Maternal FVL heterozygotes had more hypervascular villi (10% vs 3%), with significance retained controlling for delivery route (odds ratio 3.4, 95% confidence ratio 1.2–9.4, P = 0.018). Placentas from infants heterozygous for FVL mutation had more avascular villi than controls (odds ratio 2.9, 95% confidence interval 1.5–5.6, P = 0.001). Fetal or maternal FVL heterozygosity was not associated with infarcts, small-for-gestational-age placentas, or fetal thrombotic vasculopathy. This analysis demonstrates that pathologic findings associated with placental hypoxia, specifically focal avascular villi, increased numbers of syncytial knots, and hypervascular villi, also correlate with FVL heterozygosity in infants or mothers.

Pregnancy-related Venous Thromboembolism

Pulmonary embolism (PE), although rare, remains the leading cause of maternal death in Western countries. Furthermore, deep venous thrombosis (DVT) is a cause of significant maternal morbidity. The actual incidence of pregnancy-related venous thromboembolic (VTE) events during pregnancy is unknown. This is probably due in part to the issue of asymptomatic versus clinically symptomatic thrombosis. VTE is excluded in approximately 75% of patients who present with suspected disease and are then subjected to objective testing such as Doppler ultrasound or venography. When DVT has been diagnosed and medical therapy instituted, the incidence of PE and maternal death is significantly reduced. Due to the pregnancy-induced changes to the coagulation system, pregnancy is a hypercoagulable state and confers an increase risk for VTE. Certain inherent and environmental risk factors increase this risk. The goal of this review is to facilitate the recognition of the clinical signs and symptoms of VTE disorders, review the use of various diagnostic and treatment modalities, and describe a rational approach to the hypercoagulable workup.

Coarctation of the abdominal aorta in pregnancy: Diagnosis by magnetic resonance imaging

Background Coarctation of the aorta is rare, affecting one per 2000–3000 women. Abdominal coarctation is more commonly identified in women than in men, but only two cases have been reported in pregnancy. Case A 26-year-old woman was diagnosed with hypertension at 15 years of age. Her blood pressure was controlled adequately with beta-blockers. During her pregnancy, she was found to have coarctation of the abdominal aorta by magnetic resonance imaging. Conclusion Magnetic resonance imaging is a safe, reliable means by which to confirm clinically suspected coarctation of the aorta during pregnancy.

Human Leukocyte Antigen DQ α Sharing Is Not Increased in Couples With Recurrent Miscarriage

PROBLEM: The results regarding human leukocyte antigen (HLA) DQ a allele sharing in recurrent miscarriage couples are conflicting. The purpose of this study was to determine the frequency of HLA DQ α allele sharing in our unexplained recurrent spontaneous abortion (RSA) patients using modern DNA analytical techniques.

Family history of venous thromboembolism and identifying factor v leiden carriers during pregnancy

OBJECTIVE: To estimate whether there is a correlation between family history of venous thromboembolism and factor V Leiden mutation carriage in gravid women without a personal history of venous thromboembolism. METHODS: This is a secondary analysis of a prospective observational study of the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden mutation. Family history of venous thromboembolism in either first- or second-degree relatives was self-reported. Sensitivity, specificity, and positive and negative predictive values of family history to predict factor V Leiden mutation carrier status were calculated. RESULTS: Women without a personal venous thromboembolism history and with available DNA were included (n=5,168). One hundred forty women (2.7% [95% confidence interval (CI) 2.3–3.2%]) were factor V Leiden mutation–positive. Four hundred twelve women (8.0% [95% CI 7.3–8.7%]) reported a family history of venous thromboembolism. Women with a positive family history were twofold more likely to be factor V Leiden mutation carriers than those with a negative family history (23 of 412 [5.6%] compared with 117 of 4,756 [2.5%], P<.001). The sensitivity, specificity, and positive predictive value of a family history of a first- or second-degree relative for identifying factor V Leiden carriers were 16.4% (95% CI 10.7–23.6%), 92.3% (95% CI 91.5–93.0%), and 5.6% (95% CI 3.6–8.3%), respectively. CONCLUSION: Although a family history of venous thromboembolism is associated with factor V Leiden mutation in thrombosis-free gravid women, the sensitivity and positive predictive values are too low to recommend screening women for the factor V Leiden mutation based solely on a family history. LEVEL OF EVIDENCE: II

Impact of smoking during pregnancy on functional coagulation testing

Compounds that are systemically absorbed during the course of cigarette smoking, and their metabolites, affect the coagulation system and cause endothelial dysfunction, dyslipidemia, and platelet activation leading to a prothrombotic state. In addition, smoking increases the activity of fibrinogen, homocysteine, and C-reactive protein. We hypothesize that smoking may affect functional coagulation testing during pregnancy. A secondary analysis of 371 women pregnant with a singleton pregnancy and enrolled in a multicenter, prospective observational study of complications of factor V Leiden mutation subsequently underwent functional coagulation testing for antithrombin III, protein C antigen and activity, and protein S antigen and activity. Smoking was assessed by self-report at time of enrollment (<14 weeks). None of the functional coagulation testing results was altered by maternal smoking during pregnancy. Smoking does not affect the aforementioned functional coagulation testing results during pregnancy.