von Willebrand factor antigen: a biomarker for severe pregnancy complications in women with hereditary thrombotic thrombocytopenic purpura?

BACKGROUND: Hereditary thrombotic thrombocytopenic purpura (hTTP) is associated with severe obstetric morbidity (SOM) during pregnancy. Treatment with fresh frozen plasma (FFP) mitigates the risk in some women, but others respond poorly and continue to suffer obstetric complications. OBJECTIVES: To determine a possible association between SOM and elevated nonpregnant von Willebrand factor (NPVWF) antigen levels in women with hTTP and whether the latter can predict the response to FFP transfusion. METHODS: This was a cohort-based study of women with hTTP due to homozygous c.3772delA mutation of ADAMTS-13 who had pregnancies both with and without FFP treatment. Occurrences of SOM were determined from medical records. Generalized estimated equation logistic regressions and receiver operating characteristic curve analysis determined the NPVWF antigen levels associated with the development of SOM. RESULTS: Fourteen women with hTTP had 71 pregnancies; of which 17 (24%) culminated in pregnancy loss and 32 (45%) were complicated by SOM. FFP transfusions were administered in 32 (45%) of the pregnancies. Treated women had decreased SOM (28% vs 72%, p < .001) and preterm thrombotic thrombocytopenic purpura exacerbations (18% vs 82%, p < .001) and higher median NPVWF antigen levels than those of women with uncomplicated pregnancies (p = .018). Among the treated women, median NPVWF antigen levels were higher in those with SOM than in those without SOM (225% vs 165%, p = .047). Logistic regression models demonstrated a significant 2-way association between elevated NPVWF antigen levels (for SOM, odds ratio, 1.08; 95% CI, 1.001-1.165; p = .046) and SOM (for elevated NPVWF antigen levels, odds ratio, 1.6; 95% CI, 1.329-1.925; p < .001). The receiver operating characteristic curve analysis demonstrated that an NPVWF antigen level of 195% had 75% sensitivity and 72% specificity for SOM. CONCLUSION: Elevated NPVWF antigen levels are associated with SOM in women with hTTP. Women with levels >195% may benefit from increased surveillance and more intensive FFP treatment during pregnancy.

Human leukocyte antigen HLA-C, HLA-G, HLA-F, and HLA-E placental profiles are altered in early severe preeclampsia and preterm birth with chorioamnionitis.

BACKGROUND: The extravillous trophoblast expresses each of the nonclassical major histocompatibility complex class I antigens-human leukocyte antigens E, F, and G-and a single classical class I antigen, human leukocyte antigen C. We recently demonstrated dynamic expression patterns of human leukocyte antigens C, G, and F during early extravillous trophoblast invasion and placentation. OBJECTIVE: This study aimed to investigate the hypothesis that the immune inflammatory mediated complications of pregnancy such as early preeclampsia and preterm labor may show altered expression profiles of nonclassical human leukocyte antigens. STUDY DESIGN: Real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry were performed on placental villous tissues and basal plate sections from term nonlaboring deliveries, preterm deliveries, and severe early-onset preeclampsia, both with and without small-for-gestational-age neonates. RESULTS: Human leukocyte antigen G is strongly and exclusively expressed by the extravillous trophoblast within the placental basal plate, and its levels increase in pregnancies complicated by severe early-onset preeclampsia with small-for-gestational-age neonates relative to those of healthy term controls. Human leukocyte antigen C shows a similar profile in the extravillous trophoblast of preeclamptic pregnancies, but significantly decreases in the villous placenta. Human leukocyte antigen F protein levels are decreased in both extravillous trophoblast and villous placenta of severe early-onset preeclamptic pregnancies, both with and without small-for-gestational-age neonates, compared with those found in term and preterm birth deliveries. Human leukocyte antigen E decreases in blood vessels in placentas from preeclamptic pregnancies relative to its levels in term and preterm birth deliveries. Placental levels of human leukocyte antigens F and C are increased in cases of preterm birth with chorioamnionitis relative to those of cases of idiopathic preterm birth. CONCLUSION: Dysregulation of placental human leukocyte antigen expression at the maternal-fetal interface may contribute to compromised maternal tolerance in preterm birth with chorioamnionitis and excessive maternal systemic inflammation associated with severe early-onset preeclampsia.

Fetal Dilated Cardiomyopathy Associated With Variants of Uncertain Significance in MYH7 and DSG2 Genes: A Case Report and Review of the Literature.

BACKGROUND: Fetal dilated cardiomyopathy (DCM) is an uncommon prenatal diagnosis associated with significant morbidity and mortality. CASE: This report describes a patient with a diagnosis of fetal DCM at 310 weeks gestation, several weeks after a maternal flu-like illness. Spontaneous improvement was noted on serial echocardiograms. Maternal Coxsackievirus B titers were significantly elevated at 1:80, although post-natal cord blood test results were negative. Genetic panel testing for DCM demonstrated two heterozygous variants of uncertain significance in the MYH7 and DSG2 genes. Although an early post-natal echocardiogram demonstrated a normal left ventricular ejection fraction, right ventricular dysfunction was noted with subsequent cardiac decompensation requiring temporary inotropic support. An echocardiogram at the age of 2 years confirmed normal biventricular function. CONCLUSION: The finding of fetal DCM should trigger a broad evaluation. In the setting of limited fetal cardiac reserve, the significant hemodynamic changes that occur post-natally may trigger additional decompensation. Clinicians should be aware of the prognostic value of right ventricular function, as measured by fractional area change, in addition to the limitations of serologic and genetic testing.

Fetal human leukocyte antigen-C and maternal killer-cell immunoglobulin-like receptors in cases of severe preeclampsia.

INTRODUCTION: The pathogenesis of preeclampsia may involve inadequate trophoblast invasion caused by excessive inhibition of uterine natural killer cells (uNK) by extravillous trophoblast cells (EVT). This may be the result of a combination of maternal killer-cell immunoglobin-like receptor (KIR) AA genotype and fetal human leukocyte antigen-C2 (HLA-C2) genotype. A few studies have reported a significantly increased frequency of the maternal KIR AA/fetal HLA-C2 combination in cases of preeclampsia compared to controls. METHODS: Study subjects were 259 cases of severe preeclampsia/eclampsia and 259 matched pregnant women without preeclampsia or eclampsia. All pregnancies were singleton pregnancies, and mothers were preferentially primigravidae. Blood samples from women and their newborns were obtained from the Danish National Birth Cohort (DNBC) and the Danish Neonatal Screening Biobank. Significant differences in the frequencies of KIR AA and HLA-C2 between cases and controls were investigated. RESULTS: No significant difference was observed between cases and controls in the frequency of maternal KIR AA (OR = 0.86, 95%CI = 0.60-1.23, P = 0.41), neither when the fetus carried an HLA-C2 allele (OR = 0.85, 95%CI = 0.52-1.38, P = 0.51), nor when the fetus carried an HLA-C2 allele more than its mother (OR = 0.75, 95%CI = 0.34-1.64, P = 0.47). CONCLUSION: The Results show no influence of HLA-C/KIR genetic variation on the risk of severe preeclampsia, contrary to what some previous studies have observed. An explanation could be that severe preeclampsia represents a separate pathological entity compared to mild preeclampsia.

Do Early Fetal Measurements and Nuchal Translucency Correlate With Term Birth Weight?

OBJECTIVE: Traditionally, physiological variation in fetal weight is believed to emerge during the latter half of pregnancy. Although recent evidence suggests that crown-rump length (CRL) and nuchal translucency (NT) measured at 11-14 weeks correlate with abnormal fetal growth, findings have been limited by dating accuracy in spontaneous gestations. Therefore, we sought to determine whether CRL or NT measurements correlated with term birth weight (BW) or BW ratio in a cohort of IVF pregnancies, in which the date of conception is precisely known. METHODS: This retrospective cohort study included 227 term, singleton IVF pregnancies. Subjects were included if they had an early first-trimester ultrasound examination and subsequent nuchal translucency (NT) screening. The difference between the measured and the expected CRL and the biparietal diameter (BPD) and NT measurement were calculated and correlated with the actual term BW or BW ratio. The BW ratio was calculated using the actual BW and the expected BW for GA. RESULTS: The difference between measured and expected mid-first-trimester CRL, and the BPD at NT assessment, correlated with BW ratio at delivery (rSpearman = 0.15, P = 0.023 and rSpearman = 0.27, P < 0.001, respectively). Absolute NT measurements and NT percentiles (adjusted for CRL) correlated with BW ratio at delivery (rSpearman = 0.18, r = 0.14, and P = 0.005 and 0.038, respectively). CONCLUSION: In this well-dated IVF population, we report a significant correlation between BW ratio and first-trimester CRL, BPD, and NT measurements. These findings support the hypothesis that physiological variation in BW can be reflected by variation in first-trimester fetal measurements.

Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition.

PROBLEM: The extravillous trophoblasts (EVT) express HLA-C and HLA-G, but HLA-E and HLA-F are the subject of conflicting reports. In this study, we define the HLA expression profile during active EVT placental implantation, pregnancy development, and parturition. METHOD OF STUDY: Immunohistochemistry, q-PCR, and Western blot were used to investigate HLA-C, HLA-E, and HLA-F placental expression across gestation from the early first trimester, late first trimester, second trimester (n=10 in each), preterm gestation (n=6) to elective term cesarean section and term vaginal deliveries (n=12, 38-41 weeks). EVT explants and Swan71 cells were used to assess HLA-C and HLA-F during active EVT migration. RESULTS: HLA-G, HLA-C, and HLA-F were expressed by 1st-trimester EVT and became intracellular and weaker as gestation progressed. HLA-E was only expressed in 1st-trimester placenta. HLA-F and HLA-C mRNA and protein expression levels showed a significant increase in the fetal villous mesenchyme across gestation. HLA-C levels increased with labor. We detected a 100-kDa HLA-F band in early pregnancy suggesting dimer formation on the EVT surface. These results were confirmed in EVT outgrowths and Swan71 trophoblast which showed that HLA-F and HLA-G are increased on the cell surface of migrating EVT, while HLA-C was internalized. CONCLUSION: Expression of HLA-F and HLA-G on the cell surface of actively migrating EVT supports their specific role in early EVT invasion and interactions with uterine natural killer cells. HLA-C's limited expression to the proliferative EVT suggests a protective role in the earliest events of implantation but not in active EVT invasion. We also show for the first time that HLA-C may be involved in parturition.

The safety of methimazole and propylthiouracil in pregnancy: a systematic review.

BACKGROUND: Hyperthyroidism is one of the most common endocrine disorders in pregnant women, and it can severely complicate the course and outcome of pregnancy. Methimazole (MMI) and propylthiouracil (PTU) are the standard anti-thyroid drugs used in the treatment of hyperthyroidism in pregnancy. Traditionally, MMI has been considered to have clearer evidence of teratogenicity than PTU. Recent studies suggest that PTU can be hepatotoxic, leading to a United States Food and Drug Administration "black box alert." We wished to systematically review the effects of PTU and MMI during pregnancy, and to compare maternal and fetal safety. METHODS: We conducted a systematic search of PubMed, EMBASE, TOXNET, TOXLINK, DART, Medscape, EBSCO, and Google. Both English and non-English publications were included. We excluded studies using anti-thyroid therapies other than PTU and MMI, studies not allowing interpretation of results, and abstracts of meetings. RESULTS: Overall, insufficient statistical power precluded determination of accurate rates of either MMI teratogenicity or PTU hepatotoxicity in cohort studies. However, a case-control study helped identify the relative risk of MMI-induced choanal atresia. A second case-control study failed to show that aplasia cutis congenita is associated with MMI. PTU has been associated with a rare but serious form of hepatic failure. CONCLUSION: MMI causes a specific pattern of rare teratogenic effects after first trimester exposure, while PTU therapy may be followed by rare but severe hepatotoxic sequelae. It is therefore appropriate to use PTU to treat maternal hyperthyroidism during the first trimester of pregnancy, and to switch to MMI for the remainder of the pregnancy.

Effect of methotrexate treatment of ectopic pregnancy on subsequent pregnancy.

QUESTION: My last pregnancy was diagnosed as ectopic, and I was treated successfully with intramuscular methotrexate (MTX) 8 weeks ago. I am currently planning for another pregnancy; however, I have read that MTX causes birth defects and that it stays in my body for a very long time, ranging from 1 to 12 months after treatment. When is it safe to conceive? ANSWER: We suggest that the outcomes of pregnancies conceived shortly after MTX therapy for extrauterine pregnancy are most likely to be favourable and similar to those pregnancies conceived 6 months after MTX treatment. However, as data are not sufficient to draw a definitive conclusion or to confirm the exact safe timing after MTX treatment, at least a 3-month waiting period is recommended for women who are planning pregnancy. Nevertheless, conception within 3 months of MTX treatment of extrauterine pregnancy should not be considered a definite indication of termination, and further targeted fetal anatomy assessment is recommended. Further retrospective and prospective studies are needed to define the safety period before 3 months and to solidify this recommendation.

The association of maternal BMI with fetal echogenic intracardiac foci and echogenic bowel.

OBJECTIVES: To evaluate the impact of maternal body mass index (BMI) as well as maternal ethnicity on the detection of either echogenic intra-cardiac focus (EIF) or echogenic bowel (EB). METHODS: This prospective study identified 74 uncomplicated singleton fetuses in which EIF and/or EB were detected between 18 and 21 weeks of gestation (i.e. study group). Seventy four consecutively scanned fetuses without EIF or EB, at the same gestational age, were selected as controls. The differences in maternal BMI and maternal ethnicity were compared between the two groups using the chi(2) test, Fisher's exact test, and the Student t-test. A multivariable logistic regression model was constructed to control for confounders. Odds ratios (OR) and their 95% confidence interval (CI) were computed. RESULTS: The mean maternal BMI was significantly lower in the study group as compared to controls (22.9 +/- 3.1 vs. 28.0 +/- 7.5 kg/m(2), respectively; p < 0.0001). Patients with fetal EIF and/or EB were significantly more likely to be Asians (20.3% vs. 5.4%, OR = 4.5; 95% CI 1.3-16.9). Using a multivariable analysis, controlling for ethnicity, the association between maternal BMI and fetal EIF or EB remained significant (OR = 0.83; 95% CI 0.76-0.91). However, based on this model Asian ethnicity was not an independent risk factor for the detection of EIF and/or EB (OR = 2.6; 95% CI 0.8-8.9). CONCLUSIONS: Our data suggests an inverse relationship between the maternal BMI and the detection of fetal EIF and/or EB. Moreover, it appears that low maternal BMI, and not Asian ethnicity, is an independent risk factor for the detection of these echogenic fetal findings.

Monochorionic dizygotic twins in a spontaneous pregnancy: a rare case report.

Traditionally, monochorionicity in multiple pregnancies is associated with monozygocity. We present a case of a spontaneous, monochorionic dizygotic, sex-discordant twin pregnancy. The diagnosis of monochorionicity was initially done during first-trimester ultrasound evaluation and then confirmed by postnatal placental pathology. Furthermore, both twins were found to have blood chimerism. We also review the literature on dizygotic-monochorionic twins and blood-chimerism. We suggest that further prospective postnatal genetic studies are needed to define the reliability of prenatal diagnosis of identical twins in cases of monochorionicity.

Reduced third-trimester levels of soluble human leukocyte antigen G protein in severe preeclampsia.

OBJECTIVE: Recently, lower maternal plasma human leukocyte antigen (HLA)-G protein levels in preeclampsia (PE) in the first and second trimester was reported. Thus, we sought to evaluate the levels of HLA-G protein in patients with severe PE during the third trimester. STUDY DESIGN: In this prospective case control study, amniotic fluid and maternal and cord blood samples were aspirated from 50 pregnant women during the third trimester. The study group included 26 pregnant women diagnosed with severe PE and 24 women without PE serving as controls. A soluble HLA-G-specific enzyme-linked immunosorbent assay was used to measure protein levels. Statistical analysis included the Student t test and simple regression analysis. RESULTS: Maternal serum HLA-G levels in PE pregnancies were found to be significantly lower as compared with normal pregnancies (10.97 +/- 6.55 vs 36.05 +/- 34.53 microg/mL; P = .003). CONCLUSION: A reduced level of maternal HLA-G protein was associated with severe PE during the third trimester. This finding may suggest an essential role for HLA-G in normal and preeclamptic pregnancies.

The impact of maternal age, body mass index and maternal weight gain on the glucose challenge test in pregnancy.

OBJECTIVE: The aim of this study was to determine whether maternal age, prepregnancy and mid-trimester body mass index (BMI), or excessive mid-pregnancy weight gain predict abnormal glucose challenge test (GCT) results. METHODS: A retrospective chart review of 75 consecutive singleton pregnancies was performed. Patients were screened at 24-28 weeks of gestation with a 50-g oral GCT. Prepregnancy BMI and pregnancy weight gain up to the time of GCT testing, as well as other demographic data, were recorded. Statistical analysis included regression analysis and Student's t-test, receiver-operator characteristic curve and multivariate logistic regression. RESULTS: Maternal age and prepregnancy and mid-trimester BMI were significantly higher in women with an abnormal GCT (p<0.05). A direct correlation was found between these parameters and GCT results (R(2)=0.08, R(2)=0.102 and R(2)=0.116, respectively; p<0.05). Mid-trimester maternal BMI of >or=30 kg/m(2) and maternal age >or=32 years are the optimal predictors of abnormal GCT results. CONCLUSIONS: Mid-trimester maternal BMI of >or=30 kg/m(2) and maternal age >or=32 years are useful predictors of abnormal GCT results. We suggest that these factors should also be considered when selective screening for gestational diabetes mellitus is practiced.

Combined analysis with amniotic fluid index and estimated fetal weight for prediction of severe macrosomia at birth.

OBJECTIVE: To evaluate combined analysis with amniotic fluid index (AFI) and estimated fetal weight (EFW) for prediction of severe macrosomia at birth. STUDY DESIGN: In this retrospective case-control study, 50 term severe macrosomic newborns (birthweight [BW] > or = 97th percentile) were included in the study group and 100 appropriate for gestational age newborns served as controls. All pregnancies underwent a third-trimester sonographic evaluation in which AFI and EFW were measured. The association between BW and AFI and EFW percentiles was examined. The statistical analysis included Student t test, simple regression and receiver-operating curve analyses, and 2x2 tables. RESULTS: The mean mid-third-trimester AFI percentile and EFW percentile in severe macrosomic infants were 72.4 +/- 22.5 and 83 +/- 12, respectively, which was significantly higher than in controls (P < .0001). Significant correlations were detected between BW and AFI and EFW percentiles (r = 0.44 and r = 0.72, respectively; P < .0001). Receiver-operating characteristic analysis identified AFI > or = 60th percentile and EFW > or = 71st percentile as best predictors of severe macrosomia. The combined analysis with AFI > or = 60th percentile and EFW > or = 71st percentile resulted in a positive predictive value of 85%. CONCLUSION: There is a significant correlation between mid-third-trimester AFI and BW. AFI > or = 60th percentile and EFW > or = 71st percentile during the mid third trimester are useful predictors of severe macrosomia at birth.

HLA-G antigen and parturition: maternal serum, fetal serum and amniotic fluid levels during pregnancy.

OBJECTIVE: To determine whether soluble HLA-G1 (sHLA-G1) concentrations in maternal serum and in amniotic fluid are lower at term than in the second trimester. METHODS: In this prospective study amniotic fluid and maternal serum samples were aspirated from 21 pregnant women during genetic amniocentesis at 16-20 weeks' gestation, and from 19 women undergoing a cesarean section at term. In the latter group arterial umbilical cord blood was aspirated as well. sHLA-G1 levels were determined using ELISA assay. This assay included the anti-HLA-G monoclonal antibodies 87G and 16G1, both as capture antibodies and horseradish-peroxidase-labeled rabbit anti-human beta(2)-microglobulin antibodies, as the detection antibody. The relative concentrations of sHLA-G1 were measured from the absorbancy of the blue product at 650 nm. Student's t test was used for statistical analysis. RESULTS: sHLA-G1 levels in amniotic fluid were significantly lower at term than in the second trimester (0.160 +/- 0.05 vs. 0.272 +/- 0.150 OD units; p < 0.05). Levels of sHLA-G1 in maternal serum declined toward term, but the difference from the second trimester was not statistically significant (0.266 +/- 0.157 vs. 0.205 +/- 0.120 OD units; p = 0.193). There was a strong correlation of sHLA-G1 concentrations between cord serum and maternal serum (R(2) = 0.79; p < 0.001), but not between cord serum and amniotic fluid (R(2) = 0.00004) or amniotic fluid and maternal serum (R(2) = 0.02). CONCLUSIONS: sHLA-G1 antigen expression is higher in amniotic fluid than in maternal-fetal compartments and significantly decreases toward term. We speculate that the declining amniotic fluid sHLA-G1 levels may stimulate a maternal immunological response against the fetus and contribute to the initiation of parturition.

Lost levonorgestrel IUD: diagnosis and therapy.

A lost intrauterine device (IUD) is an uncommon event. Recently, a new levonorgestrel-releasing intrauterine system was introduced. In view of several cases of an unusual diagnostic discrepancy in the location of a lost levonorgestrel-releasing IUD in our department, we sought to determine if the extrauterine location of lost levonorgestrel-releasing IUDs differs from that of lost copper IUDs. The medical files of all patients with a diagnosis of lost IUD who were admitted to Rabin Medical Center from 2000 to 2003 were reviewed. Fourteen women were identified, 9 with levonorgestrel-releasing IUDs and 5 with copper IUDs. In six of the nine cases of a lost levonorgestrel-releasing IUD, there was a clear discrepancy between the presumed location of the device by diagnostic evaluation and its actual location on surgical extraction. All six devices were embedded in the omentum; four were located in the upper abdomen. No such discrepancies were noted for the copper IUDs (0 vs. 66%, p < 0.05). No significant difference in peritoneal adhesions was noted between the groups (55% vs. 66%, respectively, p = 0.095). It is concluded that lost levonorgestrel-releasing IUDs are associated with a higher rate of localization errors by clinical evaluation than copper IUDs. Lost levonorgestrel-releasing IUDs might be found in the mid-upper abdomen, embedded in omentum tissue, and this area should be explored first during laparoscopy.