Isolated proteinuria is a risk factor for pre-eclampsia: a retrospective analysis of the maternal and neonatal outcomes in women presenting with isolated gestational proteinuria.

OBJECTIVE: To examine maternal and neonatal outcomes of isolated proteinuria and define maternal characteristics for progression to pre-eclampsia. STUDY DESIGN: Retrospective cohort study. Data from all hospitalized pregnant women between 2009 and 2014 with new onset isolated proteinuria of over 300 mg/24 h at admission were obtained. Follow-up was performed from the time of admission to the hospital to the time of discharge postpartum. Obstetrical, maternal and neonatal outcomes were obtained. RESULT: Ninety-five pregnant women diagnosed with new onset isolated proteinuria were followed to term. Thirteen women developed pre-eclampsia during pregnancy and eight developed pre-eclampsia postpartum. Maternal characteristics for progression to pre-eclampsia were greater maximal values of proteinuria. Earlier pre-eclampsia onset was associated with early-onset proteinuria and multiple gestation. Although greater values of proteinuria were associated with increased risk for intrauterine growth restriction and lower Apgar scores, maternal outcome was favorable, regardless of pre-eclampsia progression. Isolated proteinuria progressing to pre-eclampsia was associated with late pre-eclampsia onset and favorable maternal and neonatal outcomes. CONCLUSION: A significant proportion of women with new onset isolated proteinuria will develop pre-eclampsia. In these women, close follow-up is recommended until after delivery.

Thrombophilia and pregnancy.

Preeclampsia, intrauterine growth restriction and placental abruption greatly contribute to maternal and fetal morbidity and mortality. Thrombophilia is an inherited or acquired condition that predisposes individuals to venous and/or arterial thrombosis. Recently, three important inherited thrombophilias have been discovered. An inherited mutation in the gene coding for coagulation factor V (factor V Leiden), and a mutation in prothrombin that is associated with higher plasma levels of prothrombin. Both mutations result in an increased susceptibility to develop venous thrombosis. Hyperhomocysteinemia, which is associated with mutations in the gene for methylenetetrahydrofolate reductase, is a risk factor for venous and arterial thrombosis. The presence of antiphospholipid antibodies, an acquired thrombophilic condition, is associated with venous and arterial thrombosis. The term placental vasculopathy, is used to describe pathological placental changes that have been associated with preeclampsia, intrauterine growth restriction, placental abruption and fetal loss. The known thrombotic nature of the placental vasculopathy and the increased thrombotic risk with the presence of thrombophilias suggest, a cause-and-effect relationship between inherited and acquired thrombophilias and a number of severe obstetric complications. Testing patients with these complications for thrombophilias may have therapeutic implications for future pregnancies.

Prediction of fetal weight by ultrasound: the contribution of additional examiners.

OBJECTIVES: To assess the contribution of additional examiners to: the average discrepancy between estimated and actual fetal weights; the correlation between estimated and actual fetal weights; the reduction in major (> 10%) discrepancies between estimated and actual fetal weights. DESIGN: Three experienced sonographers independently measured fetal biparietal diameter, head circumference, abdominal circumference and femur length in 39 fetuses at term. The estimated fetal weights were calculated for each examiner. Fetal biometric measurements were analyzed to obtain the source of differences in estimations among the examiners. Discrepancy, correlation and number of major (> 10%) discrepancies between the estimated and actual fetal weights were calculated for each examiner, and the contribution of additional examiners was analyzed. RESULTS: The differences in measurements of the biparietal diameter and femur length were lower than those of the head and abdominal circumferences. For each of the three examiners, the average discrepancy between the estimated and actual fetal weights was 6.1%, 5.9% and 6.3%. When the estimation was based on two examiners, the discrepancy decreased to 4.8-5.6%. The contribution of a third examiner was nil. Major (> 10%) discrepancies between estimated fetal weight and actual birth weight were found in seven, eight and nine estimations of the examiners. Estimation by two examiners decreased the number of major discrepancies, and estimation by all three examiners further decreased by approximately 50% the number of major discrepancies between the estimated and actual fetal weights. CONCLUSION: Measurements by multiple examiners changes only slightly the average number of discrepancies between estimated and actual fetal weights. However, the reduction in major (> 10%) discrepancies is statistically and clinically significant.

Persistent right umbilical vein: incidence and significance.

OBJECTIVES: To conduct a prospective evaluation of the incidence and neonatal outcome of fetuses with persistent right umbilical vein. This condition had traditionally been considered to be extremely rare and to be associated with a very poor neonatal prognosis, but later evidence has raised some doubts about the veracity of these contentions. METHODS: Between August 1995 and November 1998, 8950 low-risk patients were prospectively evaluated at two medical centers. The sonographic diagnosis of a persistent right umbilical vein was made in a transverse section of the fetal abdomen when the portal vein was curved toward the stomach, and the fetal gall bladder was located medially to the umbilical vein. RESULTS: Persistent right umbilical vein was detected in 17 fetuses during the study. Four of them had additional malformations, of which three had been detected antenatally. CONCLUSIONS: We established that the incidence of persistent right umbilical vein in a low-risk population is 1 : 526. We believe that the sonographic finding of this anomaly is an indication for conducting targeted fetal sonography and echocardiography. When the persistent right umbilical vein is connected to the portal system and other anomalies are ruled out, the prognosis can generally be expected to be favorable.

Placental apoptosis in discordant twins.

OBJECTIVE: To investigate placental apoptosis in discordant dichorial twins. METHODS: Placental samples were obtained from 7 third-trimester suitable twins. Discordancy was defined as a >25 per cent difference in newborn birth weight. Light microscopy using hematoxylin and eosin (H&E)-stained paraffin slides and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) methods were used to confirm the incidence of apoptosis. Investigators were blinded to pregnancy outcome. RESULTS: Both methods revealed that the incidence of apoptosis in the placentas of the smaller fetuses was significantly higher than in placentas of the larger fetuses. The incidence of TUNEL-positive cells in the former was 1.4+/-0.26 per cent: this was significantly higher than the incidence of apoptosis in the placental specimens of the latter (0.9+/-0.07 per cent, P< 0.02 Wilcoxon rank test). The same results were obtained with H&E: the incidence of apoptosis detected in placentas from the former was 1.07+/-0.1 per cent compared to 0.72+/-0.08 per cent in those of the latter (P< 0.02 Wilcoxon rank test). CONCLUSIONS: Despite similar environment conditions, placental apoptosis is increased in the smaller fetus and thus might play a role in discordancy between twins. Since increased placental apoptosis has also been found in singleton intrauterine growth restriction, this supports the hypothesis that the smaller twin is selectively growth restricted.

Effect of fetal gender on first trimester markers and on Down syndrome screening.

OBJECTIVES: The purpose of the present study was to evaluate whether a gender-related difference exists in first trimester markers used for Down syndrome screening, namely nuchal translucency (NT), maternal serum pregnancy-associated plasma protein-A (PAPP-A), and free beta-human chorionic gonadotrophin (beta-hCG), and whether this has an influence on screening performance. METHODS: A total of 1325 patients with a singleton pregnancy underwent combined first trimester screening at 10-13 weeks' gestation. Maternal serum PAPP-A and free beta-hCG were analyzed by fluoroimmunoassay, nuchal translucency (NT) was measured by transvaginal sonography. Only patients with normal outcomes and known fetal gender were included in the study. Data were categorized by gestational age and by fetal gender. RESULTS: There were no significant gender-related differences in NT and PAPP-A levels. However, free beta-hCG was significantly higher (p=0.00004) in the presence of a female fetus than in the presence of a male fetus. Women with female fetuses had a higher median calculated Down syndrome risk (1:5490) compared to those having males (1:6451). This difference was not, however, statistically significant. CONCLUSION: First trimester free beta-hCG is significantly higher in pregnancies with a female fetus.

Second-trimester maternal serum alpha-fetoprotein (MSAFP) is elevated in women with adverse pregnancy outcome associated with inherited thrombophilias.

Obstetric complications, such as severe pre-eclampsia, fetal growth restriction, abruptio placentae, or stillbirth are associated with abnormally elevated second-trimester maternal serum alpha-fetoprotein (MSAFP) and beta subunit of human chorionic gonadotrophin (betahCG). This has been attributed to placental abnormalities. Women with thrombophilias have been shown to have abnormalities of the placenta resulting in adverse pregnancy outcome in these patients. The purpose of the present study was to evaluate whether women with pregnancy complications and inherited thrombophilias have abnormally elevated second-trimester MSAFP or betahCG. Sixty-two women with pregnancy complications were tested for inherited thrombophilias several months after delivery. The thrombophilia group included 29 women with pregnancy complications and an inherited thrombophilia and the control group included 33 other patients without thrombophilia. Patients in the thrombophilia group had a higher median MoM MSAFP compared to the controls (1.337 vs. 1.086, p=0.0516). The incidence of abnormally elevated MSAFP (>2.5 MoM) was also significantly higher in the thrombophilia group compared to controls (21% vs. 3%, p=0.04). Neither the median MoM betahCG nor the incidence of abnormally elevated betahCG were significantly different between the groups. We conclude that second trimester MSAFP, but not betahCG, is abnormally elevated in patients with thrombophilia and obstetric complications.

Increased erythrocyte adhesiveness and aggregation in peripheral venous blood of women with pregnancy-induced hypertension.

OBJECTIVE: To study the state of erythrocyte adhesiveness/aggregation in the peripheral blood of women with pregnancy-induced hypertension as well as in matched controls using a simple slide test and image analysis. METHODS: We recruited 25 women with pregnancy-induced hypertension. Twenty-five age- and gestational age-matched normotensive volunteers took part in the study and served as controls. Blood smears were evaluated by an image analysis system (INFLAMET). Quantitative measures of erythrocyte aggregation were used to describe the state of erythrocyte adhesiveness/aggregation such as vacuum radius, which measures the spaces between the aggregated erythrocytes. The number of participants was established by power analysis (given alpha of 0.05 and 80% power and considering a minimum difference to detect 4 microm in vacuum radius with a standard deviation of approximately 5). RESULTS: A significant (P =.002) increment in the state of erythrocyte aggregation was noted in the study group compared with the controls, the vacuum radius values being 16.1 +/- 1.3 and 10.3 +/- 1.2, respectively. Erythrocyte sedimentation rate but not fibrinogen concentration was significantly elevated in the study group. The increased aggregation correlated significantly with fibrinogen concentration, systolic, and diastolic blood pressures. CONCLUSION: We observed increased aggregability of red blood cells in hypertensive conditions of pregnancy. Our findings are significant in that they reveal blood pressure-related increment in red cell adhesiveness/aggregation despite there being no significant increment in clottable fibrinogen concentrations.

First trimester PAPP-A in the detection of non-Down syndrome aneuploidy.

Combined first trimester screening using pregnancy associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotrophin, and nuchal translucency (NT), is currently accepted as probably the best combination for the detection of Down syndrome (DS). Current first trimester algorithms provide computed risks only for DS. However, low PAPP-A is also associated with other chromosome anomalies such as trisomy 13, 18, and sex chromosome aneuploidy. Thus, using currently available algorithms, some chromosome anomalies may not be detected. The purpose of the present study was to establish a low-end cut-off value for PAPP-A that would increase the detection rates for non-DS chromosome anomalies. The study included 1408 patients who underwent combined first trimester screening. To determine a low-end cut-off value for PAPP-A, a Receiver-Operator Characteristic (ROC) curve analysis was performed. In the entire study group there were 18 cases of chromosome anomalies (trisomy 21, 13, 18, sex chromosome anomalies), 14 of which were among screen-positive patients, a detection rate of 77.7% for all chromosome anomalies (95% CI: 55.7-99.7%). ROC curve analysis detected a statistically significant cut-off for PAPP-A at 0.25 MoM. If the definition of screen-positive were to also include patients with PAPP-A<0.25 MoM, the detection rate would increase to 88.8% for all chromosome anomalies (95% CI: 71.6-106%). This low cut-off value may be used until specific algorithms are implemented for non-Down syndrome aneuploidy.

Serum levels of inhibin B, unlike inhibin A and activin A, are not altered in women with preeclampsia.

PROBLEM: To investigate whether inhibin A, inhibin B, and activin A serum levels are altered in women with preeclampsia. METHOD OF STUDY: Serum samples of 20 women with preeclampsia (study group) and 20 normotensive pregnant women, matched for maternal and gestational age and parity, were assayed for inhibin A, inhibin B and activin A by specific enzyme-linked immunosorbent assay. RESULTS: Median serum concentrations of inhibin A and activin A were significantly higher among women with preeclampsia than in women with normotensive pregnancies, while inhibin B levels were comparable in both groups. Activin A levels were positively correlated with those of inhibins A and B, and inhibin A levels were positively correlated with diastolic blood pressure and inhibin B concentration in the study group. CONCLUSIONS: Inhibin A and activin A, but not inhibin B, serum levels are markedly increased in women with preeclampsia. These hormones might serve as an endocrine marker for preeclampsia.

Persistent postpartum urinary retention in contemporary obstetric practice. Definition, prevalence and clinical implications.

OBJECTIVE: To prospectively evaluate the prevalence, presumed etiologies and clinical implications of persistent postpartum urinary retention in modern obstetric practice. STUDY DESIGN: The study population comprised 8,402 consecutive, unselected parturients delivered in a university-affiliated maternity hospital over a one-year period. If a woman was unable to void spontaneously until the third postpartum day despite intermittent use of a Foley catheter, a diagnosis of persistent postpartum urinary retention was established. Patients were treated by insertion of a Foley catheter for up to two weeks and subsequently by a suprapubic catheter. Obstetric data were collected from the hospital records. RESULTS: Four patients (0.05% of the study population), aged 29-37 years, developed persistent postpartum urinary retention. Risk factors included vaginal delivery after cesarean section, prolonged second stage of labor, epidural analgesia, and delayed diagnosis and intervention. Urodynamic evaluation, performed on two patients one month after removal of the suprapubic catheter, revealed genuine stress incontinence in one and detrusor instability in another. None had had any lower urinary tract symptoms before pregnancy and delivery. CONCLUSION: Persistent postpartum urinary retention in contemporary obstetric practice is rare but may be associated with long-term bladder dysfunction. Early diagnosis and intervention are required to prevent irreversible bladder damage.

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.

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

OBJECTIVE: To 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. METHODS: The 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. RESULTS: Low-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). CONCLUSIONS: This 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.

Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia.

OBJECTIVE: To compare placental pathology between women with and without thrombophilia who had severe preeclampsia, intrauterine growth retardation, severe abruptio placentae, or stillbirth. METHODS: After delivery, 68 women with singleton pregnancies with one of the above complications were evaluated for an inherited thrombophilia: factor V Leiden, methylenetetrahydrofolate reductase and prothrombin gene mutation, and deficiencies of protein S, protein C, and antithrombin III. Thirty-two women were thrombophilic (group A), and 36 women were not (group B). There was no difference in maternal age, parity, and type of pregnancy complication. A single pathologist examined each placenta. RESULTS: The gestational age at delivery, birth weight, and placental weight were significantly lower in group A. Three parameters showed significant differences between the groups: thrombophilic women had a higher number of villous infarcts (P <.01), more multiple infarcts (P <.05), and a higher incidence of placentas with fibrinoid necrosis of decidual vessels (P <.05). CONCLUSION: Placentas of women with severe complications and thrombophilia have an increased rate of vascular lesions.

The use of prophylactic Stamey bladder neck suspension to prevent post-operative stress urinary incontinence in clinically continent women undergoing genitourinary prolapse repair.

The present study was undertaken to evaluate the efficacy of Stamey bladder neck suspension in preventing post-perative stress urinary incontinence in clinically continent women undergoing surgery for genitourinary prolapse. Thirty clinically continent women with severe genitourinary prolapse were found to have a positive stress test with re-positioning of the prolapse. They all had significant urethrovesical junction hypermobility. In addition to the genitourinary prolapse repair, these patients underwent a prophylactic Stamey procedure to prevent the possible development of post-operative stress urinary incontinence. The mean duration of follow-up was 8+/-4.5 months (range, 3-19 months). Seven (23.30%) patients developed overt post-operative stress urinary incontinence that was confirmed urodynamically. Eleven (36.7%) other patients denied stress incontinence; however, post-operative urodynamics demonstrated sphincteric incontinence. Post-operative complications were uncommon and minor. In conclusion, continent patients with a positive stress test demonstrated on re-positioning of the prolapse during pre-operative urodynamic evaluation are considered to be at high risk of developing post-operative stress urinary incontinence. In these patients, an additional, effective anti-incontinence procedure should be considered during surgical correction of genitourinary prolapse. The Stamey procedure, although simple and safe, does not appear to be the optimal solution to this clinical problem.

Contribution of human papillomavirus testing by hybrid capture in the triage of women with repeated abnormal pap smears before colposcopy referral.

OBJECTIVE: The purpose of this work was to evaluate the ability of testing for high-risk human papillomavirus (HPV) types using the hybrid capture technique to predict the presence of cervical intraepithelial neoplasia (CIN) II,III in patients with repeated atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LGSIL) on Pap smears. METHODS: Hybrid capture testing and tissue biopsy were performed on 503 consecutive women with ASCUS or LGSIL on repeated Pap smears who were referred for colposcopy. RESULTS: A highly significant association (P < 0.0001) was found between a positive test for high-risk HPV types and CIN II,III, with an 87.0% positive predictive value and a 95.7% negative predictive value. In 226 women with ASCUS on repeated Pap smears, a positive test for high-risk HPV types had a 85.7% sensitivity and a 97% specificity for CIN II,III. In 277 patients with LGSIL on repeated Pap smears, a positive test for high-risk HPV types had an 88.2% sensitivity and a 94.7% specificity for CIN I,II. Reserving colposcopy examination for women who were positive for high-risk HPV types would have reduced the number of referrals for colposcopy to 24.6% and maintained a sensitivity of 87.0% for CIN II,III. CONCLUSIONS: A positive hybrid capture test for high-risk HPV types was highly sensitive and specific for the presence of CIN II,III in patients with ASCUS and LGSIL on repeated Pap smears. We believe that improved methodology will eventually enable more selective colposcopy referrals without affecting patient safety among these women.

High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss.

BACKGROUND: It has been reported recently that obstetric complications are associated with thrombophilias. Our objective was to investigate the association between pregnancy complications and the guanine 20210 adenine (G20210A) mutation in prothrombin gene. METHODS: Two hundred and twenty-two women (study group) with obstetric complications were tested for the prothrombin mutation. Indications for testing were: severe preeclampsia, mild preeclampsia, intrauterine growth retardation, severe abruptio placentae, unexplained stillbirth, second trimester loss, and three or more consecutive spontaneous abortions. We also tested 156 healthy women who had at least one normal pregnancy and comprised the control group. RESULTS: Demographic data of the study and control groups were similar. Twenty-eight women of the study group (13%) were found to be heterozygous carriers of the 20210 variant of the prothrombin gene compared to five (3.2%) of the control group, p=0.001, odds ratio (OR) 2.9; 95% confidence interval (CI) 1.3-6.5. Compared to the control women, the prothrombin gene mutation was significantly more prevalent in women with IUGR, abruptio placentae, and second trimester loss but not in women with mild or severe preeclampsia, stillbirth and habitual abortion. CONCLUSIONS: Our data demonstrate that the mutation in the prothrombin gene is associated with specific pregnancy complications.

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.