Neta Benshalom-Tirosh

First Trimester Pregnancy Loss and the Expression of Alternatively Spliced NKp30 Isoforms in Maternal Blood and Placental Tissue

Capsule: We observed that first trimester pregnancy loss is associated with an altered expression profile of the three isoforms of the NK receptor NKp30 expressed by NKs in PBMC and placental tissue. In this study, we aimed to investigate whether first trimester pregnancy loss is associated with differences in expression of NKp30 splice variants (isoforms) in maternal peripheral blood or placental tissue. We conducted a prospective case–control study; a total of 33 women undergoing dilation and curettage due to first trimester pregnancy loss were further subdivided into groups with sporadic or recurrent pregnancy loss. The control group comprises women undergoing elective termination of pregnancy. The qPCR approach was employed to assess the relative expression of NKp30 isoforms as well as the total expression of NKp30 and NKp46 receptors between the selected groups. Results show that in both PBMC and placental tissue, NKp46 and NKp30 expressions were mildly elevated in the pregnancy loss groups compared with the elective group. In particular, NKp46 elevation was significant. Moreover, expression analysis of NKp30 isoforms manifested a different profile between PBMC and the placenta. NKp30-a and NKp30-b isoforms in the placental tissue, but not in PBMC, showed a significant increase in the pregnancy loss groups compared with the elective group. Placental expression of NKp30 activating isoforms-a and -b in the pregnancy loss groups was negatively correlated with PLGF expression. By contrast, placental expression of these isoforms in the elective group was positively correlated with TNFα, IL-10, and VEGF-A expression. The altered expression of NKp30 activating isoforms in placental tissue from patients with pregnancy loss compared to the elective group and the different correlations with cytokine expression point to the involvement of NKp30-mediated function in pregnancy loss.

Hypothyroidism and diabetes mellitus – a risky dual gestational endocrinopathy

Objectives. Diabetes mellitus (DM) and hypothyroidism are each associated with increased rate of pregnancy complications. However, their combined morbidity during gestation is poorly studied. Therefore, the aims of this study were to determine the prevalence of the combined morbidity of DM & hypothyroidism and whether it is associated with adverse maternal and neonatal outcome. Study design. This population based retrospective cohort study included 87,213 women who had 232,293 deliveries. All deliveries were divided into the following groups: (1) hypothyroidism & DM (n = 171); (2) hypothyroidism (n = 1502); (3) DM (n = 13,324); and (4) deliveries of women with neither endocrinopathy, who served as a control group (n = 217, 296). Results. The prevalence of DM & hypothyroidism in our population was 0.17%. In comparisons to the other study groups, women with DM & hypothyroidism had higher rates of infertility (p < 0.001), preeclampsia (p < 0.001), chronic hypertension (p < 0.001), preterm birth (p < 0.001), and cesarean deliveries (p < 0.001). In Generalized Estimating Equations (GEE) model, hypothyroidism & DM was an independent risk factor for cesarean section (OR 3.46; 95% CI 2.53–4.75) and for preeclampsia (OR 1.82; 95%CI 1.16–2.84). Conclusion. The combination of DM & hypothyroidism is rare, yet it is associated with higher rate of infertility, cesarean sections, preterm deliveries, and hypertensive disorders of pregnancy than the rest of the population. This dual endocrinological combination is an independent risk factor for preeclampsia and cesarean section. These findings suggest that these patients are at risk for perinatal complications and should be followed and delivered as high risk pregnancies.

A prior placenta accreta is an independent risk factor for post-partum hemorrhage in subsequent gestations

OBJECTIVE The rate of placenta accreta, a life threatening condition, is constantly increasing, mainly due to the rise in the rates of cesarean sections. This study is aimed to determine the effect of a history of placenta accreta on subsequent pregnancies. STUDY DESIGN A population based retrospective cohort study was designed, including all women who delivered at our medical center during the study period. The study population was divided into two groups including pregnancies with: (1) a history of placenta accreta (n=514); and (2) control group without placenta accreta (n=239,126). RESULTS (1) A history of placenta accreta is an independent risk factor for postpartum hemorrhage (adjusted OR 4.1, 95% CI 1.5-11.5) as were placenta accreta (adjusted OR 22.0, 95% CI 14.0-36.0) and placenta previa (adjusted OR 7.6, 95% CI 4.4-13.2) in the current pregnancy, and a prior cesarean section (adjusted OR 1.7, 95% CI 1.3-2.2); (2) in addition, placenta accreta in a previous pregnancy is associated with a reduced rate of mild preeclampsia in future pregnancies (1.8% vs. 3.4%, RR 0.51, 95% CI 0.26-0.98); (3) however, in spite of the higher rate of neonatal deaths in the study group, a history of placenta accreta was not an independent risk factor for total perinatal mortality (adjusted OR 1.0, 95% CI 0.5-1.9) after adjusting for confounders. CONCLUSION A history of placenta accreta is an independent risk factor for postpartum hemorrhage. This should be taken into account in order to ensure a safety pregnancy and delivery of these patients.

Second stage disorders in patients following a previous cesarean section: vacuum versus repeated cesarean section

ObjectiveTo investigate whether vacuum extraction due to failure of labor to progress (dystocia) during the second stage in a delivery following a previous cesarean section (CS) is related to increased adverse maternal and perinatal outcomes as compared with repeated CS.Study designA retrospective cohort study of pregnancy and delivery outcomes of patients in their second deliveries attempting a vaginal birth after cesarean (VBAC) following one CS was conducted. Patients who delivered by vacuum extraction were compared with patients who underwent a repeated CS for failure of labor to progress during the second stage.ResultsDuring the study period, 319 patients with a previous CS suffered from a prolonged second stage of labor in their second delivery. Of these, 184 underwent vacuum extraction and 135 patients underwent a repeated CS. No significant differences in relevant pregnancy complications such as perineal lacerations, uterine rupture, and post-partum hemorrhage and perinatal outcomes were noted between the groups. There were no cases of perinatal mortality in our study.ConclusionWhen managing second stage labor disorders, vacuum extraction does not seem to be an unsafe procedure in patients with a previous CS.

The more you lose the more you miss: accuracy of postpartum blood loss visual estimation. A systematic review of the literature.

Abstract Midwives and nurses have a key role in monitoring postpartum period. They represent the first line professional figure in quantifying blood loss, initiating early diagnosis of obstetric hemorrhage, and mobilizing a team response, if needed. These actions are crucial in determining maternal outcome in postpartum hemorrhage (PPH). In our review we aimed to: (1) Provide a picture of PPH including its pathophysiology, epidemiology, and associated complications; (2) Discuss diagnosis of this dangerous postpartum event; and, (3) Especially evaluate the efficiency of the employment of visual blood loss estimation as a rapid way to suspect PPH and activate the patient assessment.

The frequency and type of placental histologic lesions in term pregnancies with normal outcome

Abstract Objective To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome. Methods This retrospective cohort study included placental samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion. Results (1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) maternal and fetal vascular lesions of malperfusion were detected in 35.7% and 19.7%, respectively. Two or more lesions with maternal or fetal vascular features consistent with malperfusion (high-burden lesions) were present in 7.4% and 0.7%, respectively. Conclusion Most placentas had lesions consistent with inflammatory or vascular lesions, but severe and/or high-burden lesions were infrequent. Mild placental lesions may be interpreted either as acute changes associated with parturition or as representative of a subclinical pathological process (intra-amniotic infection or sterile intra-amniotic inflammation) that did not affect the clinical course of pregnancy.

The clinical utility of sonographic cervical length in the management of preterm parturition at 28–32 weeks of gestation

Abstract Objectives: The aim of this study was to evaluate the role of cervical length measurement in early third trimester (28–32 weeks) as a predictor of preterm delivery (PTD), in women presenting with preterm parturition. Methods: Cervical length was measured prospectively, in singleton pregnancies at 28–32 weeks with preterm contractions (PTC). A multivariate linear regression model was performed to assess the association between cervical length and gestational age at delivery. Logistic regression analysis with PTD before 34 and 37 weeks of gestation as the outcome variable was performed to control for confounders. Results: Fifty-six women were included, mean gestational week at presentation and at delivery were 29.88 ± 1.13 and 37.05 ± 2.86, respectively. There was a direct association between short cervical length at admission and gestational week at delivery (p = 0.027). This association remained significant even after controlling for confounders. Short cervical length was significantly associated with PTD before 34 (p = 0.045) or 37 (p = 0.046) weeks of gestation. Conclusions: Third trimester cervical length measurement in patients with PTC is associated with gestational week at delivery, as well as PTD prior to 34 and 37 weeks of gestation. Therefore, examining cervical length is clinically valuable and probably cost-effective during early third trimester.

Maternal total cell-free DNA in preeclampsia and fetal growth restriction: Evidence of differences in maternal response to abnormal implantation

Objectives Preeclampsia and fetal growth restriction are obstetrical syndromes associated with abnormal placental implantation and changes in the activation status of maternal leukocytes. This study is aimed to determine by a simple, rapid fluorescent assay the changes in maternal serum total cell-free DNA (t-cfDNA) concentrations in women with preeclampsia and those with fetal growth restriction (FGR). Study design A cross-sectional study was conducted measuring maternal serum t-cfDNA concentrations. Women were classified into the following groups: 1) patients with preeclampsia (n = 21); 2) FGR-estimated fetal weight below the 10thpercentile (n = 28); and 3) normal pregnancy (n = 39). Serum samples were directly assayed for t-cfDNA using a rapid fluorescent SYBR Gold assay. Elevated maternal serum t-cfDNA concentrations were defined as a cutoff>850ng/ml. Nonparametric statistics were used for analysis. Results Women with preeclampsia had a higher median maternal serum concentration (802 ng/ml, 400–2272 ng/ml) than women with a normal pregnancy (499 ng/ml, 0–1892 ng/ml, p = 0.004) and those with FGR (484 ng/ml, 72–2187 ng/ml, p = 0.012). Moreover, even patients with FGR <5th percentile and abnormal Doppler had a lower median maternal serum t-cfDNA than those with preeclampsia (median 487 ng/ml, 144–1971 ng/ml, p = 0.022). The median concentration of t-cfDNA did not differ between women with a normal pregnancy and those with FGR (p = 0.54), as well as those with fetuses <5th percentile and abnormal Doppler (p = 0.7). Women with preeclampsia had a higher proportion of elevated t-cfDNA than those with a normal pregnancy (p = 0.015) and patients with FGR (p = 0.025). Conclusions Preeclampsia is associated with higher maternal serum t-cfDNA concentration than normal pregnancy or FGR. This observation may reflect an increased systemic activation of the maternal inflammation, rather than placental; this assumption is supported by the fact that we did not observe a significant change in the maternal serum t-cfDNA in patients with placental-mediated FGR.

Mechanisms of death in structurally normal stillbirths

Abstract Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered “raised”. Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect.

The association between cervical inflammation and histologic evidence of HPV in PAP smears and adverse pregnancy outcome in low risk population

OBJECTIVE Recent studies suggest an association between Human Papilloma Virus (HPV) infection, cervical inflammation and obstetric complications (i.e. spontaneous preterm parturition and cervical insufficiency). It has been proposed that viral inflammation of the placenta causes changes in the mothers immune reaction to bacterial pathogens, which leads to enhanced inflammatory reaction and preterm delivery. Therefore, the aim of this population-based study was to determine the association between abnormal cervical cytology prior to pregnancy and obstetric outcomes. STUDY DESIGN A Retrospective population-based cohort study was designed, including all women who had a Pap smear up to two years prior to delivery or during first trimester of pregnancy (n = 15,357). Women were divided into the following groups, according to Pap smear results: group 1 - Normal PAP smear (n = 11,261); group 2 - Pap smear with evidence of an inflammatory process (n = 3895); and group 3 - Pap smear with evidence of HPV infection (n = 201). Obstetrical outcomes, gestational age at delivery, and pregnancy complications were compared among the groups. RESULTS The rate of HPV infection in our study population was 1.3%. The rate of preterm delivery (group 1 - 8.5%, group 2 - 8.5%, group 3 - 7%, p = 0.7), preterm PROM (group 1 - 1.7%, group 2-1.6%, group 3 - 2%, p = 0.66) and cervical insufficiency (group 1 - 0.5%, group 2 - 0.7%, group 3 - 1.5%, p = 0.11) did not differ significantly among the study groups. There was no statistical difference in the rate of premature rapture of membranes, newborn small-for-gestational-age, preeclampsia or placental abruption. Women with abnormal cervical cytology, either due to inflammation or HPV infection, had similar obstetric outcome in comparison to those with a normal cervical cytology. CONCLUSION This population-based retrospective cohort study indicates no association between positive HPV testing with Pap smear and obstetric complications such as preterm delivery, cervical insufficiency, placental abruption, PROM, Preterm PROM, neonatal SGA and preeclampsia, in a population with low prevalence HPV infection.