Držislav Kalafatić

Uterine anomalies and pregnancy outcome following resectoscope metroplasty.

Objective: To compare reproductive outcome in women with uterine anomalies and women with a normal uterus, and evaluate the effect of resectoscope metroplasty. Methods: The pregnancy outcomes, past and present, of 105 women with congenital uterine anomalies were compared with those of 182 women with a normally shaped uterus. The outcomes of 25 women with septate and bicornuate uteri before and after resectoscope metroplasty were also analyzed. The χ2 and Mann‐Whitney U test were used for statistical analysis, with P < 0.05 considered statistically significant. Results: Uterine anomalies were associated with higher rates of spontaneous abortion, preterm delivery, intrauterine growth retardation, breech presentation, and cesarean delivery (P < 0.001). The highest incidence of early spontaneous abortion was noted among women with septate uteri, and the highest incidence of preterm labor was noted among women with arcuate or bicornuate uteri. Among women with arcuate uteri, significantly lower gestational age and birth‐weight were observed compared with any other type of adverse outcome. Compared with their previous pregnancies, the abortion rates were lower and delivery rates were higher in women who conceived following hysteroscopic metroplasty (P < 0.001). Conclusion: Resesctoscope metroplasty significantly improved pregnancy outcome in women with uterine anomalies.

Maternal plasma interleukin-6, interleukin-1β and C-reactive protein as indicators of tocolysis failure and neonatal outcome after preterm delivery

Objective. To investigate whether maternal serum interleukin-6 (IL-6), interleukin-1β (IL-1β) and high sensitive C-reactive protein (CRP) could be used as markers of tocolysis failure and adverse neonatal outcome in pregnancies with preterm labor (PL). Methods. Forty-seven maternal blood samples taken because of PL at admission and delivery were analyzed. Control samples were taken from 20 gravidas with normal pregnancies. Differences in interleukins and CRP levels with or without chorioamnionitis, connatal infection or periventricular leukomalacia (PVL) were analyzed. Cut-off values were estimated for prediction of tocolysis failure and adverse neonatal outcome. Results. All three parameters were significantly higher in patients delivering prematurely than in patients delivering at term. All three parameters were significantly higher with than without histologic chorioamnionitis (p < 0.001), with than without connatal infection (p < 0.01), with than without PVL (p < 0.01 for IL-6 and IL-1β, p < 0.05 for CRP), and in pregnancies with preterm premature rupture of membranes (PPROM) delivered within 48 hours compared to those more prolonged (p < 0.01). Choosing 50.9 pg/mL of IL-6 and a CRP of 19.7 as cut-offs in maternal blood admission concentrations for neonatal PVL, resulted in sensitivity of 81% and specificity of 91% and sensitivity of 91% and specificity of 81%, respectively. At respective maternal blood admission cut-off levels of 27.8 pg/mL of IL-6 and 8.9 of CRP, both parameters were effective predictors of connatal infection. Conclusions. Maternal blood IL-6 and CRP could become useful in predicting tocolysis failure and intrauterine treat for the fetus.

Maternal neonatal outcome in quadruplet and quintuplet versus triplet gestations

OBJECTIVE Examination and comparison of the natural histories of triplet versus quadruplet and quintuplet gestations. STUDY DESIGN A retrospective study of sixty-four multifetal pregnancies (fifty-two sets of triplets, nine sets of quadruplets and three sets of quintuplets) cared for during past 12 years in our department. Quintuplets and quadruplets were compared with triplet pregnancies according to gestational age, birthweight, pregnancy complications and perinatal outcome. Students t-test, Fisher exact test and chi2 test were used for statistical analysis, considering P value of <0.05 as statistically significant. RESULTS Although mean gestational age at delivery between triplets and higher order gestations was not significantly different, birthweight of quadruplets and quintuplets was significantly lower. Pregnancy complications, including intrauterine growth retardation, were equally distributed between the groups. Early neonatal and perinatal mortality were significantly higher in quadruplets and quintuplets than in triplets. Surprisingly, survival of growth retarded fetuses was better than survival of their eutrophic counterparts. The spontaneous loss rate was 11.5% for entire triplet gestation and 16.7% for quadru- and quintuplet pregnancies. CONCLUSIONS As the spontaneous loss rate of triplets and higher order pregnancies observed in our study is quite similar to pregnancy loss rate caused by multifetal pregnancy reduction, conservative management of multifetal pregnancies in specialised tertiary centers seems to be a prudent solution.

Pregnancy outcome in renal transplant recipients

Objective: To correlate pregnancy outcome with complications in pregnancy and transplantation‐to‐pregnancy interval in renal transplant recipients in Croatia. Method: Data on 23 pregnancies after prepregnancy stabilization of blood pressure and normalization of graft function were retrospectively analyzed. Result: The mean interval between transplantation and conception was 3.1 years. Primary renal disease was chronic glomerulonephritis in 7, chronic pyelonephritis in 7 and agenesis of right kidney and stenosis of left renal artery in 1 patient. There were 10 term and 5 preterm deliveries, 6 induced and 2 spontaneous abortions. The mean gestational age was 38.1 weeks and the mean newborn birthweight was 3015 g. The prematurity rate was 21.7%. Patients with arterial hypertension in pregnancy, elevated serum creatinine level and bacteriuria, as well as those with conception occurring less than 2 years after transplantation, had a higher rate of therapeutic and spontaneous abortions, preterm deliveries and low birth weight infants. Conclusion: The interval between transplantation and conception, as well as allograft function during pregnancy, seem to be of great importance for successful obstetric outcome in renal transplant patients.

Hospitalization vs. outpatient care in the management of triplet gestations

Objective: To compare the course and outcome of triplet gestations under a preventive care strategy that includes hospitalization, surveillance, bed rest, and daily specialized care from the beginning of the second trimester, with pregnancies managed according to the Croatian standard outpatient care protocol for multiplets. Methods: A retrospective study of 79 triplet pregnancies. Preventive hospitalization from the beginning of the second trimester, with complete bed rest and all necessary interventions, was chosen by 55 women (Group I). The remaining 24 women (Group II) elected the standard outpatient protocol for multiple pregnancies. Outpatient management with prophylactic bed rest was initiated at home as soon as the multiple pregnancy was diagnosed. After 28 weeks of gestation, all outpatients were hospitalized until delivery irrespective of symptoms. Results: There was no difference between the groups regarding maternal age, race, pre‐pregnancy weight and height, weight gain during the first 24 weeks of pregnancy, or the proportion of pregnancies achieved with assisted reproductive technology. Four out of 55 women (7.2%) from Group I and 4 out of 24 women (12.5%) from Group II had monochorionic triplet pregnancies (P=n.s.). Nulliparity was more frequent in Group I than in Group II (P=0.006). Elective cesarean delivery was significantly more frequent in Group I (46 out of 55 gestations, 72.7%) than in Group II (9 out of 24 gestations, 37.5%), P=0.024. Gestational age at delivery and mean birth weight were significantly higher in Group I than in Group II (P<0.001). Deliveries up to 28 weeks of pregnancy were infrequent in Group I (P=0.02). Thirty‐three gestations in Group I (60%) and 6 (25%) in Group II had a duration of 33–36 weeks (P<0.001). Two out of 55 triplet gestations in Group I (3.6%) and 4 out of 24 in Group II (16.7%) ended in spontaneous abortion (P=0.053). The survival of the three triplets was more frequent in Group I than in Group II (P=0.048). For gestations reaching 24 weeks or more, the fetal and perinatal death rate was significantly lower in Group I (P<0.001). In Group I the intrauterine death rate for fetuses weighing 1500 g or less was also significantly lower (P=0.007), and the early neonatal death rate was almost half (15.8 vs. 28.9%, P=0.157). There were no differences in other pregnancy complications between the two groups except significantly more frequent preterm premature rupture of membranes and preterm labor requiring parenteral tocolysis in Group II (P=0.042 and 0.036, respectively), and significantly more frequent fetal growth retardation in Group I (P<0.001). Conclusion: Preventive hospitalization offers a better outcome for triplets even though prolonged hospitalization and all other procedures necessary to achieve optimal pregnancy outcome are also offered in the Croatian standard outpatient care protocol for multiplet pregnancies.

Antenatal predictors of the neurologic sequelae at 3 years of age : a multivariate analysis

OBJECTIVE To study the association between fetal blood flow abnormalities and the occurrence of long-term neurologic sequelae. STUDY DESIGN Umbilical, aortic and middle cerebral artery blood flow parameters were obtained by Doppler examination and retrospectively analyzed in 128 high-risk singleton pregnancies, followed by neurologic examination of the surviving children at 3 years of age. Traditional parameters of neurologic outcome (Apgar scores, intrauterine growth retardation (IUGR), umbilical artery pH and base deficit, gestational age, birth weight, newborn encephalopathy, mode of delivery, fetal heart rate, neurosonographic examination) were included as possible confounding factors. Mann-Whitney U-test, Students t-test, analysis of variance or Fishers exact test, where applicable, were used for the univariate analysis. A stepwise logistic regression procedure was conducted to test the independent association of selected perinatal risk factors on neurological outcome. Statistical significance was assumed at P<0.05. RESULTS Eighteen out of 114 surviving children suffered neurologic illness at 3 years of age. Four children had major neurologic dysfunction and the remaining 14 suffered minor or mild form of the disease. Although blood flow parameters and various perinatal parameters did not differ significantly between the group of children with major neurologic dysfunction and healthy children, aortic resistance index showed an independent association with occurrence of minor or mild neurologic disabilities. CONCLUSION Antenatal evaluation of the aortic blood flow might be an important predictive variable for permanent neurologic disturbances.

PTCH1 gene polymorphisms in ovarian tumors: potential protective role of c.3944T allele.

In this study we investigated the types and role of different genetic changes of PTCH1 gene in three different types of ovarian tumors: carcinomas, fibromas and dermoids. LOH of the PTCH1 region was detected in 27.3% ovarian carcinoma samples, 18.18% ovarian fibroma samples and 55.56% ovarian dermoid samples. No point mutations were detected in any of the three types of ovarian tumors. SNP c.3944C>T showed significant differences between ovarian carcinoma and control samples with the minor T allele being significantly higher in controls compared to ovarian carcinomas. Interestingly, a new polymorphism c.-1184G>A was found only in tumor samples and further analyses should be performed in order to elucidate its potential role in ovarian tumors.

Non-canonical Hedgehog signaling activation in ovarian borderline tumors and ovarian carcinomas

Hedgehog signaling pathway has been implicated in the pathology of ovarian cancer, and Survivin (BIRC5) has been suggested as a novel target of this pathway. Herein we investigated the role of Hedgehog signaling pathway and Survivin in ovarian carcinoma and borderline tumor samples. We aimed to determine possible ways of pathway modulation on primary ovarian cancer cells and an established cell line. RNA was extracted from fresh tumors and control tissues and gene expression was examined using qRT-PCR. Pathway activity in cell lines was examined after treatment with cyclopamine, SHH protein, GANT-61 or lithium chloride using qRT-PCR, western blot and confocal microscopy. The difference between control tissue, borderline tumors and carcinomas can be seen in GLI1 and SUFU gene expression, which is significantly higher in borderline tumors compared to carcinomas. SUFU also shows lower expression levels in higher FIGO stages relative to lower stages. BIRC5 is expressed in all tumors and in healthy ovarian tissues compared to our control tissue, healthy fallopian tube samples. Primary cells developed from ovarian carcinoma tissue respond to cyclopamine treatment with a short-term decrease in cell proliferation, downregulation of Hedgehog pathway genes, including BIRC5, and changes in protein dynamics. Stimulation with SHH protein results in increased cell migration, while GLI1 transfection or PTCH1 silencing demonstrate pathway upregulation. The pathway activity can be modulated by LiCl at the GSK3β-SUFU-GLI level, suggesting at least partial non-canonical activation. Downregulation of the pathway with GANT-61 has proved to be more effective than cyclopamine. GLI inhibitors may be a superior treatment option in ovarian cancer compared to SMO inhibitors.