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To present antenatal management and use of ex utero intrapartum treatment (EXIT) in different fetal neck and high airway anomalies.We have presented four different cases of fetal neck or airway pathology which were indications for EXIT, at our department.In three cases of fetal neck tumors, the primary precise antenatal diagnoses of tumors were confirmed after birth. The airways of all three fetuses were properly secured during EXIT by laryngologist. All these newborns survived. In the fourth case, a primary, antenatal diagnosis of congenital high airway obstruction syndrome due to severe trachea obstruction was not confirmed after birth. Finally, due to complete trachea dysgenesis, neither tracheoscopy nor tracheostomy was done during EXIT and the baby died.Despite a failure of intrapartum treatment in the fourth case, we strongly recommend this procedure for deliveries of fetuses with a suspicion of airway obstruction.

Purpose Endometriosis is considered to be an estrogen-related chronic inflammatory disease. The 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) converts estrone to 17β estradiol. The role of HSD17B1 937 A>G (rs605059) single nucleotide polymorphism (SNP) in development of endometriosis is still disputable. This study evaluated the association of the HSD17B1 937 A>G (rs605059) SNP with infertile women affected by endometriosis from Polish Caucasian population. Methods The genotyping of cases (n = 290) and fertile women (n = 410) was conducted by high-resolution melting curve analysis. Results Statistical analysis demonstrated that the HSD17B1 937 A>G SNP is associated with endometriosis in stages I and II. The p trend and p allelic values calculated for the HSD17B1 937 A>G polymorphism were statistically significant and were equal to 0.001 and 0.0009, respectively. There was a significant association for the dominant model: (AG + GG vs AA) OR = 1.973 (95% CI = 1.178–3.304), p = 0.009, and for the recessive model: (GG vs AG + AA) OR = 1.806 (95% CI = 1.178–2.770), p = 0.006. However, we did not find statistical association of HSD17B1 937 A>G polymorphism with all infertile women with endometriosis or infertile women with endometriosis in stages III and IV. Conclusion Our genetic study demonstrated HSD17B1 937 G variant as a risk factor for infertility in women with stage I and II endometriosis in Polish Caucasian patients. Electronic supplementary material The online version of this article (doi:10.1007/s10815-017-0911-9) contains supplementary material, which is available to authorized users.

It has recently been reported that vitamin D blood plasma levels are associated with reduced risk of endometriosis. The present study aimed to investigate whether the vitamin D binding protein (GC), vitamin D receptor (VDR), and retinoid X receptor (RXR) gene variants may be genetic risk factors for endometriosis‑associated infertility. The subjects consisted of 154 women with endometriosis‑associated infertility and 347 controls. Using polymerase chain reaction restriction fragment length polymorphism and high resolution melt techniques, the GC rs1155563, rs2298849 and rs7041; RXRA rs10881578, rs10776909 and rs749759; VDR BsmI rs1544410; and FokI rs2228570 single nucleotide polymorphisms (SNPs) were investigated in the patients with endometriosis and the healthy controls. The results indicated that no significant differences were observed between the genotype and allele frequencies of all experimental SNPs in the vitamin D signaling pathway genes in women with endometriosis-associated infertility and controls. However, a significant association was present between the A‑T haplotype, consisting of VDR rs1544410 and rs222857 minor alleles, and endometriosis-associated infertility [OR=1.659 (1.122‑2.453), P=0.011]. The results of the present study suggested that VDR gene variants act as genetic risk factors for endometriosis‑associated infertility.

Objectives: The aim of the study was to analyze the levels of pro-inflammatory interleukins in cervical secretions of women with PROM, depending on Ureaplasma spp. infection and the time elapsed since the rupture of the membranes, and to correlate their concentration in cervical secretions and in cord blood of the newborns. Material and methods: The study included 30 women with PROM between 24 and 33+6 weeks of gestation. Cervical swabs from women with confirmed rupture of membranes taken at certain intervals and umbilical cord blood of their newborns constituted the study material. Cervical secretions were evaluated microbiologically and by the PCR method. Concentrations of IL-6, IL-19, IL-10 and TNF-α were analyzed by ELISA. Results: Ureaplasma spp. were the most frequently isolated microorganisms in cervical secretions of women with PROM. Secretion of interleukins in the cervix was not influenced by time elapsed since the PROM. Comparison of interleukin levels in cord blood of newborns born to mothers with and without Ureaplasma spp infection revealed significantly higher levels of IL-6 in the case of Ureaplasma spp. A positive correlation between IL-6 and TNF-α levels in cervical secretions and in cord blood of mothers with PROM and Ureaplasma spp. was detected. Conclusions: 1. Cervical culture method appears to be sufficient for detecting Ureaplasma spp. 2. Pro-inflammatory interleukins, especially IL-6, obtained by non-invasive methods can be used to predict fetal inflammatory response.

The article is a review of the literature on the use and clinical applicability of Doppler examination in the second half of pregnancy. Nowadays, despite its accessibility, Doppler ultrasound in pregnancy is often contraindicated. At the same time, the is no evidence of clinical utility of Doppler studies in a low-risk pregnancy. The main indications for Doppler examinations in pregnancy include intrauterine growth restriction (IUGR), suspicion of fetal anemia, and complications of monochorionic twin pregnancy. As far as IUGR is concerned, Doppler allows to diagnose IUGR associated with placental insufficiency and to differentiate IUGR from small for gestational age fetuses (SGA). Doppler is also very useful in making the decision about the time of delivery of IUGR fetuses. The assessment of the peak systolic velocity in the middle cerebral artery (PSV-MVA) reduced the rate of invasive procedures due to fetal anemia by approximately 70%. Complications of the second half of pregnancy which are indications for Doppler ultrasound include selective IUGR, TTTS and TAPS. Similarly to the first trimester, the mid-trimester assessment of the blood flow in the uterine arteries plays an important role in the prediction of preeclampsia and IUGR, especially early-onset forms of these complications.

Objective: The aim of the study was a long-term follow-up of children with prenatally found increased nuchal translucency (NT) and normal karyotype. Material and methods: The study was conducted among 147 pregnant women who underwent amniocentesis due to increased fetal NT with or without other structural anomalies in the fetus. The final analysis concerned children with prenatally found increased NT and normal karyotype who were at least 2 years of age. A questionnaire was sent to all patients who underwent amniocentesis in order to assess the development of the children. Results: Normal karyotype was found in 101 (68.7%) fetuses with increased NT. Complete information on the outcome of pregnancy and further development of the children was submitted by 70 patients (69.3%). An abnormal outcome of pregnancy, congenital structural anomalies and abnormal development was found finally in 17.1% of the children. In case of normal result of the second-trimester fetal ultrasound scan, normal further development was found in 93% of the children. Conclusions: 1. Further development of the children with prenatally found increased NT and normal karyotype is usually normal. 2. The degree of NT increase and the result of the second-trimester fetal anatomy scan seem to play the key role in the prognosis of further, postnatal outcome of the fetuses with increased NT. 3. Normal karyotype in fetuses with increased NT does not exclude the possibility of an existing genetic syndrome

There are inconsistent data on the contribution of vascular endothelial growth factor (VEGF) -460 C/T (rs833061), +405 G/C (rs2010963) and +936 C/T (rs3025039) single-nucleotide polymorphisms (SNPs) to endometriosis in different ethnicities. Therefore, using high-resolution melting curve analysis, the present study examined the distribution of these SNPs in females with endometriosis-related infertility and a control group. None of the three VEGF SNPs were associated with endometriosis-related infertility in the domi- nant and recessive models. The lowest P-values of the trend were observed for the VEGF +936 C/T (rs3025039) SNP in endometriosis-related infertility (Ptrend=0.149). Similarly, haplotype analyses of VEGF SNPs did not demonstrate any SNP combination as a risk for endometriosis-related infertility, and the lowest overall P-values, P=0.141 and Pcorr=0.395, were observed for a haplotype (TGT) of the above SNPs. Taken together, these results did not demonstrate the contribution of VEGF C/T, +405 G/C and +936 C/T SNPs to endometri- osis-related infertility.

Heparin has a beneficial effect in the treatment of recurrent miscarriages and positively affects implantation rates in the IVF procedure in women with reproductive disorders not associated with thrombophilia. Several studies have indicated that heparin, by blocking the enzymatic activity of heparanase, may affect the structure and function of the extracellular matrix (ECM) and related growth factors. Disturbances in the remodeling (ECM) are believed to be the potential cause of implantation disorders and recurrent miscarriages. Objectives: The aim of the study was the evaluation, on an in vitro model, of the effect of low molecular weight heparin (LMWH) on the expression of heparanase (HPSE) and, important for successful implantation and invasion of trophoblast, heparan sulfate (HS) - binding growth factors, i.e. heparin-binding epidermal growth factor-like (HB-EGF), vascular endothelial growth factor (VEGF-A), fibroblast growth factor (FGF2) in the endometrium, during the implantation window in women with recurrent miscarriage. Method: Biopsy samples, obtained from 10 patients with two or more unexplained miscarriages, were used to construct a co-culture of glandular epithelial cells and stroma. Endometrium in vitro model was supplemented with steroid hormones and enoxaparin 5ug/ml. Using the qPCR, we assessed relative levels of the HPSE, HB-EGF, VEGF-A and FGF2 transcripts in glandular epithelium and stroma in cell culture. Using ELISA, we measured concentrations of the mentioned above factors in culture medium. Results: A statistically significant increase in the relative level of HPSE, HB-EGF, VEGF-A, FGF2 transcripts in the cells of the glandular epithelium and stroma (p

Objective Overexpression of DNA methyltransferase 3A (DNMT3A) and aberrant methylation of various genes in eutopic endometrium have been demonstrated in women with endometriosis. We aimed to study whether DNMT3A polymorphisms could be a genetic risk factor for endometriosis and endometriosis-related infertility. Study design We studied 5 SNPs (rs2289195, rs7590760, rs13401241, rs749131 and rs1550117) located in the DNMT3A gene in 357 women with endometriosis and 640 controls. Results We did not observe significant differences between genotype and allele frequencies of rs2289195, rs7590760, rs13401241, rs749131 and rs1550117 SNPs in women with endometriosis, endometriosis-related infertility, and controls. The lowest p values of the trend test were observed for DNMT3A rs1550117 in endometriosis and endometriosis-related infertility ( p trend =0.049 and p trend =0.055, respectively). Conclusions Our results did not supply evidence for the contribution of SNPs located in DNMT3A to either endometriosis or endometriosis-related infertility.

In this review article we describe the ante- and perinatal management of fetal neck tumors. Although there are rare congenital anomalies, the clinical consequences for the fetus may be fatal and include airways obstruction, heart insufficiency, pulmonary hypoplasia and cosmetic effect. The right management allows to decrease the fetal and neonatal mortality and morbidity associated with the disease. It includes intrauterine therapy in some cases, mostly in a goitrus hypothyroidism of the fetus, but firstly, an assessment of the fetal airways patency with a subsequent, eventual Ex-Utero Intrapartum Treatment (EXIT).

We report the case of fetal goiter which occurred in two consecutive pregnancies in the same patients. The first one, due to too late diagnosis and no intrauterine treatment, contributed to the immediate postnatal death of the newborn; the second one was properly diagnosed at 19 weeks and then effectively treated prenatally which allowed to avoid the fatal complications for the fetus and the newborn.

Objective Endometriosis has been considered an epigenetic disease. Single nucleotide polymorphisms (SNPs) located in genes encoding enzymes of the folate and choline metabolism may affect DNA methyltransferase activity. Study design We studied 16 SNPs in 12 folate and choline metabolism genes, including BHMT (rs7356530 and rs3733890), BHMT2 (rs625879), CBS (844ins68), CHDH (rs893363 and rs2289205), CHKA (rs7928739), MTHFD1 (rs2236225), MTHFR (rs1801133), MTR (rs1805087), MTRR (rs1801394), PCYT1A (rs712012 and rs7639752), PEMT (rs4244593 and rs4646406) and TCN (rs1801198) in one hundred and sixty-three infertile women with minimal endometriosis and one hundred and fifty fertile women. Results There were no significant differences between genotype and allele frequencies of these gene variants in infertile women with endometriosis ( n =163) and controls ( n =150). The lowest, but not statistically significant, p values of the trend test were observed for the CBS 844ins68 and MTR rs1805087 ( p trend =0.0527 and p trend =0.0771, respectively) polymorphisms. However, the exhaustive multifactor dimensionality reduction analysis revealed an epistatic interaction between rs1801133 of MTHFR and rs4244593 of PEMT in endometriosis-associated infertility ( p =0.0240). Conclusions Our results showed moderate evidence for the contribution of SNPs located in genes encoding folate and choline metabolism enzymes to infertility in women with endometriosis.

In fertile women, HOXA-10 and HOXA-11 expression rises during the luteal phase, with the peak occurring during the implantation window, and stays at a high level until the end of the cycle. We evaluated the transcript and protein levels of HOXA-10 and HOXA-11 in the endometria of patients with idiopathic infertility (n = 15) and control patients (n = 10). The amounts of mRNA were determined by reverse transcription and real-time quantitative PCR. The protein levels were evaluated by Western blotting analysis. Using immunohistochemical techniques, we compared the localization of HOXA-10 and HOXA-11 proteins in the implantation window between the study and control groups. We observed statistically significantly decreased HOXA-10 and HOXA-11 transcript levels (p = 0.003, p = 0.012 respectively) in infertile patients compared to controls. There was no significant decrease in HOXA-10 protein levels between these groups (p = 0.074). However, we observed a significantly higher level of HOXA-11 protein in the endometria of infertile patients compared to controls (p = 0.015). HOXA-10 and HOXA-11 proteins were localized in the nuclei of the endometrial stromal cells. Immunohistochemical analyses did not reveal differences between amounts of HOXA-10 and HOXA-11 protein levels in infertility and control groups. Our results suggest that HOXA-10 and HOXA-11 gene expression in the endometrium during the implantation window may not be altered in patients with idiopathic infertility. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 1, pp. 111–118)

Recent human and animal studies have suggested that reduced HOXA10 expression in the implantation window of eutopic endometrium may contribute to infertility in women with endometriosis. Therefore, we examined the HOXA10 transcript, protein and HOXA10 promoter methylation levels in midluteal eutopic endometrium from 17 infertile women with minimal endometriosis and 15 healthy fertile women from a Polish cohort. Real-time quantitative PCR (RQ-PCR) and western blotting analysis revealed significantly lower levels of HOXA10 transcript (P = 0.019) and protein (P = 0.048) levels in eutopic endometrium from infertile women with endometriosis as compared to healthy fertile women. Moreover, sodium bisulfite sequencing of three HOXA10 CpG islands showed significantly higher methylation levels of genomic DNA from midluteal eutopic endometrium from infertile women with endometriosis as compared to healthy fertile women (P = 0.006). We confirmed that DNA hypermethylation can be one of the potential molecular mechanisms silencing HOXA10 expression in the midluteal endometrium associated with infertility in women with endometriosis.

Problem To determine the value of leukemia inhibitory factor (LIF) assessment for predicting the reproductive outcome. Method of study Two phase study. Phase I: assessment of LIF in uterine flushing. Phase II: 1,5 years after examining the last patient, a questionnaire was sent to all participants of the phase I. Phase I: Uterine flushing and endometrial samples were collected during implantation window from infertile patients with stage I/II endometriosis (n = 14), patients with idiopathic infertility (n = 27), luteal phase deficiency (n = 13), and fertile control (n = 21). LIF was assessed in uterine flushings in all patients by ELISA. In endometrium, semiquantitative RT-PCR was performed for LIF mRNA expression. Phase II: questionnaire has been sent to all infertile women taking part in the first phase of the experiment, regarding their reproductive outcome. Results 65.4% patients who had returned the questionnaire did get pregnant. LIF concentration at a cut-off point of 2.31 pg/ml had a 95.7% sensitivity and 81.8% specificity in predicting the reproductive outcome. Conclusion This prospective study for the first time in literature indicates that the LIF assessment can be used as a predictor of reproductive success.

The article is a review of the literature on the use and clinical applicability of Doppler examination in the second half of pregnancy Nowadays, despite its accessibility Doppler ultrasound in pregnancy is often contraindicated. At the same time, the is no evidence of clinical utility of Doppler studies in a low-risk pregnancy The main indications for Doppler examinations in pregnancy include intrauterine growth restriction (IUGR), suspicion of fetal anemia, and complications of monochorionic twin pregnancy As far as IUGR is concerned, Doppler allows to diagnose IUGR associated with placental insufficiency and to differentiate IUGR from small for gestational age fetuses (SGA). Doppler is also very useful in making the decision about the time of delivery of IUGR fetuses. The assessment of the peak systolic velocity in the middle cerebral artery (PSV-MVA) reduced the rate of invasive procedures due to fetal anemia by approximately 70%. Complications of the second half of pregnancy which are indications for Doppler ultrasound include selective IUGR, TTTS and TAPS. Similarly to the first trimester, the mid-trimester assessment of the blood flow in the uterine arteries plays an important role in the prediction of preeclampsia and IUGR, especially early-onset forms of these complications.

Objective: To evaluate cytokine levels (IL-1β, TNF-α, IL-6, IL-8), soluble intercellular adhesion molecule-1 (sICAM-1) and number of macrophages in peritoneal fluid (PF) of women with no minimal endometriosis and associated (or not) infertility in order to discriminate between infertility and/or endometriosis. Study design: Cytokines and sICAM-1 were measured by using quantitative enzyme-linked immunosorbent assay (ELISA) while the macrophages were identified by May-Grunwald-Giemsa and non-specific esterase staining and presented as medians. The measurements were performed in 78 women belonging to four selected subgroups according to their endometriosis and/or infertility status. Statistical analysis was performed using Kruskal–Wallis non-parametric ANOVA test. Additionally, discriminant function analyses were performed. Results: We have found the most elevated macrophage numbers in the groups of women with endometriosis. IL-1β did not present any statistically significant values differentiating the analysed subgroups. IL-6 (110.0 pg/ml) and TNF-α exhibited the highest concentrations (statistically significant) in a group of fertile women with endometriosis. IL-8 clearly differentiated between the subgroups with infertility and sICAM-1 was statistically significantly elevated in the subgroups of infertile women. In the forward discriminant analysis, when subdividing the studied population according to its infertility status (we considered macrophages, IL-8 and IL-6 in order of probability values), we have found striking probability value of 92% for the correct classification into an infertile population. Conclusion: Out of the range of the analysed factors we have found only the sICAM-1 to be singled out between the standard discriminant analysis and the forward one. However, this important flagging molecule might be of considerable value for discrimination between different types of pathology at the level of immune effector function. The increased levels of TNF-α and IL-6 signified a group of fertile women with endometriosis; however only IL-6 presented a discriminating value in multifunctional analysis of examined subgroups. The analysed range of factors had a greater tendency to discriminate between infertility status rather than endometriosis.

Objective To assess the total antioxidant potential of women with endometriosis-associated infertility, women with idiopathic infertility, and fertile controls. Design Retrospective study. Setting University medical hospital. Patient(s) Sixty-five women admitted for diagnostic laparoscopy. Main outcomes measure(s) Peritoneal fluid samples were analyzed for superoxide dismutase activity and total antioxidant status on spectrophotometry, glutathione peroxidase activity on enzyme-linked immunosorbent assay, and lipid peroxides levels on colorimetry. Result(s) Mean activity of superoxide dismutase, glutathione peroxidase, and total antioxidant status was lowest and lipid peroxide level was highest among infertile patients with endometriosis. Women with idiopathic infertility, in contrast, had the highest superoxide dismutase, glutathione peroxidase, and total antioxidant status activity and the lowest lipid peroxide level. Conclusion(s) High antioxidant potential is not a contributing factor in women with idiopathic infertility. Low total antioxidant status and low activity of antioxidant enzymes in the peritoneal fluid of infertile women with endometriosis probably do not influence fertility in these women, but these factors may play a role in the development of the disease.

Endometriosis is considered to be an epigenetic disease. It has previously been reported that the DNA methyltransferase 3-like (DNMT3L) rs8129776 single nucleotide polymorphism (SNP) contributes to endometrioma. In the present study, high‑resolution melting curve analysis was used to investigate the risks associated with the DNMT3L c.910‑635A/G (rs8129776), c.832C/T (rs7354779), c.812C/T (rs113593938) and c.344+62C/T (rs2276248) SNPs on stage I‑II endometriosis‑associated infertility. Included in the present study were patients presenting with stage I‑II endometriosis‑associated infertility (n=154) and a control cohort of healthy patients with confirmed fertility (n=383). No significant association between the above‑listed DNMT3L SNPs and the development of endometriosis‑associated infertility was identified. The lowest P‑values generated from trend analysis were observed in the DNMT3L c.832C/T (rs7354779) SNP (Ptrend=0.114). Furthermore, haplotype analyses of the DNMT3L SNPs failed to reveal any risk association between the development of endometriosis‑associated infertility and the above‑listed polymorphisms, even when the SNPs were present in combinations. Finally, a meta‑analysis was performed to examine the association between the DNMT3L rs8129776 SNP and the development of endometrioma, from which no association between the two was identified. On the basis of these results, the present study has demonstrated that variations in the DNMT3L gene do not contribute to stage I-II endometriosis-associated infertility.

Heparin has a beneficial effect in the treatment of recurrent miscarriages and positively affects implantation rates in the IVF procedure in women with reproductive disorders not associated with thrombophilia. Several studies have indicated that heparin, by blocking the enzymatic activity of heparanase, may affect the structure and function of the extracellular matrix (ECM) and related growth factors. Disturbances in the remodeling (ECM) are believed to be the potential cause of implantation disorders and recurrent miscarriages.The aim of the study was the evaluation, on an in vitro model, of the effect of low molecular weight heparin (LMWH) on the expression of heparanase (HPSE) and, important for successful implantation and invasion of trophoblast, heparan sulfate (HS)--binding growth factors, i.e., heparin-binding epidermal growth factor-like (HB-EGF), vascular endothelial growth factor (VEGF-A), fibroblast growth factor (FGF2) in the endometrium, during the implantation window in women with recurrent miscarriage.Biopsy samples, obtained from 10 patients with two or more unexplained miscarriages, were used to construct a co-culture of glandular epithelial cells and stroma. Endometrium in vitro model was supplemented with steroid hormones and enoxaparin 5 ug/ml. Using the qPCR, we assessed, relative levels of the HPSE, HB-EGF, VEGF-A and FGF2 transcripts in glandular epithelium and stroma in cell culture. Using ELISA, we measured con- centrations of the mentioned above factors in culture medium.A statistically significant increase in the relative level of HPSE, HB-EGF VEGF-A, FGF2 transcripts in the cells of the glandular epithelium and stroma (p0.001), as well as their increased concentration in the medium of cultures treated with steroid hormones (p0.001) were observed. However we found no effect of LMWH supple- mentation on the level of the investigated factors.Our results show that the importance of the HPSE hydrolytic activity in the endometrium, during the implantation window, may have a secondary function, and/or that beneficial effects of LMWH in women with impaired reproduction have no significant, direct connection with the, catalyzed by HPSE, reconstruction of the ECM and with release of heparin-binding growth factors.

Data suggests that dopamine receptor DRD2 gene variants may contribute to hyperprolactinemia and that they may be risk factors for endometriosis-related infertility. The purpose of the present study was to determine whether nucleotide variants of the DRD2 gene may be associated with infertility related to endometriosis. Five DRD2 SNPs, rs1800497, rs6277, rs2283265, rs4245146 and rs4648317, which are located in different blocks of linkage disequilibrium, were studied in 151 cases and 381 controls. No significant differences between DRD2 rs1800497, rs6277, rs2283265, rs4245146 and rs4648317 genotype, allele nor haplotype frequencies were observed in women with endometriosis-related infertility compared with the control group. The present results did not confirm DRD2 gene variants to be genetic risk factors for endometriosis-related infertility.

Infertility remains a challenge to modern medicine. Despite extensive diagnostic and therapeutic procedures, the achievement of pregnancy remains an elusive goal in some patients. The endometrium is one of the key factors in embryo implantation. Older methods of describing endometrial receptivity like histology or ultrasound, did not bring noticeable improvement in pregnancy rates. New technologies, including genomics, proteomics, lipidomics, and secretomics promise to improve the detection of the implantation window in the endometrium and result in better counseling of patients with infertility.

Objective: To measure the levels of antigamete antibodies in serum and peritoneal fluid of women with endometriosis and/or infertility. Design: Antibody activity against human sperm and porcine oocytes was analyzed in selected subgroups of women. Setting: Clinic of reproduction. Patient(s): Women with endometriosis and/or infertility. Intervention(s): No treatment was implemented before peritoneal fluid and blood sample collection. Main Outcome Measure(s): Quantitative ELISA. Result(s): Four groups of women (n = 98) were analyzed for the presence of antizona and antisperm antibodies: infertile with endometriosis (n = 30), idiopathic infertility (n = 28), fertile with endometriosis (n = 20), and healthy fertile controls (n = 20). Antibodies were analyzed simultaneously in serum and peritoneal fluid. No statistically significant differences in antibody levels were detected in serum samples among the analyzed groups. The median values for antizona and antisperm antibodies in peritoneal fluid were significantly higher in women with idiopathic infertility than in the control group. In women with unexplained infertility, a high degree of correlation (Spearman) was found between the presence of antizona antibodies in peritoneal fluid and serum (r = 0.579). A positive predictive value of 80% was calculated for the presence of antizona antibodies (>5 ng/oocyte) in the peritoneal fluid of patients with infertility. Conclusion(s): Antizona antibodies locally produced in the peritoneal fluid have diagnostic value for infertility status; however, they cannot be treated as a marker or prognostic factor for minimal endometriosis and/or its treatment.

Objective To answer the question as to whether the markers of thrombophilia in pregnant women, whose pregnancies ended in success, are reflected in the level of inflammation in the blood of the umbilical cord of the newborn. Materials and methods Umbilical cord blood and placenta after childbirth were secured from 16 patients with inherited (n = 7), acquired (n = 9) thrombophilia, and control group (n = 20). The concentrations of cytokines IL1β, IL10, TNFα, C5a anaphylatoxin, and granzyme A were assessed. decay accelerating factor (DAF) and membrane cofactor protein (MCP) levels were determined in the placentas, and the incidence of thrombotic changes was evaluated. Results Higher levels of anaphylatoxin C5a (P = 0.041), TNFα (P = 0.016), and IL1β (P = 0.037) were observed in the study group compared to the control group. In the study group, C5a levels correlated with the levels of TNFα (P = 0.018) and IL1β (P = 0.012). Higher levels of DAF and MCP proteins in study group were found in the control group (P

Objectives: Comparison of fetal umbilical and middle cerebral artery flow between early- and late-onset preeclampsia. Material and methods: Our study was conducted among 50 patients with preeclampsia in the third trimester of pregnancy and included 30 women with early-onset and 20 with late-onset disease. Early-onset preeclampsia (EOP) and late-onset preeclampsia (LOP) were defined as onset of the disease before and after 34 weeks of gestation, respectively. Doppler examinations of the fetal umbilical and middle cerebral artery were performed in all patients. Pulsatility Index (PI) and cerebral-umbilical ratio (CUR) were measured each time. Results: Mean value of the umbilical artery PI was significantly higher in fetuses of patients with EOP in comparison to LOP, whereas mean PI value in MCA was significantly lower in fetuses from the group with EOP than LOP. The percentage of abnormal results of fetal Doppler examinations, both in the umbilical artery and middle cerebral artery, was significantly higher in EOP than in LOP. The same tendency was observed for CUR. Conclusions: 1. Early-onset preeclampsia is characterized by significantly higher degree of placental insufficiency than late-onset disease. 2. The obtained results indicate a significant, pathological role of the placenta in early-onset preeclampsia. 3. Pathophysiological differences between early- and late-onset preeclampsia lead to different clinical approach to patients, depending on the type of the disease, including emphasis on Doppler examination in the early-onset preeclampsia. 4. The presence or absence of placental insufficiency in pregnancy complicated by preeclampsia seems to determine the clinical course of the disease, thus allowing for an alternative classification of the condition into placental and maternal preeclampsia.

Objectives: The object of our study was to assess the efficacy, measured as achievement of pregnancy, of artificial insemination with husband sperm in couples that fulfilled the WHO criteria for infertility. Material and methods: We have identified 120 patients that were diagnosed with infertility, defined as at least one year of unprotected intercourse without achieving pregnancy. After 2 year follow up the study group comprised 96 women and their partners. All couples had normal outcome of all standard infertility test, except for some with decline in sperm parameters that allowed the husband sperm to be used for fertilization in the IUI procedure according to the 2010 WHO guidelines. After IUI procedure patients were followed either by contact with their physicians, mail questionnaire, or by identification of their national ID number in computerized database of our hospital. Results: A total of 32 patients got pregnant (33%). Of those that achieved pregnancy during the two year follow up period, fifteen (46.9%) had done so as a result of AIH, another 15 as a result of spontaneous conception, and two as a result of IVF (6.2%). The mean number of AIH procedures in a group of women that did achieve pregnancy was 3,56 (median 3.0), and was statistically higher than the number of AIH in those patients who have failed to achieve pregnancy (mean 2.54; median 2.0; p=0.009). Conclucions: Our study seems to support the new criteria for assessment of sperm parameters. Judging the sperm according to the new, lessened criteria, did produce comparable pregnancy rates as with historical cohortsbased on old criteria.

Objectives: Assessment of serum concentrations of antiangiogenic factors, triglycerides, glucose, insulin and SHBG in women with two forms of preeclampsia (placental and maternal). Material and methods: The study was conducted among 30 patients with placental preeclampsia and 20 women with maternal form of the disease. All patients were hospitalized at the Division of Reproduction, Poznan University of Medical Sciences, between 2010-2012. The placental form of preeclampsia was diagnosed in cases when Doppler signs of placental insufficiency were present. The maternal type of the disease was diagnosed in the absence of coexisting markers of placental insufficiency in the Doppler study. ELISA was used to determine the concentrations of antiangiogenic factors (sFlt-1 and sEng). Results: The placental form of preeclampsia was diagnosed significantly earlier than maternal type of the disease. In women with placental preeclampsia the gestational age at delivery and newborn birth weight were significantly lower than in patients with maternal preeclampsia. IUGR incidence (expressed as a percentage) was significantly higher in patients with placental preeclampsia as compared to the women with maternal form of the disease. Serum concentrations of sFlt-1 and sEng were significantly higher in women with placental preeclampsia. No differences in concentrations of glucose, insulin, triglycerides and SHBG were found between groups. Conclusions: 1. The Two Stage Model of preeclampsia, characterized by increased concentrations of antiangiogenic factors in maternal blood secondary to decreased placental blood flow, seems to better explain the pathophysiology of the placental form of preeclampsia than the maternal one. 2. Late onset of clinical symptoms in maternal preeclampsia, lower incidence of IUGR, as well as lower concentrations of antiangiogenic factors in maternal blood, do not indicate the primary role of placental pathology in the pathogenesis of the disease. 3. In spite of no difference in metabolic abnormalities in third trimester of pregnancy between two types of preeclampsia, the patophysiology of the two forms of the disease seems to be different. 4. The obtained results of metabolic markers in women with two types of preeclampsia justify the need of further studies in this field in first trimester of pregnancy.

Objective Endometriosis is recognized as an estrogen-dependent disease. There are conflicting data demonstrating single nuclear polymorphisms (SNPs) of CYP17 and CYP19 steroidogenic genes as related to endometriosis risk. We assessed the CYP17 5′-untranslated region -34 A/G (rs743572) and CYP19 Ex10 + C1558T (rs10046) SNPs in stage I–II endometriosis. Design Case–control study. Setting Division of reproduction at a university department in Poland. Population A total of 115 women with diagnosed stage I–II endometriosis according to the revised American Society for Reproductive Medicine (rASRM) classification and 197 fertile women as controls. Methods The SNPs CYP17 -34 A/G and CYP19 Ex10 + C1558T were identified by high-resolution melting curve analysis. Main outcome measures Genotype prevalence and odds ratio for recessive and dominant genetic model for CYP17 and CYP19 SNPs. Results We observed a significantly increased CYP17 GG and GA genotype frequency in women diagnosed with rASRM stage I–II endometriosis compared with fertile women (OR = 2.4; 95% CI 1.4–4.2, p = 0.002). We also found a significantly increased CYP17 G allele frequency in cases compared with controls (OR = 1.6; 95% CI 1.2–2.2, p = 0.004). There were no significant differences in the distribution of the CYP17 GG genotype and CYP19 Ex10 + C1558T polymorphism between women diagnosed with rASRM stage I–II endometriosis and controls. Conclusion The CYP17 -34 G variant, previously associated with increased 17β-estradiol production, displayed a contribution to stage I–II endometriosis in women from a Polish population. Increased 17β-estradiol concentration in carriers of the CYP17 -34 G variant might contribute to endometriosis and associated pathological processes.

Although it was suggested that heparanase (HPSE) may affect implantation and pregnancy, so far there have been no wide-ranging studies on the expression of and possible disturbances in the interactions between HPSE, heparan sulfate (HS) and related growth factors, such as heparin-binding EGF-like growth factor (HB-EGF). The aim of this study was to evaluate whether the expression profile of both HPSE and HB-EGF can be associated with impaired reproduction in the endometrial implantation window, in the non-conception cycle. The study group consisted of 32 women with two or more unexplained, consecutive miscarriages, and 61 idiopathic infertility patients, while the control comprised of 22 women with normal reproductive potential. We compared the expression of HB-EGF and HPSE at the transcript (qPCR) and protein (Western Blot) levels in eutopic endometrium. Also assessed were correlations between both factors in the studied groups. In women with consecutive miscarriages we observed lower HPSE relative transcript (p = 0.003) and lower protein (p = 0.002) level compared with the control group. Level of the HB-EGF protein was decreased (p = 0.017). HPSE mRNA level was higher in idiopathic infertility (p = 0.003) compared with women with miscarriages. We found statistically significant correlations in both transcript and protein levels in all groups (p < 0.05). Our results allow the assumption of the existence of a process by which, in normal human endometrium, HB-EGF expression coincides with the synthesis of HPSE. As a result, the HB-EGF molecule can bind to the HS on the cell surface, enhancing its affinity to the receptor. Then, the release of growth factors associated with HS oligomers occurs that is catalyzed by HPSE. We suggest that one of the causes of unexplained miscarriages may result from the impaired expression of HPSE and HB-EGF.

Assessment of uterine artery blood flow in women with congenital thrombophilia and antiphospholipid syndrome (APS) in the first half of pregnancyUterine arteries blood flow was assessed in a Doppler examination in 20 women with thrombophilia (15 with congenital thrombophilia, 5 with APS) at 12 and 20 weeks gestation at the Division of Reproduction, Poznan University of Medical Sciences, between 2000 and 2012 The control group consisted of 20 multiparous pregnant women with no history of pregnancy complications. All patients with thrombophilia received enoxaparin or enoxaparin and aspirin before enrollment into the study Patients from the control group did not receive any antithrombotic prophylaxis. The mean Pulsatility Index (PI) of both uterine arteries and the presence or the absence of the "notch" was assessed, both at 12 and 20 weeks gestation in each patient from the study and from the control groups.Mean PI values in the uterine arteries at 12 weeks in patients with thrombophilia and in controls were 1.82 (1.00-3.13) and 1.52 (1.30-1.88), respectively (p = 0.08). Mean PI value in the uterine arteries was 7.27 (0.61-2.48) in women with thrombophilia at 20 weeks, which turned out to be significantly higher (p = 0.026) than in the control group 1.07 (0.8-1.24). The bilateral "notch" was found at 12 weeks gestation in 40% of patients with thrombophilia vs. 0% in the control group (p = 0.03). There was no significant difference between the groups in this parameter at 20 weeks.1. An increased impedance of flow was found in the uterine arteries in patients with thrombophilia at 12 and 20 weeks gestation in spite of antithrombotic prophylaxis. 2. Thrombotic episodes in patients with thrombophilia cannot be explained solely by the presence of placental thrombosis.

Endometriosis is defined by endometrial glands and stroma outside of the endometrial cavity Three types of endometriosis have been described: peritoneal endometriosis, ovarian endometriosis and deep infiltrating endometriosis. Endometriosis afflicts 6-15% of women population. It occurs mainly in the group of women in reproductive age, but also in the group of minors and approximately 3% of women after menopause. Within the group of women suffering from infertility the frequency of endometriosis increased to 35-50% of cases. Endometriosis is associated with pain symptoms which can bear the character of pain occurring periodically and altering into constant pain, dysmenorrhea, dyspareunia, dysuria and dyschezia. The correlation between the stage of endometriosis and intensity of pain symptoms not always has to be proportionate. Laparoscopy can be perceived as a standard procedure in endometriosis diagnostics as it allows simultaneous treatment. Profound interview as well as visual diagnostics (USG, MRI) should precede laparoscopy Treatment of endometriosis can be divided into pharmacological and surgical treatment, which can be invasive or non-invasive. The type of treatment depends on patient's age and her procreation plans, occurring ailments and endometriosis type. Important role is played by adjuvant treatment such as appropriate diet and lifestyle. Treatment of advanced endometriosis should be conducted in reference centres that are appointed with adequate equipment and have the possibility of interdisciplinary treatment. Presented standards can digest and outline the order of proceedings both in diagnostics and endometriosis treatment. The research group believes that the above compilation will facilitate undertaking appropriate decision in diagnosis and treatment of the disease, which will subsequently contribute to therapeutic success.

Introduction: Claudin-4 (CLDN4) is a transmembrane protein, responsible for cellular contact and organization. A different expression of claudin 4 in the endometrium, depending on the menstrual cycle and with peak at the aim of the ‘implantation window’, has been observed. CLDN4 is believed to play an important role in embryo implantation. The aim: The aim of the study was to compare the mRNA CLDN4 expression levels in two subgroups of infertile women (idiopathic infertility or minimal endometriosis) and compare them to fertile controls. Method: The study included 36 women with idiopathic infertility and 24 with minimal endometriosis. The control group comprised 26 women. Eutopic endometrium samples were collected with a Pipelle device during the implantation window. Firstly, mRNA was extracted from the endometrium and reverse transcribed into cDNA. Real time PCR was used for the assessment of relative expression levels. Results: The observed transcription level of CLDN4 did not differ statistically between the studied groups, but was significantly higher when compared to controls. Conclusions: Exceedingly high levels of CLDN4 might negatively influence fertility rates.

The aim of this study was to estimate the prevalence of factor V Leiden and prothrombin gene G20210A mutation among women with pregnancy loss in Poland.we analyzed a group of 396 women (mean age of 30.4 (+/- 4.6) years), who experienced at least one pregnancy loss. Patients were recruited from 6 academic centers (Poznań, Białystok, Lublin, Wrocław Bydgoszcz, Gdańsk), and were divided into the following groups: 122 patients with 3 episodes of early recurrent pregnancy loss (group 1), 87 patients with late pregnancy loss (group 2) and 46 patients with intrauterine pregnancy loss (group 3). Patients who did not fulfill the above inclusion criteria were divided into additional groups. 50 healthy women (mean age of 29.2 (+/- 4.5) years), having at least one child, constituted the control group. Factor V Leiden mutation and prothrombin G20210A gene mutation were examined in all 396 women with pregnancy loss and 50 controls. For molecular analysis peripheral blood was tested. Genome DNA isolation from lymphocyte was performed with commercial assay QIAampDNA Blood Mini Kit.Among 396 women with unexplained loss of at least one pregnancy 36 (9.1%) were carriers of inherited thrombophilia. Factor V Leiden mutation was present in 29 women (73%), prothrombin gene mutation G20210A in 6 (1.5%) and in 1 (0.3%) patient both mutations were detected. No coagulation defects were found in the control group. Factor V Leiden mutations was the most common disorder (21.7%) in patients with intrauterine demise and was significantly higher than in the group of women with early recurrent and late losses, p0.011 and p0,006 respectively The frequency of G20210 A prothrombin gene mutation did not differ substantially between the examined groups; the highest number (2.6%) was found in women with early and late pregnancy losses, and the lowest number (0.8%) was seen in women with early recurrent miscarriages.Factor V Leiden screening should be performed, regardless of negative history of thrombosis, in patients who experienced intrauterine fetal demise or recurrent early miscarriages.

The analysis of karyotypes in fetuses with increased nuchal translucency (NT) and the assessment of correlations between NT thickness, presence of other fetal anomalies and the result of karyotype.The study was conducted among 121 singleton fetuses with increased NT thickness. In all fetuses the karyotype was assessed following amniocentesis. The results of karyotypes were analyzed in the whole studied group, as well as in specific subgroups of patients according to NT value: 1) increased NT, but not exceeding 3,5mm, 2) 3,5-4,4mm, 3) 4,5-5,4mm, 4) 5,5-6,4mm, and 5)or = 6,5mm.Abnormal results of the karyotype were found in 41 out of 121 fetuses (33,9%). The most common aberration was trisomy 21. A percentage of abnormal fetal karyotypes increased with the degree of NT thickening and was 15,9% in fetuses with increased NT which did not exceed 3,5 mm and 54,5% in fetuses with NTor = 6,5 mm. The abnormal karyotype was diagnosed in 54,5% of fetuses with increased NT and other abnormalities found in ultrasound.1. Around 65% of the fetuses with an increased NT have normal karyotype. 2. A percentage of abnormal karyotypes in fetuses increases with the degree of NT thickening. 3. An ultrasound finding of an increased NT and other abnormalities in a fetus is associated with higher risk of chromosomal aberrations in comparison to cases when there is only an increased nuchal translucency.

The aim of the study was a histologic evaluation of placentas and chorions from pregnancies complicated by antiphospholipid syndrome (APS) and inherited thrombophilia in women treated with anticoagulants and in a group of women without the anticoagulant treatment.24 placentas from 18 patients with acquired and inherited thrombophilia and 23 chorions from 19 miscarriages in women with the same diagnosis were included in the study There were 33 chorions from miscarriages from healthy women and 25 placentas from uneventful pregnancies in the control group. Biopsies from placentas and chorions were stained with eosin and hematoxylin and evaluated for the presence of villous thrombosis, fibrin deposits, intraplacental hematomas, thrombosis in fetal circulation and other histological findings.In the placentas from pregnancies complicated with APS and inherited thrombophilia, the presence of fibrin deposits in the basal and villous plate, stasis in the fetal circulation and thrombosis in the villous plate and villous vessels, were statistically more frequent (p0,001) comparing with physiological pregnancies. In the material from miscarriages the presence of fibrin deposits was statistically more common (p0,001) in women with thrombophilia. The number of physiological findings in placentas of women treated with anticoagulants in pregnancy and in the non-treated ones, whose pregnancies resulted in fetal demise, were not statistically different.1. Fibrin deposits between villi and villous plate are the most recognizable features in placentas and chorions from APS pregnancies 2. In women with APS impaired trophoblast invasion seems to be the most likely cause of recurrent miscarriages 3. Anticoagulant therapy does not prevent either fibrin deposits collection or other placental changes

The aim of the study was the analysis of antiphospholipid syndrome frequency in Polish women with pregnancy loss.We analyzed 352 women with average age of 31.4 (+/- 4.3) who experienced one or more pregnancy losses. Patients from 5 University centers: Poznań, Białystok, Lublin, Wrocław and Bydgoszcz were divided into 3 groups. In the 1st group there were 150 women with recurrent early pregnancy losses before 10 weeks gestation, in the 2nd group we included 160 women with late pregnancy losses, in the 3rd group we analyzed 42 women with labor complicated by preeclampsia or placental insufficiency within or before 34 gestational week. All 352 women were screened for the presence of anticardiolipin antibodies (aCL), anti beta2glikoprotein I (abeta2GPI) and lupus anticoagulant (LA). The first two antibodies were investigated with ELISA test and the last one with APPT based test. Only the second positive result qualified patients as antiphospholipid antibody (aPL) positive. Antibodies against cardiolipin and beta2glicoprotein I were analyzed in three classes--IgA, IgG and IgM--where the laboratory criteria of positivity were titers above 40 unitsU/ml or above 99 centile.13 patients (3.69%) in the screened population of 352 women met the criteria of the antiphospholipid syndrome. The frequency of APS in women with early and late pregnancy losses were 1.33% and 6.25%, respectively. The most common antibody found was lupus anticoagulant (LA). In 3 women with late pregnancy loss all three antibodies were found. In women with premature deliveries complicated with preeclampsia and/or placental insufficiency the frequency of APS was 2.58%.1. Screening of antiphospholipid syndrome should be routinely performed in women with late pregnancy loss 2. We can conclude that APS is rarely found in women with pregnancy loss before 10 gestational week.

Background A decrease in HOXA11 expression in eutopic mid-secretory endometrium has been found in women with endometriosis-associated infertility. Methods Using Real-time quantitative PCR (RQ-PCR) and western blotting analysis we studied the HOXA11 transcript and protein levels in mid-luteal eutopic endometrium from eighteen infertile women with minimal endometriosis, sixteen healthy fertile women and sixteen infertile women with fallopian tubal occlusion from the Polish population. We also evaluated transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in these groups of women. Results There were significantly lower levels of HOXA11 transcripts (p = 0.003, p = 0.041) and protein (p = 0.004, p = 0.001) in women with endometriosis as compared to fertile women and infertile women with tubal occlusion. Moreover, we found significantly higher methylation levels of the CpG region in the first exon of HOXA11 in infertile women with endometriosis compared with fertile women (p < 0.001) and infertile women with tubal occlusion (p < 0.001). We also observed significantly increased levels of DNMT3A transcript in women with endometriosis than fertile women (p = 0.044) and infertile women with tubal occlusion (p = 0.047). However, we did not observe significant differences in DNMT1 and DNMT3B transcript levels between these investigated groups of women. Conclusions We confirmed that reduced HOXA11 expression may contribute to endometriosis-associated infertility. Moreover, we found that DNA hypermethylation can be one of the possible molecular mechanisms causing a decrease in HOXA11 expression in the eutopic mid-secretory endometrium in infertile women with endometriosis.

The pregnancy course in women with gestational ovarian mass and conservative or operative management.In retrospective analysis we analyzed 83 pregnant women with ovarian mass diagnosed between 2002-2009. We considered the following factors: gestational age when diagnosed, ultrasound picture, clinical symptoms, level of CA 125, treatment used, pathologic results and pregnancy outcome.In this group of patients 29 (35%) underwent surgery and 54 (65%) were managed conservatively In 83% of operated women ovarian mass was diagnosed before 11 gestational week. Only 27.5% of patients had pain. CA 125 level was elevated in 48.3% women. In all operated patients laparotomy was performed. The most common pathologic finding was mature teratoma (37.9%) and serous cyst (34.5%). In only one patient we diagnosed borderline serous carcinoma in both ovaries. Among operated patients, 86% delivered at term healthy newborns. In conservatively managed group level of CA 125 remain within a normal range. Patients were symptoms free and pregnancy course was uneventful. In 85% non operated women within 6 postpartum weeks ovarian masses disappeared.According to our analysis adequate ultrasound image interpretation of ovarian' tumors in pregnancy is of the highest importance in further medical management. Conservative treatment with systematic obstetric care may help to reduce the number of surgical intervention. Surgical treatment of ovarian tumors in pregnancy increases the risk of premature deliveries.

The aim of the study was to evaluate antiphospholipid antibodies and antiphospholipid syndrome frequency (according to current criteria) in women with recurrent miscarriages.We examined 105 women diagnosed due to recurrent miscarriages. Patients were divided into 2 groups: with early recurrent miscarriages and with late recurrent miscarriages. The third group was the control group composed of 30 healthy women without poor obstetric history and having at least one child. All women were screened for the presence of antiphospholipid antibodies: anticardiolipin antibodies, anti beta2-glycoprotein antibodies and lupus anticoagulant.Antiphospholipid antibodies were found in 12.4% of women with recurrent pregnancy loss and in 13.3% of the controls. Among 87 patients in group I with early recurrent miscarriages the most common antibodies were: anti-beta2-glycoprotein I (9.2%), anticardiolipin antibodies (4.6%) and lupus anticoagulant (1.1%). Anti beta2-glycoprotein antibodies were the only antibodies found in 18 women in group II with recurrent late miscarriages. There were 13.3% aPL-positive cases in the control group. Among the studied population, there were only two patients (2.3%) fulfilling the criteria of APS.1. The presence of antiphospholipid antibodies in low titers in women with pregnancy loss is unequivocal with antiphospholipid syndrome. 2. APL screening should be limited to a restricted group of women.

Examination of fetal tissue from spontaneous miscarriages shows that 50-70% of them were caused by abnormal karyotype. The most frequent genetic abnormalities include abnormal number of chromosomes, aberration of chromosomes structure and chromosome mosaic anomalies.The aim of the study was to find out whether there is any difference in the frequency of chromosomal aberrations in patients who miscarried for the first time comparing to patients with recurrent miscarriages.Examination was performed on 129 miscarriage material samples from 128 women. Fluorescent hybridization in-situ (FISH) was used for genetic examination.We received 120 results in which 45 (37,5%) were abnormal. The most frequent chromosomal aberration was trisomy followed by triploidy and monosomy of chromosome X. Among 59 samples from first miscarriage we found 25 abnormal karyotypes. In the 61 samples from the second, third and the next miscarriages we found 20 chromosomal abnormalities.Frequency of chromosomal aberrations in the tissue from the first miscarriage is significantly higher than in samples from second or following miscarriages, which means that genetic factors are less likely to induce recurrent miscarriages. Genetic results confirm that most chromosomal abnormalities arise de-novo.