Steffen Sommer

The Danish Fetal Medicine Database: establishment, organization and quality assessment of the first trimester screening program for trisomy 21 in Denmark 2008–2012

To describe the establishment and organization of the Danish Fetal Medicine Database and to report national results of first‐trimester combined screening for trisomy 21 in the 5‐year period 2008–2012.

Identification of circulating fetal cell markers by microarray analysis

Different fetal cell types have been found in the maternal blood during pregnancy in the past, but fetal cells are scarce, and the proportions of the different cell types are unclear. The objective of the present study was to identify specific fetal cell markers from fetal cells found in the maternal blood circulation at the end of the first trimester.

Cervical collagen concentration within 15 months after delivery

OBJECTIVE Cervical collagen concentration decreases during pregnancy. The increased risk of preterm birth after a short interpregnancy interval may be explained by an incomplete remodeling of the cervix. The objective of this study was to describe the changes in cervical collagen concentration over 15 months after delivery. STUDY DESIGN The collagen concentrations were determined in cervical biopsy specimens that were obtained from 15 women at 3, 6, 9, 12, and 15 months after delivery. RESULTS The mean cervical collagen concentrations were 50%, 59%, 63%, 65%, and 65% of dry weight (SD, 4.2-6.5). This increase was statistically significant until month 9, but not between months 9 and 12. CONCLUSION Low collagen concentrations in the uterine cervix may contribute to the association between a short interpregnancy interval and preterm birth.

Microarray-Based Analysis of Methylation Status of CpGs in Placental DNA and Maternal Blood DNA: Potential New Epigenetic Biomarkers for Cell Free Fetal DNA-Based Diagnosis

Epigenetic markers for cell free fetal DNA in the maternal blood circulation are highly interesting in the field of non-invasive prenatal testing since such markers will offer a possibility to quantify the amount of fetal DNA derived from different chromosomes in a maternal blood sample. The aim of the present study was to define new fetal specific epigenetic markers present in placental DNA that can be utilized in non-invasive prenatal diagnosis. We have conducted a high-resolution methylation specific beadchip microarray study assessing more than 450.000 CpG sites. We have analyzed the DNA methylation profiles of 10 maternal blood samples and compared them to 12 1st trimesters chorionic samples from normal placentas, identifying a number of CpG sites that are differentially methylated in maternal blood cells compared to chorionic tissue. To strengthen the utility of these differentially methylated CpG sites to be used with methyl-sensitive restriction enzymes (MSRE) in PCR-based NIPD, we furthermore refined the list of selected sites, containing a restriction sites for one of 16 different methylation-sensitive restriction enzymes. We present a list of markers on chromosomes 13, 18 and 21 with a potential for aneuploidy testing as well as a list of markers for regions harboring sub-microscopic deletion- or duplication syndromes.

Microarray-based analysis of methylation of 1st trimester trisomic placentas from down syndrome, edwards syndrome and patau syndrome

Methylation-based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13(T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pregnancies in an attempt to find trisomy–specific methylation differences better suited for non-invasive prenatal diagnosis. We have conducted high-resolution methylation specific bead chip microarray analyses assessing more than 450,000 CpGs analyzing placentas from 12 T21 pregnancies, 12 T18 pregnancies and 6 T13 pregnancies. We have compared the methylation landscape of the trisomic placentas to the methylation landscape from normal placental DNA and to maternal blood cell DNA. Comparing trisomic placentas to normal placentas we identified 217 and 219 differentially methylated CpGs for CVS T18 and CVS T13, respectively (delta β>0.2, FDR<0.05), but only three differentially methylated CpGs for T21. However, the methylation differences was only modest (delta β<0.4), making them less suitable as diagnostic markers. Gene ontology enrichment analysis revealed that the gene set connected to theT18 differentially methylated CpGs was highly enriched for GO terms related to”DNA binding” and “transcription factor binding” coupled to the RNA polymerase II transcription. In the gene set connected to the T13 differentially methylated CpGs we found no significant enrichments.

Polymorphisms in Genes Coding for Cytokines, Mannose-Binding Lectin, Collagen Metabolism and Thrombophilia in Women with Cervical Insufficiency

Objective: To study the association between cervical insufficiency and single nucleotide polymorphisms in seven genes coding for pro- and anti-inflammatory cytokine-related factors, mannose-binding lectin 2 (MBL2), collagen1α1 (COL1A1), factor II and factor V Leiden genes. Methods: In a case-control study, potential maternal biomarkers for cervical insufficiency were investigated in 30 women with a history of second-trimester miscarriage or preterm birth due to cervical insufficiency and in 70 control women. Results: Homozygous carriers of the interleukin 6 (IL6) -174 genotype GG had an odds ratio (OR) of 3.1 [95% confidence interval (95% CI) 1.3-7.4, p = 0.01] and MBL2 genotypes coding for low or intermediate levels of plasma MBL had an OR of 3.3 (95% CI 1.2-9.0, p = 0.01) for cervical insufficiency compared with controls. Serum MBL levels were lower in women with cervical insufficiency than in controls (median 408 and 1,985 ng/ml, respectively, p < 0.01). Conclusions: Single nucleotide polymorphisms in the IL6 gene and the MBL2 gene and low MBL levels related to the latter polymorphism may increase the risk of preterm birth due to cervical insufficiency.

Cervical collagen is reduced in non‐pregnant women with a history of cervical insufficiency and a short cervix

Preterm cervical shortening and cervical insufficiency may be caused by a constitutional weakness of the cervix. The aim of this study was to assess the cervical collagen concentration in non‐pregnant women with a history of cervical insufficiency or of a short cervix in the second trimester of pregnancy.

OC05.05: The Danish Fetal Medicine Database: establishment and quality assessment of first trimester screening for trisomy 21 in the period 2008–2010

Objectives: Prenatal screening for fetal aneuploidies is best achieved in the first trimester when there is no reliable screening test for spina bifida (SB). Early ultrasound features may be too complex to be of value in routine screening. We assessed the screening potential of simple and reproducible fetal biometric measurements at 11–14 weeks’. Methods: 34,951 unselected consecutive pregnancies including 18 subsequently found to have spina bifida. Another 28 cases of SB were referred for assessment. Each biometric measurement was expressed in multiples of the median for crown-rump length. Results: Biparietal diameter (BPD) was smaller in spina bifida (P < 0.0001). 22/44 (50%) cases with a spina bifida aperta had a BPD < 5th centile. BPD was independent of maternal adiposity and smoking status. Conclusions: Simple and reproducible BPD at 11–14 weeks gestation could detect half the cases of open fetal spina bifida by identifying 5% of pregnancies for expert scanning in the first trimester.

OC01.04: Perinatal outcome after first trimester risk assessment in monochorionic and dichorionic twin pregnancies: a Danish national database study

1.3 to 31.6). We found no differences between late preterm infants and controls in RNFL thickness (96.5 μ vs. 98.7 μ; P = 0.31), macular thickness (279 μ vs. 283.3 μ; P = 0.15) and abnormal Bender test (14.3% vs. 6.4%; P = 0.42). All the late preterm children with abnormal Bender test were born SGA. Conclusions: Although late preterm had worse perinatal outcome, neuronal and cognitive suboptimal development after 6 years are more associated with late onset growth restriction rather than late prematurity.

P11.01: Development and establishment of a national Danish fetal medicine database for quality surveillance and research

were rated to enable highly diagnostic confidence (82.9%), and produce better image quality for the near field image (94.3%), the far field image (88.6%), and overall (94.3%). Conclusions: The current study described an objective method of comparing image quality acquired using different sonographic technologies. Ultrasound transducer incorporated with PureWave Crystal technology produces significantly better image quality for diagnostic purpose.