Olav Petersen

Restricting studies of severe congenital malformations to live-born children may introduce substantial bias. In this study, we estimated the attendance to the second-trimester fetal malformation screening program. We also estimated the positive predictive value (PPV) of prenatally assigned International Classification of Disease-10 diagnoses recorded in the Danish National Patient Registry (DNPR) and the completeness of case registration. We used kidney anomalies as an example. We identified the proportion of all Danish live-born children from January 1, 2007 to December 31, 2012, who were scanned during the second trimester using the DNPR and the Civil Registration System. Details of all fetuses with specific kidney anomaly diagnoses according to the DNPR were retrieved. The PPV was estimated using the nationwide Astraia database of pregnancy medical charts or traditional medical charts, as gold standard. The completeness was assessed using the total number of cases estimated by the capture-recapture method. Of 372,263 live born infants, 97.3% were scanned during the second trimester. We identified 172 fetuses in the DNPR. Of these, 149 had kidney anomalies according to Astraia or medical chart review, corresponding to a PPV of 87% (95% CI: 81%-91%). The estimated completeness was 43% (95% CI: 38%-49%) for the DNPR and 75% (95% CI: 70%-79%) for Astraia. Almost all live-born children were scanned during the second trimester in Denmark. However, low completeness may hamper the use of the DNPR for studies of prenatally detected severe malformations, and use of the Astraia database may preferably be considered.

The short-rib polydactyly (SRP) syndromes are rare skeletal dysplasias caused by abnormalities in primary cilia, sometimes associated with visceral malformations. The pathogenesis of ductal plate malformation (DPM) varies in different syndromes and has not been investigated in SRP. We have studied liver development in five SRP fetuses and pancreatic development in one SRP fetus, with genetically confirmed mutations in cilia related genes, with and without DPMs, using the immunoperoxidase technique, and compared these to other syndromes with DPM. Acetylated tubulin expression was abnormal in DPM in SRP, Meckel syndrome, and autosomal recessive polycystic kidney disease (ARPKD), confirming ciliary anomalies. SDF-1 was abnormally expressed in SRP and two of three cases of autosomal dominant polycystic kidney disease (ADPKD) but not ARPKD or Meckel. Increased density of quiescent hepatic stellate cells was seen in SRP, Meckel, one of three cases of ARPKD, and two of three cases of ADPKD...

Non-invasive prenatal testing is increasingly available worldwide and stakeholder viewpoints are essential to guide implementation. Here we compare the preferences of women and health professionals from nine different countries towards attributes of non-invasive and invasive prenatal tests for Down syndrome. A discrete choice experiment was used to obtain participants' stated preference for prenatal tests that varied according to four attributes: accuracy, time of test, risk of miscarriage, and type of information. Pregnant women and health professionals were recruited from Canada, Denmark, Iceland, Israel, Italy, the Netherlands, Portugal, Singapore, and the United Kingdom. A total of 2666 women's and 1245 health professionals' questionnaires were included in the analysis. Differences in preferences were seen between women and health professionals within and between countries. Overall, women placed greater emphasis on test safety and comprehensive information than healt...

Array-comparative genomic hybridization (array-CGH) is a very sensitive method for identifying chromosomal imbalances and is now used on a clinical basis for prenatal diagnosis. This article reviews the advantages and disadvantages of the method, the ethical considerations and the current recommendations for prenatal use in Denmark according to a new national guideline from The Danish Society of Foetal Medicine and the Danish Society of Medical Genetics.

To develop a reference material that allows quantitative elastography of the uterine cervix using the calculation of the approximate tissue stiffness expressed as Young's modulus (N/mm(2) ). Further, to test the elastography equipment on phantoms from a clinical perspective regarding the distance dependence and the influence of a heterogeneous material. Methodological study. Aarhus University Hospital, Denmark. Six mid- and five full-term pregnant women. Reference caps and phantoms with Young's moduli between 0.07 and 0.40 N/mm(2) were made of silicone and oil. By using reference caps, the approximate Young's moduli of the cervixes were calculated from strain ratios obtained by elastography. Approximate Young's modulus of the cervix. The recordings of the phantoms revealed that the calculation of the approximate Young's moduli became unreliable at distances above 10-15 mm from the transducer. This was further increased for a phantom which included a soft layer imitating the cervical canal. The approximate Young's modulus obtained from the anterior cervical lip was 0.08 N/mm(2) in mid-term and 0.03 N/mm(2) in full-term pregnant women (Wilcoxon rank-sum test, p = 0.01). The reference cap constitutes a promising tool for quantitative elastography of the anterior cervical lip. Figures obtained from the posterior cervical lip are less plausible due to the distance from the transducer and the heterogeneity introduced by the cervical canal. The method has the potential to be used to supplement cervical length assessment when evaluating women at risk of preterm delivery and when planning induction of labor.

This paper is based on ethnographic fieldwork at an obstetric ultrasound unit in Denmark and explores the few, intense minutes of clinical interaction following a high-risk screening result for Down's syndrome. The category of high-risk transforms the routine ultrasound into a situation of inescapable choice, where the health of the foetus is questioned and decisions must be made. The clinical interactions following a high-risk result are investigated as processes of production, and the concepts of logic of choice and the logic of care are employed as analytical tools for identifying different rationales at play in the situation. The analysis shows that sonographers and women/couples collaboratively engage in logics of choice and care. Their mutual aim is to make the high-risk results meaningful and manageable so that a decision can be made. In this process initiative is shifted back and forth. Through a logic of care, complexity is reduced and statistics transformed by emphasis...

To evaluate the serological response in pregnant Danish women immunized during the 2009 pandemic by serologic infection or by vaccination with influenza A(H1N1) Pandemrix(®) and describe levels of passively acquired maternal antibody in their offspring. Observational cohort study. Department of Obstetrics, Aarhus University Hospital, Skejby, Denmark, October to December 2009. Pregnant women and their offspring METHODS: Serological analysis of antibodies to influenza A(H1N1)pdm09 by hemagglutination inhibition assay in 197 women and their offspring. Blood samples were collected consecutively at delivery from the mother and the umbilical cord. In a subgroup of 124 of the 197 women, an additional blood sample from gestational weeks 9-12 was available for analysis. Seroconversion, geometric mean titer, geometric mean-fold rise and protective antibodies. 33 of the 124 subgroup women (27%) seroconverted during pregnancy, 79% after vaccination and 17% after serologic infection (p < 0.001). The geometric mean titer after delivery in non-vaccinated, non-serologically infected women was 17.1 (95%CI 15.7-18.6). The geometric mean titer increased significantly after serologic infection with H1N1 [76.5 (95%CI 51.3-113.9), p < 0.001] and after vaccination [589.6 (95%CI 339.3-1024.7), p < 0.001]. The geometric mean-fold rise (mother at delivery/mother early pregnancy) was significantly higher after vaccination [2.23 (1.93-2.54)] than after serologic infection [1.73 (1.59-1.87), p = 0.013]. In newborns of vaccinated mothers, 89.5% had protective antibody levels compared with 15.8% in newborns of serologically infected mothers (p < 0.001). Influenza vaccination during pregnancy confers passive immunity to the newborn.

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. National register study using prospectively collected first-trimester screening data from the Danish Fetal Medicine Database. Pregnant women in Denmark undergoing first-trimester screening for trisomy 21. Data on maternal characteristics, biochemical and ultrasonic markers are continuously sent electronically from local fetal medicine databases (Astraia Gmbh software) to a central national database. Data are linked to outcome data from the National Birth Register, the National Patient Register and the National Cytogenetic Register via the mother's unique personal registration number. First-trimester screening data from 2008 to 2012 were retrieved. Screening performance was assessed for the years 2008-2012 by calculating detection rates and screen-positive rates. A total of 268 342 first-trimester risk assessments for trisomy 21 were performed in singleton pregnancies. Participation rate in first-trimester screening was >90%. The national screen-positive rate increased from 3.6% in 2008 to 4.7% in 2012. The national detection rate of trisomy 21 was reported to be between 82 and 90% in the 5-year period. A national fetal medicine database has been successfully established in Denmark. Results from the database have shown that at a national level first-trimester screening performance for trisomy 21 is high with a low screen-positive rate and a high detection rate.

Targeted non-invasive prenatal testing (NIPT) tests for trisomies 21, 18 and 13 and sex chromosome aneuploidies and could be an alternative to traditional karyotyping. The aim of this study was to determine the risk of missing other abnormal karyotypes of probable phenotypic significance by NIPT. This was a retrospective population-based analysis of all singleton pregnancies booked for combined first-trimester screening (cFTS) in Denmark over a 4-year period. Data concerning maternal demographics, cFTS and prenatal or postnatal karyotypes were collected from the Danish Fetal Medicine database. Karyotypes were classified according to whether the chromosomal anomaly would have been detected by NIPT and whether it was likely to affect phenotype. cFTS was completed in 193638 pregnancies. 10205 (5.3%) had cytogenetic or molecular analysis performed. Of these, 1122 (11.0%) had an abnormal karyotype, of which 262 (23.4%) would have been missed by NIPT, but would probably have been clinically significant. The prevalence of such 'atypical abnormal karyotypes' was increased in women above 45 years of age, in pregnancies with increased nuchal translucency (NT) thickness (≥ 3.5 mm), with abnormal levels of free β-human chorionic gonadotropin (<0.2 or ≥ 5.0 multiples of the median (MoM)) or pregnancy-associated plasma protein-A<0.2 MoM. One or more of these factors was present in 3% of women, and the prevalence of atypical abnormal karyotypes in this high-risk cohort was 1.6%. A significant proportion of karyotypic abnormalities will be missed by targeted NIPT. Women of advanced maternal age, or with increased fetal NT or abnormal biochemistry, have a higher risk of having a fetus affected by an atypical abnormal karyotype and need to be counseled accordingly when considering NIPT.

To examine placental growth factor (PlGF) in euploid and trisomy 21 pregnancies at 11-13 weeks' gestation and to model the impact on first-trimester combined screening. PlGF was measured in 509 (409 euploid and 100 trisomic) fetal serum samples derived from prospective first-trimester combined screening for trisomy 21 at 11-13 weeks' gestation. The serum samples were stored at -80°C, following the measurement of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels, for median time spans of 0.9 and 4.1 years in the euploid and trisomy 21 pregnancies, respectively. The effect of additional PlGF measurement at the time of combined screening was investigated by simulating fetal nuchal translucency (NT) measurements and multiples of the median (MoM) values for PAPP-A, free β-hCG and PlGF for 20,000 euploid and 20,000 trisomy 21 pregnancies. Patient-specific combined risks were calculated based on maternal age and fetal NT in addition to free β-hCG, PAPP-A and PlGF, PAPP-A and PlGF or free β-hCG and PlGF, and detection and false-positive rates were calculated. Median PlGF-MoM was 1.0 (95% confidence interval (CI), 0.96-1.04) in euploid fetuses and significantly lower, at 0.73 (95% CI, 0.70-0.76), in trisomy-21 fetuses (P < 0.0001). There was no significant dependency between PlGF-MoM and either gestational age at the time of blood sampling (r = 0.087, P = 0.392) or sample storage time (r = 0.028, P = 0.785). Modeled detection and false-positive rates for first-trimester combined screening (based on maternal and gestational age, fetal NT and maternal serum biochemistry) without PlGF were 85% and 2.7% for a fixed risk cut-off of 1:100. The addition of PlGF increased the detection rate to 87% and reduced the false-positive rate to 2.6%. Screening by maternal age and fetal NT in combination with PlGF and PAPP-A or in combination with PlGF and free β-hCG provided detection rates of 82% and 79%, with false-positive rates of 2.7% and 3.0%, respectively. In pregnancies with trisomy 21 PlGF is reduced. The impact on the overall screening performance for trisomy 21 is low and does not justify the measurement of PlGF solely for trisomy 21 screening. However, as PlGF is measured with the aim of assessing the risk for pre-eclampsia, further improvement in screening for trisomy 21 can be considered as an added benefit.

To report our experience with the prenatal diagnosis of fetal genital anomalies and suggest a protocol for management. A retrospective review of all the cases with fetal genital anomalies or phenotype and genotype discrepancy identified by prenatal ultrasound. Twenty cases with abnormal fetal genitalia and four with a phenotype and genotype discrepancy were diagnosed prenatally. Genital anomalies were rarely found in isolation, most were found in combination with renal or multiple structural anomalies. The etiology of abnormal genitalia was broad and included metabolic, chromosomal and genetic syndromes. Prenatal detection of genital anomalies should stimulate a detailed ultrasound examination and determination of genotypic sex. Measurement of 17-OHP and Delta(4)-androstenedione or metabolites of the cholesterol pathway in the amniotic fluid and/or maternal urine may be helpful in making a definitive diagnosis. Identification of genital anomalies in fetuses with renal or multiple abnormalities can aid prenatal diagnosis, thereby facilitating accurate counseling of parents who are then in a better position to make informed choices.

In Denmark, prevention to reduce the spina bifida birth rate has focused on two areas: folic acid supplementation (1997) and changes in the national ultrasonography screening programme (2004). Myelomeningocele (MMC) is the most severe malformation among the spina bifidas. Taking into consideration the potential negative effect of high-dose folic acid consumption, we found a need to look into the effectiveness of these two strategies in our complete MMC population. All spina bifida patients born in the western part of Denmark are differentiated into proper subgroups based on MR imaging, giving us a unique chance to study a true MMC population. The total number of the group of MMC children since 1983 is 121. One hundred and eight (89%) parents answered a questionnaire. Following the changes in the prenatal ultrasonography screening programme in 2004, a significant decline of 60% live birth MMC per year was noted, incidence rate ratio (IRR) = 40% (22-73%), p = 0.3%. We found no change in MMC birth rate after introduction of folic acid supplementation, IRR = 121% (81-181%), p = 36%. Our findings demonstrate no effect of folic acid recommendation due to lack of compliance among women of reproductive age in Denmark. However, we found an improved early detection rate of prenatal MMC by high-quality ultrasonography. Subsequent early termination of pregnancy has led to a significant reduction of birth rate of babies with MMC.

 To determine the influence of type 1 diabetes mellitus (T1DM) on the first trimester serum markers of fetal aneuploidy; pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free β-hCG) and to evaluate the influence of glycemic control on these parameters in the pregnant diabetic women.   Retrospective study.   Data were extracted from electronic obstetric and laboratory databases at two Danish University Hospitals.   Based on 36 415 pregnancies without T1DM (non-T1DM) and 331 pregnancies with T1DM; β-hCG and PAPP-A were obtained at 8+0 to 14+2 gestational weeks.   Medians for PAPP-A and free β-hCG were generated and multiple of the normal gestation-specific median (MoM) values were calculated for each separate pregnancy. After adjustment for maternal weight, ethnicity and smoking status, MoM values were compared across the T1DM and non-T1DM groups, respectively. Additionally, the relationship between PAPP-A MoM and HgbA1C was examined in 348 T1DM pregnancies by Spearman's rank correlation. MAIN OUTCOME MEASURES. Difference in biochemical marker levels between T1DM and non-T1DM.   PAPP-A was 0.86 MoM in T1DM pregnancies and 1.01 MoM in non-T1DM pregnancies, p < 0.0001. Conversely, free β-hCG was not altered in T1DM pregnancies (T1DM 0.99 MoM, non-T1DM 0.98 MoM; p=0.14). There was a significant inverse correlation between HgbA1C and PAPP-A (rho=-0.12, p=0.02).   In T1DM pregnancies, PAPP-A MoM values were lower than in non-T1DM pregnancies. This suggests that correction should be considered in first trimester biochemical screening for fetal aneuploidy in T1DM women.

To prospectively assess the risk of fetal loss associated with chorion villus sampling (CVS) and amniocentesis (AC) following combined first trimester screening (cFTS). A nationwide population-based study (Danish Fetal Medicine Database, 2008-2010) included 147987 singleton pregnant women who received cFTS. Propensity score stratification was used to assess the risk of fetal loss with and without invasive test. Analyses were performed from 3 to 21 days after cFTS for CVS and from 28 to 42 days after cFTS for AC. Results were reported as average risk differences with 95% confidence limits. The risk of miscarriage and stillbirth was not higher in women exposed to CVS or AC compared with unexposed women independent of the analysis time point. The average effect of CVS on risk of miscarriage was -0.08% (95% CI; -0.64; 0.47) for 3 days and -0.21% (-0.58; 0.15) for 21 days, while the effect on risk of stillbirth was -0.18% (-0.50; 0.13) for 3 days and -0.27% (-0.58; 0.04) for 21 days after cFTS, respectively. The analysis 28 days after cFTS showed a non-significant average effect of AC on risk of miscarriage of 0.56 % (-0.21; 1.33), while the effect of AC on risk of stillbirth was 0.09% (-0.39; 0.58) for 42 days after cFTS. CVS or AC was not associated with increased risks of miscarriage and stillbirth. The findings of this study support that the procedure-related risk of CVS and AC is very low and correlates with the indication for the procedure.

The objective of the study was to evaluate the performance of first trimester combined screening in cases of placental/fetal, mosaic or non-mosaic, autosomal trisomy other than trisomy 21, 18 or 13, and in cases of aneuploidy for a marker chromosome with focus on biochemical markers. We identified 66 cases in three large databases including 357.675 pregnancies from October 2003 to January 2014. 77 % of the 66 cases were screened positive at the combined first trimester screening (cFTS) for trisomy 21 or trisomy 18 or 13. The multiple of median (MoM) of Pregnancy Associated plasma protein A (PAPP-A) of the different aneuploidy-groups ranged from 0.2 to 0.5 MoM, whereas the MoM of maternal serum free - β - human chorionic gonadotropin (FβhCG) was approximately 1.0 MoM. The exceptions being 0.2 MoM for cases involving chromosome 8 (n=7) and 0.5 MoM for cases involving chromosome 9 (n=3). The nuchal translucency MoM was approximately 1.0 MoM in all aneuploidy-groups. The cFTS program fo...

To assess the clinical value of using high-resolution chromosomal microarray (CMA) for the examination of genomic imbalances in prenatal uncultured chorionic villus samples from fetuses with increased nuchal translucency (NT) and a normal quantitative fluorescent polymerase chain reaction (QF-PCR) result, in a clinical setting in which more than 95% of pregnant women receive first-trimester combined screening. From January 2013 to July 2014, we included 132 chorionic villus samples from consecutive ongoing pregnancies, with fetal NT ≥ 3.5  mm at 11-13 weeks' gestation, from obstetric units (publicly funded healthcare) in Central and North Denmark Regions. DNA was extracted directly from the samples and examined with QF-PCR (n = 132) and 180 kb oligonucleotide array-based comparative genomic hybridization (n =  94). In 38 cases, aneuploidies for chromosomes 18, 21 or X, or triploidy, were detected by QF-PCR. Among the 94 cases with a normal QF-PCR result, we detected pathogenic c...

We aimed to determine the diagnostic efficiency of quantitative fluorescence polymerase chain reaction (QF-PCR) in a clinical setting where most of the analyses are performed on chorion villus samples from high-risk pregnancies as determined by combined first-trimester screening. A retrospective study on QF-PCR data from all pregnancies in the Central and North Denmark Regions over a four-year period (n = 2,550) with invasive prenatal testing carried out due to a high risk of carrying a foetus with Down's syndrome. Results of QF-PCR were compared with those obtained by karyotyping. Other supplementary data were obtained from the Danish Foetal Medicine Database and the Danish Cytogenetic Central Register. QF-PCR for common aneuploidies is fast, has a low failure rate, and is associated with high positive and negative predictive values (PPV, NPV) (> 99.8%) for all analysed abnormal karyotypes except for mosaicism for trisomy 13 (PPV = 20%) and sex chromosome mosaic cases (PPV =...

In Denmark a new national guideline for prenatal screening and diagnosis was issued in 2004 according to which all pregnant women should be offered a first-trimester combined risk assessment for trisomy 21 (T21). The aim of this study was to investigate whether the new screening strategy for T21 has changed the gestational age at which trisomy 18 (T18) and trisomy 13 (T13) are diagnosed prenatally, and the number of infants born with T18 or T13. We collected from the Danish Cytogenetic Central Register information on all prenatal and postnatal chromosome analyses for T18 or T13, registered from 1997 to 2007. Information on first-trimester screening results was collected from each department of obstetrics and gynecology performing the nuchal translucency scans. The cut-off used for referral to invasive diagnostic testing for T21 and for T18/T13 was 1 : 300 and 1 : 150 at screening, respectively. In total, there were 435 cases with T18 and 168 cases with T13 between 1997 and 2007 in D...

To identify factors influencing the number of fetal cells in maternal blood. A total of 57 pregnant women at a gestational age of weeks 11-14 were included. The number of fetal cells in maternal blood was assessed in 30 ml of blood using specific markers for both enrichment and subsequent identification. Participants carrying male fetuses had a higher median number of fetal cells in maternal blood than those carrying female fetuses (5 vs. 3, p = 0.04). Certain cytokines (RANTES, IL-2 and IL-5) were significantly associated with the number of fetal cells in maternal blood. The number of fetal cells in maternal blood is associated with certain cytokines and fetal gender.