Karin Sundberg

Impact of a new national screening policy for Down's syndrome in Denmark: population based cohort study

Objectives To evaluate the impact of a screening strategy in the first trimester, introduced in Denmark during 2004-6, on the number of infants born with Down’s syndrome and the number of chorionic villus samplings and amniocenteses, and to determine detection and false positive rates in the screened population in 2005 and 2006. Design Population based cohort study. Setting 19 Danish departments of gynaecology and obstetrics and a central cytogenetic registry 2000-7. Participants 65 000 pregnancies per year. Main outcome measures The primary outcomes measured were number of fetuses and newborn infants with Down’s syndrome diagnosed prenatally and postnatally and number of chorionic villus samplings and amniocenteses carried out. Secondary outcomes measured were number of women screened in 2005 and 2006, screen positive rate, and information on screening in 2005 and 2006 for infants with a postnatal diagnosis of Down’s syndrome. Results The number of infants born with Down’s syndrome decreased from 55-65 per year during 2000-4 to 31 in 2005 and 32 in 2006. The total number of chorionic villus samplings and amniocenteses carried out decreased from 7524 in 2000 to 3510 in 2006. The detection rate in the screened population in 2005 was 86% (95% confidence interval 79% to 92%) and in 2006 was 93% (87% to 97%). The corresponding false positive rates were 3.9% (3.7% to 4.1%) and 3.3% (3.1% to 3.4%). Conclusion The introduction of a combined risk assessment during the first trimester at a national level in Denmark halved the number of infants born with Down’s syndrome. The strategy also resulted in a sharp decline in the number of chorionic villus samplings and amniocenteses carried out, even before full implementation of the policy.

Reduction of the disintegrin and metalloprotease ADAM12 in preeclampsia.

Objectives: The secreted form of ADAM12 is a metalloprotease that may be involved in placental and fetal growth. We examined whether the concentration of ADAM12 in first-trimester maternal serum could be used as a marker for preeclampsia. Methods: We developed a semiautomated, time-resolved, immunofluorometric assay for the quantification of ADAM12 in serum. The assay detected ADAM12 in a range of 78–1248 &mgr;g/L. Serum samples derived from women in the first trimester of a normal pregnancy (n = 324) and from women who later developed preeclampsia during pregnancy (n = 160) were obtained from the First Trimester Copenhagen Study. ADAM12 levels were assayed in these serum samples. Serum levels of ADAM12 were converted to multiples of the median (MoM) after log-linear regression of concentration versus gestational age. Results: Serum ADAM12 levels in women who developed preeclampsia during pregnancy had a mean log MoM of –0.066, which was significantly lower than the mean log MoM of –0.001 for ADAM12 levels observed in serum samples from women with normal pregnancy (P = .008). The mean log MoM was even lower in serum derived from preeclamptic women whose infants weight at birth was less than 2,500 g (n = 27, mean log MoM of –0.120, P = .053). Conclusion: The maternal serum levels of ADAM12 are significantly lower during the first trimester in women who later develop preeclampsia during pregnancy when compared with levels in women with normal pregnancies. Because the secreted form of ADAM12 cleaves insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5, the IGF axis may play a role in preeclampsia. ADAM12 may be a useful early marker for preeclampsia. Level of Evidence: II-2

Improved first-trimester Down syndrome screening performance by lowering the false-positive rate: a prospective study of 9941 low-risk women

To determine the performance of screening for Down syndrome (DS) and other major chromosomal abnormalities using nuchal translucency (NT), free β‐human chorionic gonadotropin (β‐hCG) and pregnancy‐associated plasma protein‐A (PAPP‐A) in a prospective study of a non‐selected population.

New treatment of early fetal chylothorax.

OBJECTIVE: To evaluate OK-432, a preparation of Streptococcus pyogenes, in the treatment of early fetal chylothorax. METHODS: A prospective study of all fetuses (n=7) with persistent early chylothorax (gestational ages 16–21 weeks) referred to the tertiary center of fetal medicine in Denmark in 2003–2005. Fetuses were injected with 0.2–1.0 mg of OK-432 into the pleural cavity. The treatment was repeated if there were persistent or increasing pleural effusions after 1–3 weeks. The main outcome measures included remission of pleural effusions and fetal and infant morbidity and mortality. RESULTS: Total remission of pleural effusions was obtained in all fetuses after one or two intrapleural injections of OK-432. No adverse effects of the treatment were observed. No fetus developed hydrops, and all experienced an uncomplicated third trimester. All children were born healthy without pleural effusions, lung hypoplasia, or hydrops. CONCLUSION: Persistent early chylothorax is a condition with a high mortality rate and no established treatment option. Use of OK-432 is a promising therapy for selected fetuses with persistent chylothorax early in the second trimester. LEVEL OF EVIDENCE: II

Increased nuchal translucency with normal karyotype: a follow-up study of 100 cases supplemented with CGH and MLPA analyses

To evaluate whether high‐resolution comparative genomic hybridization (HR‐CGH) and subtelomeric and syndrome‐specific multiplex ligation‐dependent probe amplification (MLPA) would detect minor chromosomal aberrations in fetuses with increased nuchal translucency thickness (NT) and normal karyotype on conventional karyotyping.

Antithyroid drug-induced fetal goitrous hypothyroidism

Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous hypothyroidism. Maternal levels of free T4 are the most consistent indication of maternal and fetal thyroid status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the maternal thyroid status, especially estimates of free T4 levels.

Circulating AMH Reflects Ovarian Morphology by Magnetic Resonance Imaging and 3D Ultrasound in 121 Healthy Girls

CONTEXT In adult women, Anti-Müllerian hormone (AMH) is produced by small growing follicles, and circulating levels of AMH reflect the number of antral follicles as well as primordial follicles. Whether AMH reflects follicle numbers in healthy girls remains to be elucidated. OBJECTIVE This study aimed to evaluate whether serum levels of AMH reflects ovarian morphology in healthy girls. DESIGN AND SETTING This was a population-based cohort study involving the general community. PARTICIPANTS Included in the study were 121 healthy girls 9.8-14.7 years of age. MAIN OUTCOME MEASURES Clinical examination, including pubertal breast stage (Tanners classification B1-5), ovarian volume, as well as the number and size of antral follicles were assessed by two independent modalities: magnetic resonance imaging (MRI), Ellipsoid volume, follicles ≥2 mm; and Transabdominal ultrasound, Ellipsoid and 3D volume, follicles ≥1 mm. Circulating levels of AMH, inhibin B, estradiol, FSH, and LH were assessed by immunoassays; T and androstenedione were assessed by liquid chromatography-tandem mass spectrometry. RESULTS AMH reflected the number of small (MRI 2-3 mm) and medium (4-6 mm) follicles (Pearsons Rho [r] = 0.531 and r = 0.512, P < .001) but not large follicles (≥7 mm) (r = 0.109, P = .323). In multiple regression analysis, small and medium follicles (MRI ≤ 6 mm) remained the main contributors to circulating AMH (β, 0.501; P < .001) whereas the correlation between AMH and estradiol was negative (β, -0.318; P = .005). In early puberty (B1-B3), the number of AMH-producing follicles (2-6 mm) correlated positively with pubertal stages (r = 0.453, P = .001), whereas AMH levels were unaffected (-0.183, P = .118). CONCLUSIONS Similarly to adult women, small and medium antral follicles (≤6 mm) were the main contributors to circulating levels of AMH in girls.

Diagnostic yield by supplementing prenatal metaphase karyotyping with MLPA for microdeletion syndromes and subtelomere imbalances.

The aim of the study was to retrospectively assess the relevance of using multiplex ligation‐dependent probe amplification (MLPA) for detection of selected microdeletion syndromes (22q11, Prader–Willi/Angelman, Miller–Dieker, Smith–Magenis, 1p‐, Williams), the reciprocal microduplication syndromes and imbalance at the subtelomere regions of chromosomes in a routine prenatal setting.

Invasive treatment in complicated monochorionic twin pregnancies: indications and outcome of 120 consecutively treated pregnancies

Objective. Monochorionic twin pregnancies are associated with increased risk of severe complications. Umbilical cord occlusion (UCO) and fetoscopic selective laser coagulation (FSLC) are used as invasive treatment. The study aim was to document treatment indications and pregnancy outcome where UCO and FSLC were used for treating fetal discrepancies and twin‐to‐twin transfusion syndrome (TTTS). Design. Cohort study of all consecutively treated monochorionic twin pregnancies 2004–2010. Setting. Tertiary care center. Population. One hundred and twenty pregnancies treated by FSLC (55) or UCO (65). Umbilical cord occlusion was undertaken in 49 TTTS cases, in four cases with fetal abnormality and TTTS and in 12 cases because of fetal anomaly only. Main outcome measures. Overall survival per fetus, survival per pregnancy of at least one fetus and further survival according to the Quintero stages. Infant survival until at least one week after birth. Results. Of the pregnancies studied, 84% had TTTS, 13% had a fetal malformation and 3% had both. Of TTTS cases, 69% were Quintero stage 3 and 4. In the UCO group with TTTS, 87% were in stage 3 and 4. Survival in the UCO group was 82%. In the laser group, the survival of at least one fetus was 85%. Overall survival per fetus was 60%. Conclusions. By far the most common indication for invasive treatment was TTTS in Quintero stage 3. Outcome by means of survival after FSLC and UCO were similar to what has been reported elsewhere. Cord occlusion was an acceptable treatment alternative to fetoscopic selective laser coagulation in severe TTTS cases.

Free leptin index and PAPP‐A: a first trimester maternal serum screening test for pre‐eclampsia

Prophylaxis with low‐dose aspirin may reduce the risk of pre‐eclampsia (PE) if introduced in first trimester. The performance of first trimester maternal serum screening for PE using free leptin index (fLI) and PAPP‐A, where fLI = leptin/leptin soluble receptor was studied.