K. R. Wøjdemann

Obesity-related complications in Danish single cephalic term pregnancies.

OBJECTIVE: Our objective was to investigate the relationship between prepregnancy and obstetric body mass index (BMI) as well as fetal complications in a large, unselected cohort of Danish women with single cephalic pregnancies. METHODS: A cohort of 8,092 women from the Copenhagen First Trimester Study with a registered prepregnancy BMI and a single cephalic term delivery were stratified into 3 BMI groups: normal weight (BMI < 25 kg/m2), overweight (BMI 25–29.9 kg/m2), and obese (BMI ≥ 30 kg/m2). The effects of BMI and parity on the outcome were analyzed using multivariate logistic regression analyses. RESULTS: Overweight women had an odds ratio (OR) of 3.4 for diabetes, 1.9 for hypertension, 1.7 for preeclampsia, and 1.5 for cesarean delivery. The corresponding figures for obese women were 15.3, 4.8, 2.7, and 1.7, respectively. No relationship was found between BMI and vacuum extraction. Obese women had an increased risk of delivering macrosomic but also low birth weight children. No differences existed among the 3 weight groups with regard to neonatal morbidity estimated by Apgar score, umbilical cord pH, or admittance to a neonatal intensive care unit. Nulliparous women had an increased incidence of preeclampsia (OR 2.8), hypertension (OR 1.9), emergency cesarean delivery (OR 3.4), vacuum extraction (OR 5.6), and perineal rupture (OR 1.7) but a lower frequency of elective cesarean delivery (OR 0.25). CONCLUSION: The rate of complications during pregnancy and delivery increases with an increasing prepregnancy BMI in women with single cephalic term pregnancies, particularly in nulliparous women. LEVEL OF EVIDENCE: III

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.

Early Fetal Size and Growth as Predictors of Adverse Outcome

OBJECTIVE: To evaluate the association between fetal size and growth between the first and second trimesters and subsequent adverse pregnancy outcome. METHODS: A cohort was created of 7,642 singleton pregnancies cared for in three obstetric units associated with Copenhagen University. Data were obtained from ultrasound measurements at 11–14 weeks (crown-rump length, biparietal diameter) and 17–21 weeks (biparietal diameter). Fetal size was assessed by gestation-specific z scores, and fetal growth between the first and second trimester was calculated individually using conditional centiles. The main outcome measures were preterm delivery, smallness for gestational age, and perinatal death. RESULTS: Slow growth of the biparietal diameter less than the 10th and less than the 2.5th conditional centiles between first and second trimesters occurred in 10.4% and 3.6% of the population, respectively. Biparietal diameter growth less than the 10th centile was associated with perinatal death before 34 weeks (risk 0.5% compared with 0.04%, odds ratio [OR] 16.0, confidence interval [CI] 2.9–88.7). Biparietal diameter growth less than the 2.5th centile was the best predictor of perinatal death at any gestation, with a positive likelihood ratio of 4.7 and an OR of 7.3 (CI 2.4–22.2). In contrast, the biparietal diameter, dated by crown-rump length, did not have an increased risk of perinatal death; however, there was a mildly increased risk of small for gestational age birth weight (less than the 10th customized centile) if the biparietal diameter was below the 10th centile in the first trimester (risk 17% compared with 12%, OR 1.5, CI 1.2–1.8) or in the second trimester (risk 15.8% compared with 12.4%, OR 1.3, CI 1.1–1.5). CONCLUSION: Slow growth of the fetal biparietal diameter between the first and second trimesters of pregnancy is a strong predictor of perinatal death before 34 weeks. LEVEL OF EVIDENCE: II

Fetal growth between the first and second trimesters and the risk of adverse pregnancy outcome

To relate growth rate of the biparietal diameter (BPD) between the first and second trimesters to the risk of perinatal death, intrauterine growth restriction (IUGR), macrosomia, preterm/post‐term delivery and pre‐eclampsia.

Polymorphisms in the tumor necrosis factor alpha and interleukin 1-beta promoters with possible gene regulatory functions increase the risk of preterm birth

Objective. To investigate the relation between 19 selected single nucleotide polymorphisms in three cytokine genes, tumor necrosis factor alpha (TNFA), interleukin 1‐beta (IL1B) and interleukin 6 (IL6) and preterm birth (<37 weeks’ gestation). Design. Case‐control association study. Sample. A total of 117 singleton pregnant Danish Caucasian women, including 62 preterm birth cases and 55 controls (birth ≥37 weeks). Methods. Genotyping was performed using TaqMan probes and traditional sequencing. Descriptive statistics were carried out with Fishers exact test and Wilcoxon rank‐sum test. All genetic data were tested for Hardy–Weinberg equilibrium and analyzed using logistic regression, 2×2 proportions or χ2. Haplotypes were estimated for each gene and permutation used for association testing. Results. Women carrying the TNFA −857 C>T rare allele (T) and those homozygous for the IL1B −31 T>C and IL1B −511 C>T rare alleles (C and T) have an increased risk of preterm birth with OR 3.1 (95% CI: 1.0‐10.3) and OR 6.4 (95% CI: 1.3‐60.5), respectively. Two estimated TNFA haplotypes were associated with preterm birth with OR 3.1 (p = 0.037) and OR 2.7 (p = 0.045). Conclusion. Polymorphisms in the cytokine genes TNFA and IL1B may increase the risk of preterm birth, possibly by a dysregulation of the immune system in pregnancy.

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.

First trimester Down syndrome screening : Distribution of markers and comparison of assays for quantification of pregnancy-associated plasma protein-A

Objective. First trimester screening for fetal chromosomal disease is now possible using the maternal serological markers pregnancy‐associated plasma protein‐A (PAPP‐A) and the free β‐form of human chorionic gonadotrophin (βhCG) in combination with the ultrasound marker nuchal translucency (NT) thickness. The availability of well‐defined analytical methods and reference ranges for the involved parameters, and knowledge of the correlation between markers and clinical parameters, e.g. maternal weight, parity and age, are important for the design of efficient screening programs. Material and methods. Women (n = 2702), with singleton pregnancies, participating in the Copenhagen First Trimester Screening Study had PAPP‐A and βhCG values determined and NT measured at a gestational age of 11 to 14 weeks, as determined from crown rump length (CRL). The distribution of gestational age‐independent multiples of the median (MoM) of the parameters was defined and reference intervals established. Three methods for determination of PAPP‐A, one manual in‐house poly‐monoclonal ELISA and two commercial semi‐automatic double‐monoclonal methods, i.e. PAPP‐A for the AutoDelfia platform and PAPP‐A for the Kryptor platform, were compared in 260 women. Results. All markers had log‐normally distributed MoMs. Gestational age independent reference intervals were established. Maternal weight should be included in risk algorithms. The semi‐automated PAPP‐A assays (AutoDelfia and Kryptor) gave similar values, mean difference 10.5 %, whereas the manual assay gave higher values, mean differences 50.4 % and 41.0 %, respectively, Conclusions. This calls for better standardization and a uniform quality control scheme that is focused on discriminatory ability rather than adherence to mean values from a large number of laboratories.

Placental protein-13 (PP13) in combination with PAPP-A and free leptin index (fLI) in first trimester maternal serum screening for severe and early preeclampsia

Abstract Background: Placental protein-13 (PP13) is involved in placental invasion and has been suggested as a maternal serum marker of preeclampsia (PE) development. However, the discriminatory ability of PP13 in first trimester has not been completely clarified. Methods: PP13 was measured in first trimester (week 10+3–13+6) maternal serum from 120 PE pregnancies and 267 control pregnancies and was correlated with clinical parameters. The population screening performance of PP13 in combination with the PE markers pregnancy associated plasma protein A (PAPPA) and free leptin index (fLI) was assessed by Monte Carlo simulation. Results: In severe PE (including HELLP) cases (n=26) the median PP13 concentration was 35.8 pg/mL (range: 17.8–85.5 pg/mL) and in PE pregnancies (n=10) with birth prior to week 34, the median PP13 concentration was 30.6 pg/mL (13.1–50.1 pg/mL), compared to controls with a median of 54.8 pg/mL (range: 15.4–142.6 pg/mL) (p<0.04). The population screening detection rate (DR) for a false-positive rate of 10% for severe PE and HELLP was 26% for PP13, 28% for PP13+PAPP-A, 33% for PP13+fLI, and 40% for PP13+PAPP-A+fLI. Conclusions: PP13 is a marker of severe PE and HELLP syndrome. The screening performance of PP13 can be markedly improved by combining it with fLI and PAPP-A.

Maternal Serum Resistin Is Reduced in First Trimester Preeclampsia Pregnancies and Is a Marker of Clinical Severity

Objective: To examine whether resistin levels in first trimester maternal serum are associated with insulin resistance or preeclampsia (PE). Methods: A case-control study of maternal serum resistin concentration conducted using 285 normal pregnancies and 123 PE pregnancies matched for gestational age, parity and maternal age. Samples were taken in gestational weeks 10+0–13+6. Results: There was a negative correlation between resistin and clinical severity of PE, but no correlation with IS, TNF-α, body mass index, birth weight and pregnancy length. Conclusions: Resistin is reduced in first trimester of PE pregnancies, particularly in severe PE. Inflammation and IS cannot explain this phenomenon.