First trimester growth restriction and uterine artery blood flow in the second trimester as predictors of adverse pregnancy outcome.

OBJECTIVES: To investigate if fetuses with first trimester growth restriction have poorer perfusion of the placenta compared to a control group, and to investigate whether first trimester growth restriction in combination with poor flow in the uterine arteries in the second trimester can be used to predict poor outcome. STUDY DESIGN: Women with singleton pregnancies, where the gestational age estimated by crown-rump length (CRL) at the first trimester scan was 7 days or more smaller than the gestational age estimated by last menstrual period, and a control group of women, where the gestational age was either equal to or 1 day larger than the gestational age estimated by last menstrual period, were invited to join the study. The study entailed the routine scans; Down syndrome screening in gestational week 11-14 and an anomaly scan in gestational week 18-21. In addition to the routine scans the participants were offered a growth scan in gestational week 23-24. At the anomaly scan and growth scan, umbilical and uterine artery Doppler flows were measured. RESULTS: 182 cases and 230 controls were included in the study. The case and control groups showed no significant differences in placental blood flow characteristics at 18-21 weeks or 23-24 weeks. In our logistic regression models the only outcome that showed a significant association to the case group was birth weight below 2500 g. Having a CRL 7 days or more smaller than expected increased the risk of having a child with a birth weight below 2500 g with an odds ratio of 3.29. CONCLUSIONS: We were unable to demonstrate a link between first trimester growth restriction and poor placental perfusion. The case group had increased risk of birth weight below 2500 g, but only with an odds ratio of 3. Therefore we do not recommend implementation of uterine or umbilical artery flow measurements specifically for fetuses with first trimester growth restriction.

Maternal smoking, obesity and male fetal sex predispose to a large nuchal translucency thickness in healthy fetuses.

OBJECTIVES: Our aim was to evaluate the effect of fetal sex, smoking and body mass index (BMI) on nuchal translucency (NT). METHODS: We analyzed data from 7,357 women with a normal singleton live birth outcome with information on smoking, BMI and sex of the infant. NT measurements were converted to multiples of the median (MoM(NT)) using a previously reported linear regression analysis. RESULTS: The odds ratio (OR) for MoM(NT) >95th centile was 1.5 (95% CI 1.2-1.9) for smokers compared to nonsmokers and 1.4 (95% CI 1.1-1.7) for male fetuses compared to female fetuses. Obese women (BMI ≥30) had an increased OR for a large NT of 1.7 (95% CI 1.2-2.6) compared to normal weight women. Obese smokers carrying a male fetus had an OR of 4.2 (95% CI 1.7-10.1) of a MoM(NT) >95th centile compared to normal weight nonsmoking women with a female fetus. The effects of smoking, obesity status and fetal sex were independent of each other. CONCLUSIONS: Smoking, obesity and male sex are associated to a MoM(NT) >95th centile. This may affect screening performance and entail unnecessary anxiety in these women. Further investigations, including fetuses with adverse outcome, are needed.

Maternal serum placental growth hormone, but not human placental lactogen or insulin growth factor-1, is positively associated with fetal growth in the first half of pregnancy.

OBJECTIVE: To investigate if maternal levels of human placental lactogen (hPL), placental growth hormone (PGH) and insulin-like growth factor-1 (IGF-1) are associated with growth rate of the biparietal diameter (BPD) in the first half of pregnancy. METHODS: Data on 8215 singleton fetuses from the Copenhagen First Trimester Study with measurements of BPD from ultrasound scans performed at weeks 11-14 and 17-21 of pregnancy were analyzed. Growth rate was defined as millimeters of growth/day of BPD between the two scans. Fetuses with growth rate below the 2.5(th) centile (low growth rate, n = 203) and above the 97.5(th) centile (high growth rate, n = 203) were identified. As a reference group 212 fetuses with growth rate around the median were identified (intermediate growth rate). Out of the 618 selected cases in the three growth rate groups a total of 463 cases had a blood sample taken at the time of first-trimester ultrasound (5.6% of the original sample size of 8215 pregnancies). The maternal blood serum concentrations of hPL, PGH and IGF-1 were determined in the three different growth-rate groups. Linear regression analysis without adjustment and with adjustment for known and potential confounders was used to compare serum levels between the groups. RESULTS: Simple linear regression showed a difference in serum level of log(10) PGH between the high and intermediate growth-rate groups (P = 0.037). When adjusted for maternal weight and crown-rump length, multiple linear regression analysis confirmed this difference, as fetuses with high growth rates had a 12% (95% confidence interval, 2-20%; P = 0.009) higher maternal serum level of PGH than those with intermediate growth rates. No differences in hPL and IGF-1 levels between the three different growth-rate groups were found after simple and multiple linear regression analysis. CONCLUSION: Maternal PGH levels are higher in women carrying fetuses with high first-trimester growth rates than in controls, both in a simple unadjusted analysis and in analyses adjusted for known and potential confounders. Thus, PGH may be involved in fetal growth regulation as early as in the first trimester of pregnancy.

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

OBJECTIVES: 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. METHODS: In this retrospective study, we analyzed sonographic BPD measurements at 11-14 and 17-21 weeks from 8215 singleton pregnancies in the Copenhagen First Trimester Study. Growth rate was defined as millimeters of growth per day between the two measurements and was dichotomized into growth rates < 2.5(th) vs. 2.5(th)-97.5(th) centiles, and > 97.5(th) vs. 2.5(th)-97.5(th) centiles. Odds ratios (OR) and 95% CIs for adverse outcome were calculated. RESULTS: Fetuses with growth rates < 2.5(th) centile had an OR of 4.79 (95% CI, 1.43-15.99) for perinatal death and an OR of 2.64 (95% CI, 1.51-4.62) for birth weight < sonographically estimated mean fetal weight (adjusted for gestational age) - 2 SD. Fetuses with growth rates > 97.5(th) centile had an OR of 2.83 (95% CI, 1.58-5.06) for birth weight > mean + 2 SD and an OR of 2.30 (95% CI, 1.15-4.59) for delivery in weeks 34-36. Growth rate showed no association with pre-eclampsia. CONCLUSIONS: There is a significant relationship between the growth rate of BPD from the first to the second trimester and adverse pregnancy outcome. Low growth rates are associated with an increased OR for perinatal death and IUGR, while high growth rates are associated with an increased OR for macrosomia and preterm delivery.

Detection of chromosomal abnormalities, congenital abnormalities and transfusion syndrome in twins.

OBJECTIVE: To evaluate the outcome of screening for structural malformations in twins and the outcome of screening for twin-twin transfusion syndrome (TTTS) among monochorionic twins through a number of ultrasound scans from 12 weeks' gestation. METHODS: Enrolled into this prospective multicenter observational study were women with twin pregnancies diagnosed before 14 + 6 gestational weeks. The monochorionic pregnancies were scanned every second week until 23 weeks in order to rule out early TTTS. All pregnancies had an anomaly scan in week 19 and fetal echocardiography in week 21 that was performed by specialists in fetal echocardiography. Zygosity was determined by DNA analysis in all twin pairs with the same sex. RESULTS: Among the 495 pregnancies the prenatal detection rate for severe structural abnormalities including chromosomal aneuploidies was 83% by the combination of a first-trimester nuchal translucency scan and the anomaly scan in week 19. The incidence of severe structural abnormalities was 2.6% and two-thirds of these anomalies were cardiac. There was no significant difference between the incidence in monozygotic and dizygotic twins, nor between twins conceived naturally or those conceived by assisted reproduction. The incidence of TTTS was 23% from 12 weeks until delivery, and all those monochorionic twin pregnancies that miscarried had signs of TTTS. CONCLUSION: Twin pregnancies have an increased risk of congenital malformations and one out of four monochorionic pregnancies develops TTTS. Ultrasound screening to assess chorionicity and follow-up of monochorionic pregnancies to detect signs of TTTS, as well as malformation screening, are therefore essential in the antenatal care of twin pregnancies.

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 ss-form of human chorionic gonadotrophin (sshCG) 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 sshCG 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.

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

OBJECTIVE: To determine the performance of screening for Down syndrome (DS) and other major chromosomal abnormalities using nuchal translucency (NT), free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a prospective study of a non-selected population. METHODS: Of 9941 women with an early ultrasound examination, NT was measured in 8622 singleton pregnancies with a gestational age between 10 + 3 and 13 + 6 weeks. beta-hCG and PAPP-A were analyzed in 6441 cases. Detection rates (DR) and false-positive rates (FPR) for the NT screening, the double test (beta-hCG and PAPP-A) and the combined test (NT and the double test) were calculated using a 1 : 250 cut-off. RESULTS: NT could be measured in 97.5% of cases. The DR for DS with NT screening alone was 75% with a FPR of only 1.8%. The double test detected 73% and the combined test 91%, for FPRs of 8.8% and 2.1%, respectively. We detected 80% of fetuses with other major chromosomal abnormalities with a combination of NT screening and other ultrasound findings. Low beta-hCG and PAPP-A values (below 0.4 MoM) were observed in 0.5% of the women including all cases of triploidy and trisomy 18 and 13. CONCLUSIONS: The performance of a screening strategy for DS using a combination of NT and the double test was superior to that using either NT or the double test alone due to a very low FPR and a higher DR.

First trimester screening for Down syndrome and assisted reproduction: no basis for concern.

In pregnancies obtained after assisted reproduction the false-positive rate of second trimester Down syndrome (DS) screening is increased by 1.5-3-fold. This may cause an increase in the number of amniocenteses and the fetal loss rate. The present study for the first time examined whether assisted reproductive technologies affect the results of first trimester screening. The markers PAPP-A, free beta-hCG and the nuchal translucency (NT) thickness were examined at 12-14 weeks' gestation. Screening markers in 47 in vitro fertilisation (IVF), 63 ovulation induction (OI) and 3026 spontaneously conceived singleton pregnancies were compared. The MoM (multiples of the median) value in the IVF pregnancies was 1.02 (95% CI: 0.85-1.22) for PAPP-A, 1.14 (95% CI: 0.95-1.37) for beta-hCG and 0.97 (95% CI: 0.89-1.05) for NT; the MoM value in the OI pregnancies was 0.89 (95% CI: 0.76-1.05) for PAPP-A, 1.08 (95% CI: 0.93-1.25) for beta-hCG and 1.02 (95% CI: 0.95-1.11) for NT. The first trimester marker values in assisted reproductive pregnancies and spontaneously conceived pregnancies were not significantly different. Estimated false-positive rates for a risk cut-off of 1:400 varied from 4.7% in IVF pregnancies to 5.1% in OI pregnancies. Therefore the false-positive rate in Down syndrome screening should be independent of the method of conception.

Quality assessment in prospective nuchal translucency screening for Down syndrome.

OBJECTIVES: To develop and apply a quality control system in a Down syndrome screening study using nuchal translucency as an interventional marker. METHODS: In a prospective Down syndrome screening study fetal nuchal translucency thickness was measured in 9236 of the 10 045 examined pregnancies. For quality assessment two models were introduced: firstly, image-scoring evaluation of the nuchal translucency thickness measurements and secondly, establishment of the distributions of nuchal translucency multiples of the median over time and the influence of intervention. RESULTS: The observer variability in the image-scoring evaluation was high with a kappa value of 0.48 in the overall validation. A revised model showed better interobserver agreement with a kappa value of 0.58; however, comparing the individual criteria the differences were still unsatisfactory, i.e. we found highly significant differences in the criteria "position of the fetus" (P = 0.0026) and "magnification of the image" (P = 0.0001). Regarding the distributions of the nuchal translucency multiples of the median, the median stabilized after a short learning phase representing the practical part of the sonographer's certification to nuchal translucency screening. In groups of medians of 50 nuchal translucency multiples of the median the intergroup standard deviation decreased from 0.100-0.060 after the learning phase to 0.046 after intervention. CONCLUSIONS: When well-trained certified examiners perform nuchal translucency screening, continuous evaluation of the distribution of the nuchal translucency multiples of the median seems to be a good method to assess the quality for a center and may also be used to identify individual examiners deviating from the mean performance. The image-scoring methods we introduced cannot be recommended for quality control in a nuchal translucency screening program.

Ventilatory pattern and associated episodic hypoxaemia in the late postoperative period in the general surgical ward.

Episodic oxygen desaturation is frequent in the late postoperative period and seems most pronounced on the second and third postoperative nights. However, the ventilatory pattern has not been described systematically during this period. We studied the ventilatory pattern and associated arterial oxygenation using the Edentrace II equipment (impedance pneumography and pulse oximetry) on the second and third postoperative nights in 28 patients undergoing major abdominal surgery. Ventilatory disturbances were common and included periods of hypopnoea, and obstructive, central and mixed apnoeas. Overall, the median (range) respiratory disturbance index (apnoeas + hypopnoeas per h) was 12 (0-121), with the patients spending 6% (0-65%) of the night in some kind of ventilatory disturbance. It was not possible from pre-operative snoring habits to predict patients who developed postoperative ventilatory disturbances. Overall, 23% (0-100) of the hypopnoeas and 7% (0-100) of the apnoeas were associated with episodic hypoxaemia. In conclusion, ventilatory disturbances were common in the late postoperative period in the general surgical ward and often associated with episodes of oxygen desaturation.