Pre-eclampsia screening in Denmark (PRESIDE): national validation study.

OBJECTIVES: To investigate the predictive performance of the Fetal Medicine Foundation (FMF) first-trimester screening algorithm for pre-eclampsia in a Danish population and compare screening performance with that of the current Danish strategy, which is based on maternal risk factors. METHODS: This was a prospective study of women with a singleton pregnancy attending for their first-trimester ultrasound scan and screening for aneuploidies at six Danish university hospitals between May 2019 and December 2020. Prenatal data on maternal characteristics and medical history were recorded, and measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum pregnancy-associated plasma protein-A (PAPP-A) and serum placental growth factor (PlGF) were collected without performing a risk assessment for pre-eclampsia. Information on acetylsalicylic acid use was recorded. After delivery, pregnancy outcome, including gestational age at delivery and pre-eclampsia diagnosis, was recorded. Pre-eclampsia risk assessment for each woman was calculated blinded to outcome using the FMF screening algorithm following adjustment to the Danish population. Detection rates (DRs) of the FMF algorithm were calculated for a fixed screen-positive rate (SPR) of 10% and for the SPR achieved in the current Danish screening. RESULTS: A total of 8783 pregnant women were included, with a median age of 30.8 (interquartile range (IQR), 28.1-33.9) years. The majority were white (95%), naturally conceiving (90%), non-smokers (97%) and had no family history of pre-eclampsia (96%). The median body mass index was 23.4 (IQR, 21.2-26.6) kg/m2 . A complete risk assessment including maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A was available for 8156 women (92.9%). In these women, UtA-PI was measured bilaterally with a median value of 1.58 (IQR, 1.27-1.94) and the median resting MAP of 80.5 (IQR, 76.1-85.4) mmHg in two consecutive measurements. Among these, 303 (3.7%) developed pre-eclampsia, including 55 (0.7%) cases of pre-eclampsia with delivery < 37 weeks of gestation and 16 (0.2%) cases of pre-eclampsia with delivery < 34 weeks. At a SPR of 10%, combined screening using the FMF algorithm based on maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A had a DR of 77.4% (95% CI, 57.6-97.2%) for pre-eclampsia with delivery < 34 weeks, 66.8% (95% CI, 54.4-79.1%) for pre-eclampsia with delivery < 37 weeks and 44.1% (95% CI, 38.5-49.7%) for pre-eclampsia with delivery at any gestational age. The current Danish screening strategy using maternal risk factors detected 25.0% of women with pre-eclampsia with delivery < 34 weeks and 19.6% of women with pre-eclampsia with delivery < 37 weeks at a SPR of 3.4%. When applying the FMF algorithm including maternal characteristics, MAP, UtA-PI and PlGF at the fixed SPR of 3.4%, the DRs were 60.5% (95% CI, 36.9-84.1%) for PE with delivery < 34 weeks and 45.2% (95% CI, 32.0-58.5%) for PE with delivery < 37 weeks. CONCLUSION: In this large Danish multicenter study, the FMF algorithm based on maternal characteristics, MAP, UtA-PI, PlGF and PAPP-A predicted 77.4% of cases with pre-eclampsia with delivery < 34 weeks and 66.8% of cases with pre-eclampsia with delivery < 37 weeks of gestation at a SPR of 10%, suggesting that the performance of the algorithm in a Danish cohort matches that in other populations. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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.

Different cerebrovascular effects of medroxyprogesterone acetate and norethisterone acetate in the New Zealand White rabbit.

OBJECTIVE: The lack of a cardioprotective effect of hormone replacement therapy (HRT), as suggested by the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Health Initiative (WHI) may in part be explained by the progestin used. The aim of this study was to elucidate the effect of different progestins on cerebrovascular reactivity in an animal model. METHODS: Fifty-six ovariectomized New Zealand White rabbits were randomized into seven groups receiving hormone treatment for 4 weeks: medroxyprogesterone acetate (MPA) (10 mg/day); norethisterone acetate (NETA) (3 mg/day); conjugated equine estrogens (CEE) (1.25 mg/day); 17beta-estradiol (E2) (4 mg/day); MPA + CEE (10 mg/day + 1.25 mg/day); NETA + E2 (3 mg/day + 4 mg/day); or placebo. Segments from the basilar and posterior cerebral arteries were mounted in myographs for tension recordings. Concentration-response curves to potassium, acetylcholine, sodium nitroprusside, L-NAME (N(omega)-nitro-L-arginine methyl ester), calcium and endothelin-1 were established. RESULTS: Treatment with MPA caused a significant increase in vasoconstriction, expressed as E(max) (mN/mm, mean +/- SEM; p < 0.05), in response to potassium (3.18 +/- 0.19 vs. 2.47 +/- 0.19) and calcium (4.00 +/- 0.22 vs. 3.34 +/- 0.14) in the posterior cerebral artery, and to endothelin-1 (6.88 +/- 0.69 vs. 5.22 +/- 0.30) in the basilar artery, when compared with NETA. This difference was neutralized in the groups receiving the combined treatment of MPA + CEE and NETA + E2. No overall differences were seen between CEE and E2. CONCLUSIONS: In rabbit cerebral arteries, MPA treatment causes a higher development in arterial tension compared with NETA, indicating that different progestins may display different cerebrovascular effects. However, when accompanied by estrogens, as in the case of HRT, this difference is eliminated.