Screening for pre-eclampsia with competing-risks model using placental growth factor measurement in blood samples collected before 11 weeks' gestation.

OBJECTIVES: To describe the distributional properties and assess the performance of placental growth factor (PlGF) measured in blood samples collected before 11 weeks' gestation in the prediction of pre-eclampsia (PE). METHODS: The study population consisted of pregnant women included in the Pre-eclampsia Screening in Denmark (PRESIDE) study with a PlGF measurement from the routine combined first-trimester screening (cFTS) blood sample collected at 8-14 weeks' gestation. PRESIDE was a prospective multicenter study investigating the predictive performance of the Fetal Medicine Foundation (FMF) first-trimester screening algorithm for PE in a Danish population. In the current study, serum concentration of PlGF in the cFTS blood samples was analyzed in batches between January and June 2021. RESULTS: A total of 8386 pregnant women were included. The incidence of PE was 0.7% at < 37 weeks' gestation and 3.0% at ≥ 37 weeks. In blood samples collected at 10 weeks' gestation, PlGF multiples of the median (MoM) were significantly lower in pregnancies with preterm PE < 37 weeks compared to unaffected pregnancies. However, PlGF MoM did not differ significantly between pregnancies with PE and unaffected pregnancies in samples collected before 10 weeks' gestation. CONCLUSIONS: The gestational-age range for PlGF sampling may be expanded from 11-14 to 10-14 weeks when assessing the risk for PE using the FMF first-trimester screening model. There is little evidence to support the use of PlGF in blood samples collected before 10 weeks' gestation. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Quadruplet pregnancy outcome with and without fetal reduction: Danish national cohort study (2008-2018) and comparison with dichorionic twins.

OBJECTIVES: To perform a nationwide study of quadrichorionic quadriamniotic (QCQA) quadruplet pregnancies and to compare the pregnancy outcome in those undergoing fetal reduction with non-reduced quadruplets and dichorionic diamniotic (DCDA) twin pregnancies from the same time period. METHODS: This was a retrospective Danish national register-based study performed using data from the national Danish Fetal Medicine Database, which included all QCQA quadruplets and all non-reduced DCDA twin pregnancies with an estimated due date between 2008 and 2018. The primary outcome measure was a composite of adverse pregnancy outcomes, including pregnancy loss or intrauterine death of one or more fetuses. Secondary outcomes included gestational age at delivery, the number of liveborn children, preterm delivery before 28, 32 and 37 gestational weeks and birth weight. Data on pregnancy complications and baseline characteristics were also recorded. Outcomes were compared between reduced and non-reduced quadruplet pregnancies, and between DCDA pregnancies and quadruplet pregnancies reduced to twins. A systematic literature search was performed to describe and compare previous results with our findings. RESULTS: Included in the study were 33 QCQA quadruplet pregnancies, including three (9.1%) non-reduced pregnancies, 28 (84.8%) that were reduced to twin pregnancy and fewer than three (6.1%) that were reduced to singleton pregnancy, as well as 9563 DCDA twin pregnancies. Overall, the rate of adverse pregnancy outcome was highest in non-reduced quadruplets (66.7%); it was 50% in quadruplets reduced to singletons and 10.7% in quadruplets reduced to twins. The proportion of liveborn infants overall was 91.1% of the total number expected to be liveborn in quadruplet pregnancies reduced to twins. This was statistically significantly different from 97.6% in non-reduced dichorionic twins (P = 0.004), and considerably higher than 58.3% in non-reduced quadruplets. The rates of preterm delivery < 28, < 32 and < 37 weeks were decreased in quadruplets reduced to twins compared with those in non-reduced quadruplet pregnancies. Quadruplets reduced to twins did not achieve equivalent pregnancy outcomes to those of DCDA twins. CONCLUSION: This national study of QCQA quadruplets has shown that multifetal pregnancy reduction improves pregnancy outcome, including a decreased rate of preterm delivery and higher proportion of liveborn children. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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.

Prenatal cardiac biometry and flow assessment in fetuses with bicuspid aortic valve at 20 weeks' gestation: multicenter cohort study.

OBJECTIVE: To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy. METHODS: This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups. RESULTS: Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04). CONCLUSIONS: Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Contingent first-trimester screening for aneuploidies with cell-free DNA in a Danish clinical setting.

OBJECTIVES: The primary aim of this study was to compare the screening performance for trisomy 21 (T21) between combined first-trimester screening (cFTS) with referral for invasive testing at a T21 risk ≥ 1 in 300, and contingent screening consisting of referral for invasive testing at a cFTS-T21 risk ≥ 1 in 100 and referral for cell-free DNA (cfDNA) testing at a cFTS-T21 risk between 1 in 100 and 1 in 1000. Secondary aims were to compare the incidence of fetuses diagnosed with trisomy 18 (T18), trisomy 13 (T13) or sex chromosome aneuploidy, and examine the association between fetal fraction of cfDNA in maternal blood and maternal/fetal characteristics. METHODS: Women with a singleton pregnancy and a cFTS-T21 risk of ≥ 1 in 1000 were recruited consecutively from two Danish hospitals between August 2014 and May 2015. First-trimester combined screening was based on maternal age, nuchal translucency thickness and levels of pregnancy-associated plasma protein A (PAPP-A) and ß-human chorionic gonadotropin (ß-hCG). Blood samples for cfDNA testing were analyzed for risks of T21, T18, T13 and sex chromosomal aneuploidies. cfDNA analysis was conducted blinded to the cFTS assessment and karyotype results. Pregnancy outcomes and pre- and postnatal karyotypes were obtained from the Danish Fetal Medicine Database. RESULTS: Among 6449 women who underwent cFTS risk assessment, 869 (13.5%) had a T21 risk of ≥ 1 in 1000 and 597 were included for cfDNA testing. Among these, there were 15 cases of T21, one case of T18 and two cases of T13. The sensitivity for detection of T21 was 100% using both screening strategies, while specificity increased significantly (P < 0.0001) from 97.0% using the cFTS strategy to 98.8% using the contingent approach. The sensitivity for detection of T21, T18 and T13 increased from 94.4% using the cFTS strategy to 100% using the contingent approach, with overlapping CIs, while specificity increased significantly (P < 0.0001) from 97.1% for cFTS to 98.9% for the contingent strategy. Seven pregnancies were categorized as being at increased risk of a sex chromosomal aneuploidy by cfDNA testing but chromosome analysis was discordant, corresponding to a false-positive rate of 1.2%. The fetal fraction decreased significantly with increasing maternal weight and increased significantly with the level of ß-hCG and PAPP-A and among female fetuses, in both univariate and multivariate analyses. CONCLUSIONS: In a clinical setting with efficient cFTS, contingent screening offering women with a cFTS risk of ≥ 1 in 100 an invasive test and women with a risk from 1 in 100 to 1 in 1000 a cfDNA test had the same sensitivity for T21, T18 and T13, but significantly increased specificity, when compared with offering an invasive test to all women with a risk of ≥ 1 in 300. Implementing contingent screening would therefore reduce significantly the number of invasive tests performed at no loss of sensitivity. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Long-term effects of prenatal progesterone exposure: neurophysiological development and hospital admissions in twins up to 8 years of age.

OBJECTIVES: To perform a neurophysiological follow-up at 48 or 60 months of age in children exposed prenatally to progesterone compared with a placebo and evaluate their medical histories up to 8 years of age. METHODS: In this study, Danish participants of the PREDICT study, including 989 surviving children from 498 twin pregnancies, were followed-up. PREDICT was a placebo-controlled randomized clinical trial examining the effect of progesterone for prevention of preterm delivery in unselected twin pregnancies. Medical histories of the children were reviewed and neurophysiological development was evaluated by the parent-completed Ages and Stages Questionnaire (ASQ) at either 48 or 60 months after the estimated date of delivery. We used the method of generalized estimating equation to account for the correlation within twins. RESULTS: A total of 492 children had been exposed prenatally to progesterone and 497 to placebo. There was no difference in the number of admissions to or length of stay in hospital between the treatment groups, and we found no overall difference in the rates of diagnoses made. However, the odds ratios (ORs) for a diagnosis concerning the heart was 1.66 (95% CI, 0.81-3.37), favoring placebo, among all children, 2.38 (95% CI, 1.07-5.30) in dichorionic twins and 8.19 (95% CI, 1.02-65.6) in all children when excluding diagnoses made at outpatient clinic visits. ASQ scores were available for 437 children (progesterone, n = 225; placebo, n = 212). Mean ASQ score was slightly higher in the progesterone group compared with the placebo group (P = 0.03). In dichorionic twins, the risk of having a low ASQ score (< 10(th) centile) was decreased in the progesterone group (OR, 0.34 (95% CI, 0.14-0.86)). CONCLUSION: Second- and third-trimester exposure of the fetus to progesterone does not seem to have long-term harmful effects during childhood, but future studies should focus on cardiac disease in the child. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Influence of chorionicity on perinatal outcome in a large cohort of Danish twin pregnancies.

OBJECTIVE: To assess outcome in twin pregnancies according to chorionicity. METHODS: A cohort was retrieved from local ultrasound databases at 14 obstetric departments in Denmark, comprising all twin pregnancies with two live fetuses scanned between weeks 11 and 14 in the period 1 January 2004 to 31 December 2006. Outcome data were retrieved from the National Board of Health. RESULTS: Among 2038 twin pregnancies, 1757 (86.2%) were dichorionic (DC) and 281 (13.8%) were monochorionic diamniotic (MC). In MC pregnancies, the rate of spontaneous fetal loss in both second and third trimesters was more than threefold higher than the comparable rate in DC pregnancies: 6.0% vs. 1.9% for at least one fetus in the second trimester (P < 0.001) and 2.1% vs. 0.7% in the third trimester (P = 0.03). In 98.4% of DC pregnancies and in 91.1% of MC pregnancies, at least one infant was liveborn. Amongst pregnancies with two live fetuses at 24 weeks, the proportion with two live infants at 28 days after delivery was 97.5% and 95.1%, respectively. CONCLUSIONS: The increased incidence of fetal loss in MC pregnancies compared with DC pregnancies predominantly occurs before 24 weeks' gestation. After this stage, although the risk of intrauterine fetal death is still higher in MC than in DC pregnancies, if both fetuses are alive at 24 weeks, the chance of a woman having two live infants 1 month after delivery is similar in MC and DC pregnancies.

Increased nuchal translucency, normal karyotype and infant development.

OBJECTIVE: To investigate whether chromosomally normal fetuses with a nuchal translucency (NT) ≥ 99th percentile(3.5 mm) in the first trimester have an increased risk of delayed development at 2 years of age. METHODS: The study included children of women from 10 Danish hospitals who had fetal NT either ≥ 99th percentile (Group 1) or <95th percentile (Group 2) in the first trimester. The groups were matched by gender,gestational age at birth and maternal age. There were twice as many children in Group 2 as in Group 1. Follow-up was conducted at 2 years of age, infant development being assessed by the 'Ages and Stages Questionnaire'. The cutoff value for delayed development was defined as the 5th percentile from the first 100 questionnaires from Group 2. RESULTS: In a 1-year period 202 of 33 266 fetuses (0.6%)had NT ≥ 3.5 mm. Of these, 99 (49.0%) were liveborn with normal karyotype and normal ultrasound findings during pregnancy. The response rate to the ASQ was 83.3% in Group 1 and 71.4% in Group 2. A low ASQ score was found in 1.3% (1/80) and 4.4% (6/137)in Groups 1 and 2, respectively (P = 0.265), but no difference was found in the mean ASQ score between the two groups (P = 0.160). CONCLUSION: Fetuses with NT ≥ 99th percentile, normal karyotype and normal ultrasound findings during pregnancy had no increased risk of developmental delay at 2 years of age compared with fetuses with normal NT(<95th percentile).

Late sequelae after laparoscopic sterilization in the pregnant and non-pregnant woman.

To determine the frequency of late sequelae after laparoscopic sterilization performed at the time of induced abortion, we compared data on 114 women who underwent induced first-trimester abortion and concurrent laparoscopic sterilization, with 288 women who had sterilization performed at least 3 months after induced abortion. The period of observation was 12-95 months, median 49 months. We found no statistical difference between the groups with respect to failures, low abdominal pain, dyspareunia, change in bleeding pattern, sexual life and regrets. The results of these findings, discussed here, support the practice of performing the combined procedure.

PIP: Data on 114 women who underwent induced 1st trimester abortion and concurrent laparoscopic sterilization were compared with data on 288 women who had sterilization performed at least 3 months after induced abortion. The study was done to determine the frequency of late sequelae after laparoscopic sterilization performed at the time of induced abortion. The observation period ranged from 12-95 months (median 49 months) for the post abortion group. Electrocoagulation was used in 85 patients and tubal ring application in 29 patients. For the interval group, the observation period ranged from 12-90 months (median 50 months). Electrocoagulation was used in 212 patients and tubal rings in 76 patients. There was no statistical difference between the 2 groups with respect to median age, age distribution, and number of children prior to sterilization. In the post-abortion group, 42.9% had undergone at least 1 previous legal abortion; in the interval group the figure was 26.4%. The difference was statistically significant. 10 women in the interval group and 5 women in the postabortion group became pregnant after the sterilization. 7.0% of the women in the postabortion group and 4.2% in the interval group reported dyspareunia as a consequence of the operation; the figures were 11.4% and 11.5%, respectively, for abdominal pain. Changes in bleeding pattern after the sterilization procedure were reported by 26.3% in the postabortion group and 37.7% in the interval group. The difference was not statistically significant. 213 women (52.9%) reported no changes in their sexual life. 42.8% reported an improvement and 4.3% a deterioration. 15 women (3.7%) regretted their decision to be sterilized. 12 of these women desired more children, 5 because of remarriage. The remaining women reported sexual frigidity, permanent distress due to changes in menstrual pattern, and a changed attitude to pregnancy as the reason for regret. In sum, except for a trend in the interval group towards fewer failures, there was no significant difference between the 2 groups, and nearly 96% of the women in both groups were satisfied with the operation, despite the fact that 35% of these had had at least 1 of the identified late sequelae.

Late sequelae following laparoscopic sterilization employing electrocoagulation and tubal ring techniques: a comparative study.

Data on 211 consecutive laparoscopic sterilized women were compared. Half the patients were sterilized using unipolar electrocoagulation and the rest had tubal rings. The period of observation was 21-50 months, median 36.5 months. Four failures were observed, median 15 months after the operation. Pregnancy rates were 0.32 per 100 woman years using electrocoagulation and 1.02 using tubal rings. A total of 11% had experienced low abdominal pain and 4% dyspareunia. Menstrual pattern changes were reported by 31% in the electrocoagulation group and 43% in the tubal ring group. The rates of late sequelae were statistically significant independent of the technique employed.

PIP: 2 groups of consecutive patients who were sterilized either by laparoscopic tubal diathermy or by laparoscopic application of tubal rings were reviewed. Particular reference was paid to the evaluation of late occurring problems such as safety, low abdominal pain, dyspareunia, and bleeding pattern changes. The total of 285 healthy women were sterilized over the 1978-82 period. All the operations were performed electively at the patient's request, and they were informed that the sterilization was an irreversible procedure. The laparoscopic sterilizations were performed in essentially the same manner in both groups, using a Benveniste uterine guide for better stabilization and manipulation of the uterus. The median observation time was 36.5 months (range 21-50 months). At the time of admission, 28% were pregnant, all in the 1st trimester. These women underwent sterilization immediately after induced abortion. The study patients were selected to receive different occlusion techniques with respect to the time period they were sterilized. In Group 1 (electrocoagulation), a total of 106 (50.2%) women sterilized consecutively from 1978-80 had both fallopian tubes unipolarly electrocoagulated twice without tubal division. In Group 2 (tubal ring), a total of 105 (49.8%) women sterilized consecutively from 1980-82 had both fallopian tubes ligated by means of silastic band application approximately 2 1/2 cm from the uterine corner. There was no statistically significant difference between the 2 groups of women in terms of median age, age-distribution, number and distribution of induced abortions, and number of children prior to sterilization. In the electrocoagulation group, 1 woman became pregnant after the sterilization. The pregnancy occurred 21 months after the operation. The reason for the failure was not established as the pregnancy was ectopic and had ruptured. In the tubal ring group, 3 women became pregnant after the sterilization. The failures occurred from 6-23 months after the operation. In 2 cases the tubal rings were found on the round ligaments or completely missing at 1 salpinx. In the 3rd case, both rings were situated in the correct position. 13.2% of the electrocoagulation group reported low abdominal pain and 6.6% dysparunia as new symptoms appearing after the sterilization. The corresponding rates in the tubal ring group were 8.6% and 1.9%. These differences were not statistically significant, and there also was no difference between the rates in the decades. Changes in bleeding pattern following the sterilization procedure were equally related to age and reported by 33 women in the electrocoagulation group and 45 in the tubal ring group. It is concluded that the rates of late sequelae following laparoscopic sterilization using unipolar electrocoagulation or ring application to the fallopian tubes are independent of the method used, but combining these data with the results of other studies, the ring method is found to be more suitable because of fewer ectopic pregnancies and a greater potential for reversal.

[The risks and benefits of laparoscopic sterilization]. / Risici og fordele ved laparoskopisk sterilisation.

PIP: A review over a 51.5 month period was made of 406 women who had undergone laparoscopic sterilization. Only 1 serious complication occurred, a terminal lesion of the colon sigmoideum which perforated after 3 days, requiring a laparotomy with a transversostomy. 96.1% of those questioned were fully satisfied, although 35.7% experienced complications later. 3.4% were dissatisfied and 3.7% regretted the operation. 3.7% became pregnant on an average of 20.8 months following the surgery. 32.3% experienced changes in menstrual patterns, and 13.1% had lower abdominal pain. 4.9% had dyspareunia, and 4.2% stated that they had a less satisfying sex life following the surgery. It is concluded that laparoscopic sterilization is a generally minor operation with few serious postoperative complications. It should continue to be regarded as a safe and effective method of contraception, which is more reliable than birth control pills or IUDs. However, the patients should always be advised of the risks of continued pregnancy and that the complications discussed can occur.^ieng