Introduction of a nationwide first-trimester anomaly scan in the Dutch national screening program.

BACKGROUND: A significant proportion of major fetal structural anomalies can be detected in the first trimester by ultrasound examination. However, the test performance of the first-trimester anomaly scan performed in a low-risk population as part of a nationwide prenatal screening program is unknown. Potential benefits of the first-trimester anomaly scan include early detection of fetal anomalies, providing parents with more time for reproductive decision-making. OBJECTIVE: To investigate the uptake, test performance, and time to a final prenatal diagnosis after referral. STUDY DESIGN: A nationwide implementation study was conducted in the Netherlands (November 2021-November 2022). The FTAS was performed between 12+3 and 14+3 weeks of gestation by certified sonographers using a standard protocol. Women were referred to a tertiary care center if anomalies were suspected. Uptake, test performance, and time to a final prenatal diagnosis (days between referral and date of final diagnosis/prognosis for reproductive decision-making) were determined. Test performance was calculated for first-trimester major congenital anomalies, such as anencephaly and holoprosencephaly and all diagnosed anomalies <24 weeks of gestation. RESULTS: The first-trimester anomaly scan uptake was 74.9% (129,704/173,129). In 1.0% (1313/129,704), an anomaly was suspected, of which 54.9% (n=721) had abnormal findings on the detailed first-trimester diagnostic scan and 44.6% (n=586) showed normal results. In 0.5% (n=6), intrauterine fetal death occurred. In the total group of 721 cases with abnormal findings, 332 structural anomalies, 117 genetic anomalies, 82 other findings (abnormal fetal biometry, sonomarkers, placental/umbilical cord anomaly, an-/oligohydramnios), and 189 cases with transient findings (defined as ultrasound findings which resolved <24 weeks of gestation) were found, with 1 case having an unknown outcome. 0.9% (n=1164) of all cases with a normal first-trimester anomaly scan were diagnosed with a fetal anomaly in the second trimester. Test performance included a sensitivity of 84.6% (126/149) for first-trimester major congenital anomalies and 31.6% (537/1701) for all types of anomalies. Specificity for all anomalies was 99.2% (98,055/98,830); positive predictive value 40.9% (537/1312); negative predictive value 98.8% (98,055/99,219); positive likelihood ratio 40.3; negative likelihood ratio 0.7; false positive rate 0.8% (775/98,830), and false negative rate 68.4% (1164/1701). The median time to diagnosis for structural anomalies was 20 days (6-43 days; median gestational age 16+3), for genetic anomalies 17 days (8.5-27.5 days; median gestational age 15+6 weeks), and for first-trimester major congenital anomalies 9 days (5-22 days; median gestational age 14+6 weeks). CONCLUSION: The performance of a newly introduced nationwide first-trimester anomaly scan in a low-risk population showed a high sensitivity for first-trimester major congenital anomalies and a lower sensitivity for all anomalies combined. The program was accompanied by a referral rate of 1.0%, of which 59.1% involved cases where anomalies were either not confirmed or resolved before 24 weeks gestation. Timing of diagnosis was around 16 weeks of gestation for referred cases. To evaluate the balance between benefits and potential harm of the first-trimester anomaly scan within a nationwide prenatal screening program, it is essential to assess the effectiveness of the program over time and to consider the perspectives of both women and their partners, as well as healthcare professionals.

Fetal Metabolic Stress Disrupts Immune Homeostasis and Induces Proinflammatory Responses in Human Immunodeficiency Virus Type 1- and Combination Antiretroviral Therapy-Exposed Infants.

Increased morbidity and fetal growth restriction are reported in uninfected children born to human immunodeficiency virus type 1 (HIV-1)-infected women treated with antiretroviral (ARV) therapy. Viruses and/or pharmacological interventions such as ARVs can induce metabolic stress, skewing the cell's immune response and restricting (cell) growth. Novel metabolomic techniques provided the opportunity to investigate the impact of fetal HIV-1 and combination ARV therapy (cART) exposure on the infants' immune metabolome. Peroxidized lipids, generated by reactive oxygen species, were increased in cART/HIV-1-exposed infants, indicating altered mitochondrial functioning. The lipid metabolism was further dysregulated with increased triglyceride species and a subsequent decrease in phospholipids in cART/HIV-1-exposed infants compared to control infants. Proinflammatory immune mediators, lysophospholipids as well as cytokines such as CXCL10 and CCL3, were increased whereas anti-inflammatory metabolites from the cytochrome P450 pathway were reduced in cART/HIV-1-exposed infants. Taken together, these data demonstrate that the fetal metabolism is impacted by maternal factors (cART and HIV-1) and skews physiological immune responses toward inflammation in the newborn infant.

Comparison of dolutegravir and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV.

BACKGROUND: Both dolutegravir and efavirenz are known to be effective in pregnancy and postpartum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent, these symptoms occur in pregnant and postpartum women, however, is not yet known. METHODS: This was a secondary analysis of the DolPHIN2 study, a multicentre randomized trial among women presenting late in pregnancy with untreated HIV - who received either a dolutegravir-containing or efavirenz-containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analysed during pregnancy and up to 48 weeks postpartum. RESULTS: Among 268 women, median (IQR) Edinburgh Post Natal Depression Score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir and efavirenz arm, respectively, 23.7 and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow-up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen ( P  = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir and efavirenz were 6 (5-7) and 5 (5-6.5), respectively, P  = 0.70. CONCLUSION: No statistically significant differences were observed between efavirenz-containing or dolutegravir-containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy.

Which second trimester placenta previa remains a placenta previa in the third trimester: A prospective cohort study.

OBJECTIVE: The far majority of women with a placenta previa in the second trimester will no longer have a placenta that overlies the internal os in the third trimester. Women with a placenta previa in the third trimester are at risk for complication such as preterm birth and blood loss. Four counselling purposes we aim to identify which women with a second trimester placenta previa have a low-risk and a high-risk for persistence of the placenta previa. STUDY DESIGN: A prospective cohort study of women with a placenta previa in the second trimester between 2014 and 2019. The odds for having a placenta previa in the third trimester were calculated for different baseline characteristics. Multilevel likelihood ratios for ranges of the placenta overlying the internal os in the second trimester and the corresponding ROC curve were calculated to identify the optimal cut-off values. RESULTS: We included 313 women with a placenta previa in the second trimester. The placenta was more frequently located on the posterior wall (62 %) than on the anterior wall (38 %). At evaluation in the third trimester, 37 women (14 %) still had a placenta previa. Women with a larger distance of the placenta overlying the internal os, women having a previous cesarean delivery and women after a conception with assisted reproductive technique had a significant higher risk of placenta previa persistence (p-values <0.001). Women with a placenta overlying less than 14 mm can be considered as low-risk, indicated by a likelihood ratio of 0. Women with a placenta with more than 55 mm overlap can be considered as high-risk, indicated a the likelihood ratio of ∞. CONCLUSION: The majority of the second trimester placenta previa will no longer overly the internal os in the third trimester. Placenta previa persistence is associated with the distance overlying the internal os, a previous cesarean delivery and assisted reproductive techniques. In the second trimester, women can be identified as low-risk and high-risk for persistence of placenta previa. This can be used for risk stratification, counselling and individualized care for women with a second trimester placenta previa.

Final outcome of a second trimester low-positioned placenta: A systematic review and meta-analysis.

Low-positioned placentas which are located in the lower uterine segment (LUS), either a low-lying placenta or a placenta previa, are associated with increased obstetric risks. However, most second trimester low-positioned placentas resolve during pregnancy and have a higher position in the third trimester, without posing any risks. We performed a systematic review and meta-analysis to evaluate the proportion of second trimester low-positioned placentas that have a position towards the fundus in the third trimester. Our aim was to find a cut-off value that included all women in whom the placenta will remain low in the third trimester, thus who are at increased risk of obstetric complications. Subsequently, we assessed whether an anterior or posterior placental location influenced this proportion. We searched MEDLINE and EMBASE and clinicaltrials.gov up to April 2019 for studies on the sonographic follow-up of second trimester low-positioned placentas, with a distance between the placenta and the internal os of the cervix of 20 mm or less at a gestational age of above 15 week and a follow up after 28 weeks. Studies were scored on methodological quality using the Newcastle-Ottowa Scale (NOS). A meta-analysis was conducted to summarize the proportion of second trimester low-positioned placentas with a position towards the fundus in the third trimester. We calculated the proportion at different cut-off values of the distance from the placental edge to the internal os of the cervix (0 mm, 10 mm and 20 mm). Also, anteriorly and posteriorly located placentas and women with and without a prior cesarean delivery were compared. We included 11 eligible studies which reported on 3586 women with a low-positioned placenta in the second trimester. Proportions of placentas with a position towards the fundus in the third trimester ranged between 0.63 and 1.0. Pooled proportions were 0.90 (95% CI 0.87-0.93) for IOD <10 mm and 0.80 (95% CI 0.74-0.85) for IOD < 0 mm. Due to heterogeneity between studies, the subgroup of <20 mm could not be pooled. Overall, anteriorly located placentas more often had a position towards the fundus in the third trimester, but studies did report conflicting results. Prior cesarean section had no influence except for an IOD of <0 mm, in which women without a prior cesarean delivery more often had a placenta towards the fundus. The majority of second trimester low-positioned placentas will be located towards the fundus at the time of follow-up. However, we could not determine a cut-off value for anterior and posterior placentas that included all women at high risk. The cut-off value, placental side and prior cesarean section should be assessed in a large prospective observational study.

Detection of chromosome abnormalities by quantitative fluorescent PCR in ectopic pregnancies.

OBJECTIVE: To evaluate the potential value of quantitative fluorescent polymerase chain reaction (QF-PCR) in the detection of chromosome abnormalities in ectopic pregnancies. METHODS: Seventy chorionic villi samples of ectopic pregnancies were studied by QF-PCR. Primers for chromosomes 16, 21, X and Y in chorionic villi were evaluated. Fluorescence in situ hybridization (FISH) was performed when results of QF-PCR showed aneuploidy, in case of unexplicable QF-PCR peaks, and in 10 cases with normal QF-PCR results. RESULTS: QF-PCR produced a result for chromosomes X and Y in 66 cases (94%), for chromosome 16 in 62 cases (89%) and for chromosome 21 in 55 cases (79%). Overall, QF-PCR produced a result for the chromosomes tested in 54 ectopic pregnancy cases (77%). Fifty-two of these results were normal disomic (96%) and two were abnormal, one trisomy 16 (2%) and one triploidy (2%). In 16 cases (23%) no definite QF-PCR results could be obtained for all chromosomes, 11 due to amplification failure, and 5 due to unexplicable QF-PCR peaks. In 10 cases with normal QF-PCR results, disomy was confirmed by FISH. The trisomy 16 was also confirmed by FISH. Furthermore, a result was obtained with FISH in 5 of the cases without definite QF-PCR results. CONCLUSION: Although QF-PCR can establish the chromosomal status in ectopic pregnancies for chromosomes 16, 21, X and Y in the majority of cases, the technical failure rate is still considerable and does not improve results when compared to cytogenetic techniques.