K. O. Kagan

Combined First Trimester Screening and Cell-Free Fetal DNA – “Next Generation Screening”

In the last decades, prenatal screening for aneuploidy has become increasingly effective. While first trimester combined screening is considered to be the current gold standard, the use of cell-free fetal DNA (cffDNA), which is also called noninvasive prenatal testing (NIPT), will result in a change of paradigm. Respective studies indicate that in screening for trisomy 21, the detection and false-positive rates are 99 % and 0.1 %, respectively. For trisomies 18 and 13, there is less evidence but recent studies report detection rates of 98 % and 86 %. Despite the excellent results in screening for trisomy 21, NIPT should not be considered as a diagnostic test. Due to the costs of NIPT, it is unlikely that NIPT will be applied in the near future in population-based screening for trisomy. In addition, the scope of the current approach in first trimester screening exceeds the screening for aneuploidy as it is possible to assess the risk for various pregnancy complications. Therefore, a combination of both NIPT and first trimester combined screening seems reasonable. Both examinations could be applied in a contingent model where the latter is offered to everyone and NIPT is restricted to women with an intermediate risk after first trimester combined screening. Such a policy would result in a detection rate of about 97 % for a false-positive rate of about 1 %. While NIPT currently focuses on screening for trisomy 21, 18, 13 and sex chromosomal abnormalities, the scope of NIPT will soon become broader. In this respect, some study groups have managed to examine the whole fetal genome within the course of the pregnancy. However, moral and ethical considerations need to be taken into account.

How to measure cervical length

Cervical-length measurement using transvaginal sonography (TVS) is an essential part of assessing the risk of preterm delivery. At mid-gestation, it provides a useful method with which to predict the likelihood of subsequent preterm birth in asymptomatic women. In women who present with threatened spontaneous preterm labor, TVS measurement of cervical length can help to distinguish between ‘true’ and ‘false’ spontaneous preterm labor. Additionally, there is some evidence that measurement of the cervix at the 11+0 to 13+6-week scan can help to establish the risk of preterm birth1,2. To et al.3 reported on cervical-length measurement between 22 and 24 weeks’ gestation in 39 000 women with a singleton pregnancy. The cervical length was found to be distributed normally, with a mean length of 36 mm. In about 1% of the women, the length was 15 mm or less. This cut-off is generally used to define the high-risk group in interventional studies4. In most studies focusing on asymptomatic twin pregnancies at 20 to 24 weeks, a cut-off of 25 mm is applied5. Celik et al.6 used cervical-length measurements obtained between 20 and 24 weeks’ gestation, along with maternal history, in more than 58 000 women to create computed risk models for preterm delivery. They compared patients who delivered before 28 weeks, between 28 and 30 weeks, between 31 and 33 weeks, and between 34 and 36 weeks’ gestation. For a 10% false-positive rate, the sensitivities were 81%, 59%, 53% and 29%, respectively. In a Health Technology Assessment report, Honest et al.7 summarized the results of five studies that used cervical-length measurements between 20 and 24 weeks, with cut-offs of 20–30 mm, to predict preterm birth before 34 weeks’ gestation. The resultant positive likelihood ratios ranged from 2.3 for 30 mm to 7.6 for 20 mm.

Prefrontal space ratio in second- and third-trimester screening for trisomy 21.

To evaluate the prefrontal space ratio (PFSR) in second‐ and third‐trimester euploid fetuses and fetuses with trisomy 21.

Nasal bone length, prenasal thickness, prenasal thickness-to-nasal bone length ratio and prefrontal space ratio in second- and third-trimester fetuses with Down syndrome

To evaluate nasal bone length (NBL), prenasal thickness (PT), prenasal thickness‐to‐nasal bone length (PT‐NBL) ratio and prefrontal space ratio (PFSR) as markers for Down syndrome in the second and third trimesters.

Screening for chromosomal abnormalities by first trimester combined screening and noninvasive prenatal testing.

PURPOSE To examine combined first trimester screening (FTS), noninvasive prenatal testing (NIPT) and a two-step policy that combines FTS and NIPT in screening for aneuploidy. MATERIALS AND METHODS Retrospective study involving 21,052 pregnancies where FTS was performed at the Praxis Praenatal.de in Duesseldorf, Germany. In each case, the sum risk of trisomy 21, 18 and 13 was computed. We assumed that NIPT detects 99 %, 98 %, 90 % and 99 % of cases with trisomy 21, 18, 13 and sex chromosomal abnormalities and that the false-positive rate is 0.5 %. The following screening policies were examined: NIPT or FTS with sum risk cut-offs of 1 in 50 and 1 in 250 in all patients or a two-step-policy with FTS in all patients followed by NIPT in the intermediate sum risk group. For the intermediate risk group, sum risk cut-offs of 1 in 50 and 1 in 1000 and 1 in 150 and 1 in 500 were used. RESULTS There were 127, 34, 13 and 15 pregnancies with trisomy 21, 18, 13 and sex chromosomal abnormalities. 23 fetuses had other chromosomal abnormalities with an increased risk for adverse outcome that are not detectable by NIPT. 20,840 pregnancies were classified as normal as ante- and postnatal examinations did not show any signs of clinically significant chromosomal abnormalities. FTS with a sum risk cut-off of 1 in 50 and 1 in 250 detects 81 % and 91 % for all aneuploidies. NIPT detects 88 % of the respective pregnancies. The 2-step approach with sum risk cut-offs of 1 in 50 and 1 in 1000 detects 94 % of all aneuploidies. With sum risk cut-offs of 1 in 150 and 1 in 500, the detection rate is 93 %. CONCLUSION A 2-step policy with FTS for all patients and NIPT in the intermediate risk group results in the highest detection rate of all aneuploidies.

Intra- and interoperator reliability of manual and semi-automated measurements of intracranial translucency.

To assess the reproducibility of fetal intracranial translucency (IT) measurements performed manually or with SonoNT®, a semi‐automated caliper placement technique recently introduced for nuchal translucency thickness (NT) measurement.

Comparison of three methods of cervical measurement in the first trimester: single-line, two-line, and tracing

To compare three methods of cervical length measurements using ultrasound in the first trimester: single‐line, two‐line, and tracing.

Quality Requirements for the early Fetal Ultrasound Assessment at 11-13(+6) Weeks of Gestation (DEGUM Levels II and III)

The early fetal ultrasound assessment at 11 - 13(+6) weeks of gestation remains the cornerstone of care despite the progress in diagnosing fetal chromosomal defects using cell-free fetal DNA (cffDNA) from the maternal circulation. The measurement of nuchal translucency (NT) allows the risk calculation for the fetal trisomies 21, 18 and 13 but also gives information on those fetal chromosomal defects which are at present unable to be detected using cffDNA. Nuchal translucency is the only auditable parameter at 11 - 13(+6) weeks and gives thus information on the quality of the first trimester anomaly scan. In addition it gives indirect information on the risks for fetal defects and for cardiac anomalies. Also the chances for a healthy live baby can be estimated. As experience with first trimester anomaly scanning increases, and the resolution of the ultrasound equipment has increased substantially, more and more details of the fetal anatomy become accessible at the first trimester scan. Therefore fetal anatomical defects and complex anomalies have become amenable to examination in the first trimester. This guideline describes compulsory and optional parameters for investigation at the first trimester scan and outlines a structured method of examining a first trimester fetus at 11 - 13(+6) weeks of gestation.

The Diagnosis and Treatment of Ectopic Pregnancy

BACKGROUND Extrauterine pregnancy is a complication of the first trimester of pregnancy that arises in 1.3-2.4% of all pregnancies. METHODS This review is based on articles and guidelines retrieved by a selective PubMed search. RESULTS The presentation of extrauterine pregnancy is highly variable, ranging from an asymptomatic state, to pelvic pain that is worse on one side, to tubal rupture with hemorrhagic shock. 75% of tubal pre gnancies can be detected by transvaginal ultrasonography. In patients with a vital extrauterine pregnancy, the human chorionic gonadotropin concentration generally doubles within 48 hours. Laparoscopy is the gold standard of treatment. Two randomized, controlled trials comparing organ-preserving treatment with ablative surgery revealed no significant difference in pregnancy rates after the intervention, but precise details of the surgical procedures were not provided, and long-term fertility data are lacking. Metho - trexate therapy should be used only for strict indications. CONCLUSION Further randomized, controlled trials with longer follow-up will be needed to answer currently open questions about the potential for individualized surgical treatment and the proper role of pharmacotherapy.

The cavum septi pellucidi in euploid and aneuploid fetuses

To examine whether the cavum septi pellucidi (CSP) is larger in second‐ and third‐trimester fetuses with chromosomal abnormalities than in euploid fetuses.