Denmark was one of the first countries in the world to introduce a universal and free-of-charge offer of combined first-trimester screening (CFTS) for chromosomal anomalies to all pregnant women. In the present chapter, we describe the development and current status of the program and reflect on future directions in the era of exome sequencing (ES) and cell-based noninvasive testing. Now, prenatal screening programs differ vastly all over the world and even between countries that are often considered comparable, such as Denmark and Norway. In this chapter, we will present a few such comparisons but will focus mainly on a thorough description of the Danish context. The aim is to give the reader a point of reference to consider and compare their specific, national context.
Introduction of combined screening
In 2000 the Danish Board of Health commissioned a medical working group (consisting of doctors and midwives) to prepare a possible revision of the then-existing guidelines for prenatal testing in Denmark which consisted of an offer of invasive testing for women of the age of 35 or above ( ). One motivation was to counteract emerging inequality in health due to local discrepancies, where ultrasound examinations and prenatal screening were offered only in some counties ( ). The work resulted in a significant change and new guidelines that were organized around the principle of informed choice. It introduced the offer of a CFTS for chromosomal anomalies and a second-trimester malformation scan to all pregnant women irrespective of age and residence. The main advantages of shifting from age-related screening to universal, first-trimester screening, were argued to be a higher predictive value compared to the previous regime and an expected decrease in the number of invasive tests and procedure-related miscarriages [estimated at the time to be about 1% ( )]. The official aim stated in the guidelines was to facilitate individual choice:
The aim of prenatal testing is – within the juridical framework of Danish Law – to assist a pregnant woman, if she wants such assistance, in making autonomous, reproductive decisions. Neutral and adequate information is a necessary condition to this end.… The aim of prenatal testing is not to prevent the birth of children with serious diseases or handicaps (Parliamentary Decision on Prenatal Diagnosis, May 15, 2003).
After a formal process of public hearing where patient organizations and central agencies were invited to express their opinions, in September 2004 the new guidelines on prenatal testing in Denmark were published ( ). This meant in practice that CFTS was introduced as an option for all pregnant women in Denmark.
Implementation of CFTS, effects, and public discourse
All five Danish counties were quick to follow the new guidelines and by June 2006, the whole of the country was covered ( ). However, implementing the guideline did represent a considerate, collective challenge for all departments with regards to increased requirements of equipment, staff, and education. In hindsight, these collective challenges served as a common platform, for example, for developing educational standards and for the procurement of equipment, which further developed collaboration within clinical genetics, fetal medicine, and across obstetric ultrasound units. Furthermore, the clinical collaborations following the 2004 guideline gave the medical specialties a joint understanding of the importance of a high-quality, uniform clinical practice to ensure a consistent and equal offer of prenatal screening, testing, and care to all pregnant women in Denmark. In comparison, Sweden still has considerable differences in the prenatal screening offered in the different counties ( ).
Right from the start, the screening uptake was—and has remained—very high (>90%) ( ). Today, many Danish women consider the CFTS an integral part of standard prenatal care ( ). Following the introduction of CFTS, the number of invasive procedures decreased markedly while the positive predictive value rose ( Fig. 1.1 ). Concurrently, there was an increase in prenatal diagnoses of Down syndrome (DS) ( ) ( Fig. 1.2 ). Additionally, the number of DS live births decreased suddenly and significantly but subsequently stabilized at 20–30 annual live births. Of these the majority were diagnosed postnatally, including women with a screen positive CFTS result who decided to continue pregnancy without additional testing.
Studies have shown that the majority of Danish women have a positive attitude toward CFTS and participate in screening based on an informed decision ( ). However, the high uptake has led some to concern over routine participation and lack of informed choice. Particularly the significant decline in the number of children born with DS continues to be a debate in Danish ( ) and international media ( ). An analysis of the Danish media representations of the screening program and DS identified four discourses of which only one was somewhat positive toward the screening offer. Thus despite the high screening uptake and the high percentage of women who choose to terminate the pregnancy following a prenatal DS diagnosis, the legitimacy of the screening offer continues to stir debate in Denmark.
The discussion of chromosomal microarray, karyotyping, and noninvasive prenatal testing in Denmark
Already around 2005 the much-increased diagnostic rate of chromosomal microarray (CMA) over karyotyping on children with developmental delay or malformation was universally acknowledged and, thus, provided easy diagnostic opportunity for many more syndromes than DS. CMA can detect deletions and duplications down to 0.1 Mb compared to the 10-Mb detection limit of karyotyping, and CMA can hereby provide a one-shot diagnosis of all microdeletion and duplication syndromes (as, e.g., 22q11.2 deletion syndrome). Further, the waiting time for a result is 3–5 days for CMA compared to 10–14 days for karyotyping ( ). Still, there was quite some hesitance in implementing CMA in prenatal diagnosis due to a fear of findings of unknown significance. However, for the analyses of invasive samples, an emphasis was put not only on the ability to detect more serious disorders but also on the shorter waiting time for a result. Both these points accelerated the change from karyotyping to CMA in spite of concurrent counseling difficulties with rare variants of unknown significance and susceptibility loci. However, the change was not made simultaneously between Danish laboratories, and even though CMA was the standard analysis in one region from 2015, only in 2020 were all regions offering CMA as the first-tier analysis. Several Danish regions have now published own results on the increased resolution of CMA over karyotyping on various indication, and here in 2020 this discussion weaned out, and all adhere to a national guideline suggesting CMA for all invasive samples ( ).
Internationally, noninvasive prenatal testing (NIPT) was getting increasingly popular from 2012 and onward, and several publications came out documenting decreases in the invasive rate after an NIPT offer was available ( ). Other countries have implemented NIPT as the first-line analyses for all pregnant women ( ). In Denmark the discussions on the use of NIPT versus invasive samples with CMA for different indications were also ongoing in both genetic and fetal medicine networks ( ). It played a central role in these discussions that recent Danish data documented that the risk of doing invasive testing was lower than expected previously ( ). As a result, the Danish medical societies on medical genetics and fetal medicine found it easier to recommend invasive procedures. Furthermore, one of the very early Danish NIPTs turned out to be one of the rare false negatives (iso21) ( ), and this case had a significant negative impact on the impression of NIPTs’ usefulness for screening purposes among health practitioners. Behind these discussions, there was a substantial concern among health providers for equal access to healthcare across regional borders and social groups, and NIPT quickly became accessible in private clinics, but the volume turned out to be low ( ). NIPT has been used publicly since 2017 as an alternative to invasive testing but only for trisomy 13, 18, and 21 and sex, and, thus, resolution is lower than karyotyping. Additionally, NIPT has a longer turnaround time in the regional setups in Denmark than CMA on invasive sampling due to low volumes and a need to bulk samples from several days ( ). As a result of this, there has been no decrease in the invasive rate in Denmark and less than 1% of all pregnancies are tested with NIPT.
Current status
In 2017 the Danish Board of Health revised the guidelines to include an offer of NIPT as an alternative to invasive testing or no testing for women with a high-risk CFTS result ( Fig. 1.1 ). Contrary to other countries, the majority of Danish women with a high-risk CFTS result still choose the invasive test ( ). One explanation is that the medical societies have been very vocal in their recommendation of the invasive procedure due to better diagnostic performance ( ) and the recent evidence that the risk of miscarriage following an invasive procedure is significantly lower than previously estimated ( ).
Another recent development is that we have seen an annual increase in the number of children born after a prenatal diagnosis of DS ( Fig. 1.3 ) ( ). The National Down Syndrome Association was quick to interpret this as a sign of more women actively choosing to continue a pregnancy after a DS diagnosis and the media ran this story. However, the total number of children born with DS has not increased. Rather, the increase should be interpreted as a result of the option of NIPT to women, who would previously have declined invasive procedures ( ). By opting for risk-free testing, these couples may potentially receive specialized care for their DS fetus/baby (by a cardiologist, additional surveillance during labor, checkup by a specialized pediatrician immediately after birth); however it is yet to be studied how this subgroup applies these options and whether they have any effects.
The flow from screening to diagnosis
The general practitioner as point of entry
When a woman has a positive pregnancy test, she will book an appointment at the general practitioner (GP) for the verification of pregnancy, for blood sampling, and a referral to relevant services of maternity care. It is the GP who is responsible for informing the woman about the offer of prenatal screening and making sure that she makes an informed choice about potential participation. This setup has been continuously critiqued, as both qualitative studies and clinical experiences indicate that the GPs have often not discussed the screening and potential implications in much detail. Thus women do not always consider prenatal screening an active choice. This is in concordance with findings from several other Western countries ( ).
The first-trimester ultrasound scan and combined screening
If the woman chooses CFTS, then blood samples (PAPP-A and ßhCG) are drawn and analyzed prior to the ultrasound examination. The first-trimester ultrasound is performed at the obstetric department in regional/university public hospitals, by nurses or midwives all certified in sonography by the Fetal Medicine Foundation, which includes annual audit and recertification. Prior to starting the examination, consent for CFTS should be verbally confirmed to the sonographer.
Following the ultrasound scan, the CFTS is calculated on the spot based on age, nuchal translucency, PAPP-A, and free ßhCG, and the results are delivered to the couples by the sonographer. In some departments the actual risk number is conveyed for all, while in other departments the risk is only conveyed for the high-risk group. In the case of a high-risk CFTS ( Fig. 1.4 ), some hospitals will have a fetal medicine specialist to explain the result, but in most cases it is the sonographer who provides information about the result and the options available, and—if necessary—supports the couple during their process of decision-making. The rationale behind letting sonographers do the counseling is that it is less anxiety-provoking for the couple. It is a highly stressful situation while the vast majority of cases with an increased risk are normal.
About 5% of the high-risk pregnancies choose no further diagnostics; however, of those who choose further diagnostics, 80% opt for invasive testing with CMA analysis and only 20% opt for NIPT ( ).
Turnaround time and delivery of results
It is well documented that a high-risk screening result leads to a significant increase in worry and anxiety in pregnant women ( ). As time is essential for the couples’ coping, we make short turnaround time a priority. For the vast majority (>90%) ( ), the analysis shows a normal result and from the international literature ( ), we know that the anxiety levels among these women subsequently drop to the same level as screen negative women.
Diagnoses are delivered by phone (by the obstetrics department) with an offer of follow-up at the Department of Clinical Genetics. In Denmark, all prenatal counseling is performed by clinical geneticist consultants or residents.
The second-trimester malformation scan
Another pathway to a prenatal genetic test is the malformation scan in second trimester, and 96% of all Danish pregnant women participate. If malformations are detected, then invasive sampling is offered and almost always accepted ( Fig. 1.4 ). Here only CMA is perceived a relevant analysis and not NIPT, as malformations detected at this point often are due to syndromes that are not currently picked up by NIPT. However, when an anomaly or malformation is detected in the second or third trimester, CMA offers an explanation in less than one in five cases. This means that prospective parents may need to decide to terminate or continue a pregnancy without knowing if the malformation is a symptom of a multiorgan syndrome, a treatable disease, or a single malformation. Furthermore, in ongoing pregnancies, the prenatal surveillance, the delivery, and the postnatal treatment and care are carried out without knowing the specific diagnosis/prognosis of the child, which often leads to over- or undertreatment of the child, failed or ineffective therapeutic interventions, parental anxiety, as well as uncertainty and frustration among health professionals. It is hoped that the introduction of ES may provide a higher diagnostic yield for this group. In Denmark, indications and setups for ES of these pregnancies are currently being trialed locally and soon the guideline process of evening out differences will commence.
Termination of pregnancy
The stated aim of the prenatal screening program is to provide prospective parents with reproductive choices, which includes the decision to the termination of pregnancy (TOP). In Denmark, all women have the legal right to TOP up to week 11+6. From week 12+0, TOP is only allowed after application to a regional council, permission will be granted if (1) there is a risk of severe fetal disease, or the newborn will suffer from severe physical or mental disorder, or (2) if the pregnancy or care of the child will pose a risk to the mother’s physical or mental health, or (3) because of social circumstances. Annually, there are 60,000 live births, and 500 abortions after week 12 due to severe physical or mental fetal disorder ( ). Often, the medical clinical geneticist and other staff will need to guide and support the couples during this difficult decision-making process. TOP in the third trimester is very rarely granted, and, thus, there has been a reluctance toward prenatal diagnoses in late pregnancy and a preference for postponing the diagnosis until after birth. However, recently—and propelled by the introduction of ES—we have become more aware of the value of a prenatal diagnosis even in the absence of TOP, as it allows for the couple to adjust to this information, to prepare for birth and specialized postnatal care.
Data in registries
The prenatal screening setup in Denmark is characterized by a high level of cross-regional collaboration, continuous interdisciplinary dialog between the medical societies for fetal medicine and for clinical genetics, as well as collective commitment to gathering and sharing data. As a result, Denmark has high-quality databases combining cytogenetic analyses (Danish Central Cytogenetic Registry) with prenatal ultrasound (Danish Fetal Medicine Database) with data on all pregnancies from week 12, including spontaneous abortions, TOPs, and live-born babies ( ). This collaboration and focus on high-quality data is a result of the standardization of prenatal screening initiated with the publication of 2004 national guidelines. The Danish Fetal Medicine Database enables close and consistent monitoring of a wide range of quality parameters to assess performance (e.g., false-positive rates), allow benchmarking between hospitals, and support continuous quality improvement. This availability of current and precise data has proved very valuable for generating context-specific knowledge (e.g., on the lower risk of procedure-related miscarriage) and for assessing new technologies’ potential consequences in a Danish context (e.g., the value of CMA over NIPT). Our international readers may be interested to know that data can be made available to all by application.
International comparisons
The UK context in Table 1.1 is written by Jane Fischer, Antenatal Results and Choices that is a UK-based charity providing impartial information and support to women and couples through antenatal screening and its consequences .
