History of Prenatal Diagnosis in Germany

In 1970, invasive prenatal diagnosis (PND) started with the introduction of amniocentesis (AC) for the detection of genetic defects in the second trimester. In the majority of cases, cytogenetic investigations were performed; about two dozen metabolic diseases were diagnosed in the 70s [1]. At that time, various tests for α-fetoprotein (AFP) for the detection of neural tube defects were evaluated. A registry for PND was funded by the ‘Deutsche Forschungsgemeinschaft’ (DFG, German Research Association) for the years 1973–1979.

In 1980, ultrasound (US) was introduced as a routine, non-invasive procedure for the surveillance of pregnancies. Two scans were offered in the case of a normal pregnancy. Since April 1995, three scans have become the routine standard.

In 1984, chorionic villus sampling (CVS) in the first and second trimesters started in Germany. During the phase of development, the Federal Ministry of Science and Technology funded a registry to evaluate gynaecological, cytogenetic, molecular and metabolic data for the years between 1985 and 1991. The results have recently been published [2]. With the advent of molecular genetics, DNA analysis started. By now more than 100 disorders can be diagnosed in Germany. It must be mentioned that all PND should be accompanied, or better preceded, by genetic counselling.

Beginning in the early 90s, the triple test (TT) has been used with increasing frequency. However, this test is not performed routinely and a moratorium of the Second Consensus Meeting on Maternal Serum Screening, signed by gynaecologists and human geneticists, recommended a cautious application and pointed out the importance of pretest counselling [3].

National Organisation of Prenatal Diagnosis in Germany

All procedures of invasive and non-invasive PND are done in public as well as in private settings. US is offered by gynaecologists. The TT is offered by gynaecologists and human geneticists and performed by specialised laboratories. Invasive procedures, e.g. AC, CVS, and fetal blood sampling (FBS) are done by gynaecologists only. For genetic analysis and interpretation, human geneticists from various fields, e.g. biochemists, biologists, gynaecologists and paediatricians are in charge. These specialists also are responsible for genetic counselling. Serum screening of infectious diseases is routinely done for rubella, HIV, lues and hepatitis. Other infectious diseases, e.g. CMV and toxoplasmosis, are tested when required.

For US and TT, there is no quality control. Since January 1996, the qualification to perform US examinations is a prerequisite for gynaecologists to survey pregnancies. Whenever malformations or congenital diseases are suspected, gynaecologists specialised in PND are involved. For genetic laboratories, registration is not mandatory, but most laboratories are members of the Professional Association of Medical Genetics (‘Berufsverband Medizinische Genetik’). More than 40 cytogenetic laboratories are taking part in the voluntary quality assessment study run by the association. For DNA laboratories, quality assessment tests started in 1993 under the guidance of the association. A listing of molecular diagnostics in Germany and neighbouring countries is published regularly in Medizinische Genetik. To enter this directory, a laboratory has to become a member of the association and has to participate in the quality control tests.

A minimal estimation of public and private laboratories active in genetic analysis is given in table 1.

Table 1 Number of laboratories: proportion of public and private laboratories
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Basic Data

Birth rates for 1985–1994, with a breakdown of data for the Old (former FRG) and the New Federal States (former GDR) and for Berlin are shown in table 2. Remarkably, after the reunion of Germany, the birth rates in the New States have dropped dramatically.

Table 2 Number of live-births/year
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Sources of Information

In Germany, the overall rate of congenital abnormalities is officially registered by the Federal Office of Statistics. The reported annual malformation rate varies considerably among the Federal States, indicating differences in the assessment of malformations. These official figures are most probably an underestimation of the true prevalence of malformations in newborns since a perinatal study communicates a tenfold higher rate [Kassenärztliche Bundesvereinigung (Federal Association of Practioners, FAP), pers. commun., 1995]. Due to historical reasons, there exists no obligation to register genetically caused malformations or genetic diseases.

Local registries collecting thoroughly the number of children with congenital abnormalities exist in few areas (e.g. Magdeburg, Mainz). In Berlin, all cases of hospital infant mortality with/without congenital abnormalities are registered since 1985.

No data of prenatal diagnoses have been registered systematically. Data concerning AC or CVS for specific time intervals (see Introduction) are available. The number of performed invasive and non-invasive procedures can be partially derived from data provided by the FAP [pers. commun., 1995]. In 1994, for example, 2.07 million routine US scans and a additional 0.19 million specialised scans have been reported to the FAP [pers. commun., 1995]. Figure 1 shows the number of invasive procedures from 1988 to 1994. However, it must be kept in mind that these data are biased by several factors: e.g. (to mention only two): (1) the register covers only the Old States; (2) it includes no data about patients with private health insurances, and therefore a different social status. Therefore, the actual number of examinations must be significantly higher. As a rough estimation, patients with private health insurances comprise ⩾ 10% of all patients.

Fig. 1.
figure 1

Number of AC, CVS and FBS registered by the FAP [pers. commun., 1995] from 1988 to 1994.

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In Berlin, a complete register of pre- and postnatal chromosomal findings was started in 1980 at the Institute of Human Genetics [4].

Impact of Prenatal Diagnosis

The impact of PND on the prevalence of genetic disorders can be shown most reliably for trisomy 21. As mentioned above, a thorough study on this topic was been performed at the Institute of Human Genetics Berlin for the years 1980 to 1994 [4]. The findings clearly demonstrate an increase in the rate of trisomy 21 detected prenatally during the period of the study (fig. 2). Almost all of these pregnancies were terminated. The ratio of about 1:4 of prenatally to postnatally recognised trisomies 21 from 1980 to 1984 increased to about 1:2 or even more between 1985 and 1994.

Fig. 2.
figure 2

Number of pre- and postnatally detected cases of trisomy 21 registered in West Berlin from 1980 to 1994.

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Although perinatal mortality has significantly decreased in recent years (fig. 3), an effect of PND on the number of infants lost due to congenital malformations is not yet apparent. The effect of the new guidelines on motherhood care offering three US scans, at about the 10th, 20th and 30th week of pregnancy (since 1995), on the frequency of post-partum-malformations will perhaps only show in the next years.

Fig. 3.
figure 3

Hospital infant mortality with/without congenital abnormalities in West Berlin from 1987 to 1991 [M. Obladen, pers. commun.].

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There is no nationwide data base concerning the detection of severe malformations in utero.

The following reasons for performing PND are widely accepted by pregnant women in Germany:

  • reduction of parental anxiety concerning fetal malformations;

  • prevention of the birth of a severely handicapped child;

  • early mental preparation of the parents to the birth of a handicapped child;

  • option of a fetal treatment in utero for certain conditions;

  • advantage to optimize pregnancy care as well as place and mode of delivery in case of a malformed infant. In general, there is a positive attitude towards PND in the public [5].

In 1994, more than 2.1 million US exams have been performed in the Old Federal States, which can be related to a birth rate of about 694,000, to a number of 45.300 AC and to a number of 3,100 CVS [FAP, pers. commun., 1995]. Conclusively, considering that the figures concern only patients with a public health insurance (see above), the uptake of invasive procedures during pregnancy can be estimated to be in the order of 10%.

Pretest counselling is mandatory for invasive procedures and for all prenatal genetic tests. It is done by gynaecologists and human geneticists including specialised PhDs. Human geneticists also perform counselling in cases of abnormal results. Involvement of psychologists is not frequent. However, in case of a pathological result the management of such situations varies widely from place to place.

Diagnostic Procedures Currently in Use for Prenatal Diagnosis

US screening/diagnosis is acknowledged as a common and routine examination. Gynaecologists are obliged to inform pregnant women above the age of 34 years about the possibility of invasive techniques in PND. US-guided invasive techniques of PND are available in all parts of the country. AC is used most frequently. CVS and FBS are performed by specialised experts in perinatal centres in hospitals as well as by specialised gynaecologists working in private offices. Moreover, biochemical serum screening is offered in widely varying frequencies between different places.

A steadily increasing number of conditions are currently diagnosed in utero by molecular techniques (table 3).

Table 3 List of disorders prenatally detectable by molecular diagnostic in Germany
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AFP concentration is routinely determined in amniotic fluid after AC and in maternal serum after CVS. TT is increasingly offered for a non-invasive risk calculation for trisomy 21 when a pregnant woman is reluctant to undergo invasive PND.

Professional Guidelines

Obstetrics/Gynaecology

This specialty is regulated by a complex system of qualifications also including the field of PND. The licence to perform general or specialised US examinations, including fetal echocardiography, is imparted by the local board of the association of practitioners (‘Kassenärztliche Vereinigung’) following federal regulations (‘Ultraschall-Vereinbarung’, Ultrasond agreement; effective as of February 10, 1993).

Following specialisation as a gynaecologist, additional qualifications can be obtained in three fields. In the context of PND, the specialty of ‘obstetrics/perinatal medicine’ is of importance:

Subsequent to specialisation as a gynaecologist a 1.5-year training is required, which includes (number of cases):

  • ultrasound scans, 30 malformations (200)

  • duplex scans of female genital tract (200)

  • duplex scans fetal vessels/fetal echocardiography (200)

  • cardiotocography (600)

  • AC (100)

Additional qualifications that are certified by the general Medical Council (‘Ärztekammer’) may be obtained.

Human Genetics

Since 1995, a specialisation in human genetics for MDs and PhDs (‘Facharzt für Humangenetik’ for MDs, ‘Fachhumangenetiker’ for PhDs) is offered that requires a training of 5 years in all fields of human genetics.

Guidelines or proposals for genetic counselling, cytogenetic diagnostics and molecular diagnostics have been published by the ‘Berufsverband Medizinische Genetik’ ‘Association for Medical Genetics’ or by the Society of Human Genetics (Commission for Public Relation and Ethical Issues) in Medizinische Genetik.

Improved and extended guidelines are being elaborated and will become effective most probably in 1997.

Proposals on how to deal with specific diseases have been issued case by case by the Society of Human Genetics whenever necessary, e.g. for Huntington’s disease [Med Genet 1996;8:208] or for BRCA1 analysis [Med Genet 1995;7:8].

Areas under Development

Improvement of PND is a high priority in all institutions and multifarious projects are in progress. Therefore, the following enumerations represent only a small subjective selection of applied research done in Germany.

Obstetrics/Gynaecology

It is difficult to obtain information on research activities. Five of 16 tertiary referral centers answered our questionnaire. Research topics are:

  • fetal haemodynamics (Munich, Singen, Würzburg)

  • laser coagulation in twin-to-twin transfusion syndrome (Ulm)

  • early AC (Ulm)

  • recognition of fetal malformations by US (Munich, Berlin, Würzburg)

  • significance of fetal echocardiography (Singen, Berlin)

Genetics

The application of interphase cytogenetics to PND is studied in several institutes and laboratories. Fluorescence in situ hybridisation (FISH), chromosome painting or reverse chromosome painting techniques are used and improved in several places. They are seen as a complementary investigation to chromosome studies when the origin of chromosomal aberrations cannot be identified or is equivocal. Also, comparative genomic hybridisation (CGH) is being developed in several laboratories.

For early PND, AC at the 11th to 13th week of pregnancy is studied with respect to fetal risk, cytogenetic performance and reliability of results.

A few groups concentrate on research of fetal cell enrichment from maternal blood for investigation of a non-invasive technique.

First-trimester biochemical screening is not done yet in Germany. The advantage of such a test is discussed, however, some laboratories will be ready to offer the test in the near future.

Funding Arrangements for Prenatal Diagnosis

PND is paid for by public as well as private health insurances.

Guidelines for surveillance of pregnancies (Motherhood guidelines, FAP). Since April 1, 1995: 3 US scans per pregnancy are offered at 09–12, 19–22 and 29–32 weeks of pregnancy.

Current Legislation Surrounding Prenatal Diagnosis

Legislation concerning termination of pregnancy (TOP): German Civil Code: § 218, valid since October 1, 1995.

There are three reasons for TOP: § 218 a (1): ‘Fristenregelung’ (term indication): TOP up to the end of 12 weeks after conception on request of the pregnant woman (3 days after obligatory counselling according to § 219); § 218 a (2): ‘mütterlich medizinische Indikation’ (maternal indication for medical reasons): TOP at any time of pregnancy without obligatory counselling; § 218 a (3): ‘kriminologische Indikation’ (criminological indication): TOP in case of rape up to the end of 12 weeks after conception (3 days after obligatory counselling according to § 219).

The former so-called embryopathological/fetopathological indication for TOP has been abolished, e.g. has become part of the medical indication (§218 a (2)):

The law reads: ‘the termination is allowed if, from a medical point of view, it prevents danger of life or a danger of severe impairment of the physical or psychological health of the pregnant woman in the present or in the future and this danger cannot be abolished by other means to be offered to her.’

Manipulation of the embryo is strictly forbidden by the Embryo Protection Law (‘Embryonenschutzgesetz’). However, there are controversies as to whether this also applies to pre-implantation diagnosis.

The Society of Human Genetics and the ‘Berufsverband Medizinische Genetik’ have published several papers on their positions concerning the problems arising from PND. To name a few: comments on prenatal paternity testing, on prenatal sexing for sex selection, on the application of the maternal serum TT-screening for detection of chromosomal aberrations and on the new legal situation concerning TOP were given.

Problems Faced and What of the Future?

Quality Assessment

Obstetrics/Gynaecology. Although a complex system of qualifications for non-invasive PND is in effect, there is no quality control after qualification has been achieved. Since 1996 all standard US examinations must be done by the gynaecologist first consulted. Without obligate referral to a specialised centre, this may result in a reduced number of recognised fetal malformations. This situation would improve if the second routine US scan, scheduled for the 20th week of pregnancy, were done by a referral centre for specialized US.

Genetics. The number of laboratories starting with prenatal tests is still increasing. To maintain the high quality of results reported by the laboratories, the professional association ‘Berufsverband Medizinische Genetik’ must envisage structures for supervision. Although, at the moment, many laboratories participate in the voluntary quality assessment test of the Society of Human Genetics, regulations must become mandatory for any laboratory working in such a sensitive field.

Appropriate Use of Tests

Some prenatal tests are performed without adequate pretest genetic counselling. This is seen in particular for the TT and may also result from first trimester serum testing. More efforts are necessary to reduce unreasonable maternal anxiety by adequate counselling.

Budget Problems

The spendings of the German health system are very high and are still increasing. Thus, decisions will be required on how to reduce the costs.

Claim to Get a Healthy Baby

The availability of sophisticated techniques has led to increased claims for a ‘healthy child’. The still-improving quality of non-invasive PD, due to US devices which provide the gynaecologist with excellent tools to detect fetal malformations antenatally, results in parental pressure on gynaecologists and human geneticists to confirm the well-being of the fetus and delivery of a healthy newborn. This may lead to reduced awareness and responsibility for the disabled. Moreover, a higher rate of legal suits dealing with questions about the state of the art in prenatal diagnosis can be expected.

Ethical Problems

The new legislation concerning TOP allows the mother to opt for TOP after the 24th week in the case of severe fetal malformations. This leads to the ethical dilemma to perform TOP on request of the mother at a time when the malformed fetus might be viable.