III Guideline
1 Methodology
The guideline was registered with AWMF on September 1, 2013. Professors Dörr and Binder
compiled an initial draft of the guideline based on the consensus of the guideline
group and sent the draft by e-mail to all persons involved. Drafts were circulated
by e-mail between all authors and revised until the group reached a consensus.
Use of existing guidelines on the same topic
Existing guidelines AWMF Registry numbers 027/022, 027/047 and 078/015 which contain
material relevant to the topic under discussion were consulted during the compilation
of this guideline.
External review and adoption
A version of the S1-guideline was placed online (on the homepage of DGKED) for public
consultation for a period of 5 weeks (13.05.2014 – 16.06.2014) and the members of
the involved medical societies were informed. Comments were collected and processed
by the guideline group. Changes to the text of the guideline were done based on consensus.
Everyone who sent in a comment was informed about the procedures used to process comments.
The guideline group and the board of the DGKED approved the final version of the guideline
in September 2014. This was followed by the final adoption of the guideline by the
boards of the involved medical societies/organizations. During this procedure the
board of Deutsche Gesellschaft für Kinder- und Jugendmedizin (DGKJ) withdrew its mandate
and did not approve the final version of the guideline. Despite several discussions
to clarify the issues, it proved impossible to obtain the approval of the DGKJ. The
boards of the other 5 medical societies involved were then informed about the circumstances,
and the importance and necessity of having an S1 recommendation for action in the
current form was emphasized. The positive responses of the 5 other medical societies
were filed with the secretariat of the DGKED by July 1, 2015. The final version of
the guideline was submitted to AWMF on July 2, 2015.
2 Introduction
The authors are well aware that it is impossible to create an evidence-based guideline
for a non-approved therapy. This S1-guideline therefore represents an opinion; the
guideline summarizes the current situation and offers recommendations for further
action.
3 Preamble
Female neonates with classic congenital adrenal hyperplasia due to congenital deficiency
of 21-hydroxylase (CAH) are usually born with intersex external genitalia. The therapy
administered prenatally to treat CAH has the following aims: preventing the virilization
of female fetuses with CAH; preventing corrective genital surgery; and avoiding psychosocial
stress for the family when their daughter is born with intersex genitalia. Complex
genitoplasty procedures have their own surgery-related problems and are also associated
with psychosocial stress for the affected patient and family.
As the differentiation of female genitalia starts in the 7th week after conception,
therapy must be initiated immediately after establishing pregnancy. As no prenatal
diagnosis is possible at this point in time, all pregnancies at risk for CAH are initially
treated without knowing the diagnosis. The drug of choice is dexamethasone, which
cannot be metabolized by the placenta and therefore achieves a maternal-fetal gradient
of 1 : 1. Dexamethasone is administered immediately after the pregnancy has been established
to women who have an increased risk of giving birth to a child with classic CAH. Therapy
is only continued until the end of pregnancy if the prenatal diagnosis shows that
the child is female and has classic CAH. In all other cases prenatal therapy is terminated.
The use of dexamethasone for the prenatal therapy of CAH is an off-label use. Nevertheless,
this experimental therapy has been used all over the world for almost 30 years. The
results published to date show that prenatal therapy – if it is administered correctly
– can prevent virilization of the external genitalia in females [1 ], [2 ], [3 ], [4 ], [5 ]. The therapy is controversial because of the ethical dilemma (unaffected children
are also treated) and because some data have shown that the therapy may have negative
emotional and cognitive consequences. These data are from studies with small case
numbers. Larger studies are therefore urgently required, along with follow-up examinations
of all children treated prenatally, to determine or exclude possible side effects
such as fetal programming from prenatal dexamethasone. The therapy requires the close
cooperation of all involved physicians, particularly between prenatal medical centers
and human genetics departments. Written parental consent is required after the physician
has had an in-depth talk with the parents. Only gynecologists working closely with
gynecology and/or internal endocrinology departments and certified prenatal medical
centers can offer the appropriate care to the pregnant mother.
There is currently no standardized evidence-based protocol for the prenatal therapy
of fetuses with CAH in Germany. The recommendations for prenatal therapy are based
on empirical experience and data obtained from the literature. A careful and detailed
documentation of the administered prenatal therapy should be a matter of course. In
addition, it will be necessary to develop and implement protocols to follow-up children
treated prenatally and their mothers.
4 Definition and Basic Information
(See also the guidelines with AWMF registry numbers 027/022, 027/047 and 078/015)
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CYP21A2)
is the most common disorder of cortisol biosynthesis in the adrenal cortex, with a
prevalence of more than 90 %. The inheritance pattern for this disorder is autosomal
recessive; the CYP21A2 gene is located on the short arm of chromosome 6 in the HLA
III region in close proximity to a highly homologous pseudogene. Depending on the
severity of the genetic defect and the extent of residual 21-hydroxylase activity,
CAH occurs in one of 2 forms: classic CAH and non-classic CAH [6 ].
Female newborns with classic CAH present with intersex external genitalia (disorder
of genital differentiation but normal female karyotype) at birth. Virilization of
genitalia already starts in utero. The inner genitalia are always female, i.e. a uterus
and ovaries are present. The severity of virilization is classified using the Prader
scale and ranges from simple clitoral hypertrophy (Prader score 1) to complete fusion
of the labioscrotal folds, an enlarged phallus-like clitoris, and extension of the
urethra with a urethral opening in the glans penis (Prader score 5). Genital corrective
surgery is often considered for girls with intersex genitalia (Prader score 3 and
higher).
Female neonates born with non-classic CAH are unremarkable at delivery; while still
prepubescent they may sometimes present with premature pubarche and/or acne. During
puberty and after the conclusion of puberty girls with non-classic CAH are characterized
by hyperandrogenemia, disorders of the menstrual cycle, and infertility.
5 Diagnosis
5.1 Prior to pregnancy
Affected families usually have an index case (a previous child with CAH). In rare
cases parents may be known to be heterozygous without an index case. Detailed genetic
counseling with genetic diagnosis of the index case and of the parents should be done
prior to conception. An interdisciplinary consultation about the therapeutic options
and the approach used in prenatal therapy should also be done prior to conception.
Parents should be informed during a detailed consultation that in the case of autosomal
recessive inheritance, both boys and girls have a 1 in 4 risk of developing CAH. It
follows from the above that as long as the sex of the child is still unknown, 7 of
8 fetuses will be treated unnecessarily, i.e., 3 girls who do not require treatment
and 4 boys who do not require treatment, as boys with CAH do not require treatment.
The family must be informed of the benefits and the possible downsides (potential
side effects for the mother and child; experience in animals and humans, long-term
risks) of prenatal therapy as well as the risks involved in prenatal diagnosis.
The parents must also be informed of the fact that there is currently no standardized
protocol for this treatment. There are also no protocols in Germany for the long-term
follow-up care of children treated prenatally (or of their mothers), and treatment
in Germany is currently based on protocols and data from other countries such as Sweden
and the USA [1 ], [7 ].
All forms of genetic testing and the isolation of fetal DNA from maternal blood are
diagnostic tests which are subject to the relevant provisions of the German Genetic
Diagnosis Act.
Possible combinations of factors where prenatal therapy should be considered:
Families with one affected child (index case) with classic CAH (CYP21A2).
Known parental heterozygosity for classic CAH (no index case).
New relationship of a parent of a child with classic CAH if the new partner is known
to be a carrier for classic CAH.
Homozygosity or compound heterozygosity for classic CAH of one parent when the other
parent is a heterozygous gene carrier for classic CAH.
Genetic counseling is more difficult if the potential parents have differing mutations
and there is no index case in the family with compound heterozygosity for these mutations.
Example: The mother has a typical mutation for classic CAH, while the father has a mutation
for non-classic CAH (e.g. exon 7 Val281Leu). In this case the child could be compound
heterozygous for CAH. The phenotype generally follows the mutation associated with
higher residual activity, in other words, non-classic CAH. This means that in this
family prenatal therapy is not indicated.
5.2 Prenatal diagnosis
The prenatal diagnosis of CAH is made based on an invasive procedure, typically chorionic
villus sampling (CVS) performed approximately in the 11th week of gestation (GW).
The childʼs sex is determined using genetic methods or chromosome analysis after cells
are briefly cultured. In the event that testing finds a female karyotype, genetic
testing is then used to investigate whether the expected child is homozygous/compound
heterozygous or heterozygous or only has the wild-type allele. In principle, prenatal
genetic diagnosis could be done as part of amniocentesis. But as amniocentesis is
performed later in pregnancy (from the 14th GW), prenatal diagnosis using CVS is preferable
as it ensures that the period of potentially unnecessary dexamethasone intake is as
short as possible. The risk of miscarriage is 0.5–1 % for amniocentesis and approximately
1 % for chorionic villus sampling.
Recently, 2 independent studies showed that it is possible to determine the sex of
the fetus using the SRY test [8 ] and that correct genotyping [9 ] using cell-free fetal DNA (cffDNA) from maternal blood was possible in pregnancies
at risk for CAH. In the study by Tardy-Guidollet et al., the SRY test was positive
from the 5th week of gestation (4 weeks + 5 days). This avoided prenatal therapy with
dexamethasone in 68 % of male fetuses [8 ]. In the study by New et al., the earliest time of diagnosis was the 6th week of
gestation; based on the results of the diagnostic procedure, prenatal therapy was
initiated even prior to the 9th week [9 ].
Non-invasive fetal sex determination using cffDNA is not yet a routine diagnostic
procedure in Germany, but it is offered as part of NIPT (non-invasive prenatal testing)
from the 7th GW after the last menstrual cycle as the percentage of fetal DNA in the
free DNA present in maternal blood should be high enough by that point (around 10 %).
The result is usually available within one week after obtaining the blood sample [10 ], [11 ].
6 Current Experimental Therapy
There is currently no standardized therapy protocol approved by the respective medical
societies in Germany. As sexual differentiation starts early, from the 7th week after
conception, therapy was usually initiated immediately after establishing the pregnancy
and without yet knowing the diagnosis.
The drug of choice is the glucocorticoid dexamethasone, which is not metabolized by
the placenta and which therefore achieves a maternal-fetal gradient of 1 : 1 [12 ]. The recommended starting dose of dexamethasone (suggested dosage calculation formula:
20 µg/kg BW/day) is divided into 3 individual doses administered over a period of
24 h [13 ], [14 ]. This dosage was determined empirically; there are no controlled studies on the
optimal dosage or duration of therapy.
Some studies have also reported achieving the same effect with low dexamethasone dosages
[15 ]. The physician should therefore select the lowest maternal dexamethasone dose that
will ensure suppression of the fetal adrenal cortex.
Therapy is only continued if the fetus is female and has classic CAH. If the fetus
is not a mutation carrier and is not heterozygous or male, then the current practice
is to reduce the dexamethasone dose by 0.5 mg every 2nd day.
The care provided to a pregnant high-risk woman must be closely coordinated by her
gynecologist with a prenatal medical and/or endocrinology center. To the best of our
knowledge, the procedure followed up to now in Germany is as follows:
During pregnancy
Sampling of maternal serum (approx. 2 ml): determination of cortisol (to verify suppression
of the maternal adrenal cortex) and determination of estriol (to verify suppression
of the fetal adrenal cortex) at the start of therapy and then every 4 weeks until
birth [16 ]. The Swedish PREDEX protocol measures DHEAS prior to initiating therapy (6th GW
after the last menstrual cycle) and then every 4 weeks until the 36th GW and measures
estriol in gestational weeks 16–36 [7 ]. High-risk pregnancies are continually monitored and parameters (e.g. blood pressure,
weight changes, urine tests) are recorded.
During birth and postpartum
The dexamethasone dose administered to the mother is gradually reduced postpartum
by 0.5 mg every 2nd day. Contacting the pediatric endocrinologist is recommended to
discuss further diagnostic procedures and therapies. It is not necessary to arrange
for an immediate transfer of the neonate to a pediatric hospital.
In the neonate
Neonatal screening should be done on the 3rd day of life; in addition, venous blood
samples should be collected to determine serum electrolyte levels, for blood gas analysis,
and to determine 17-OHP, androstenedione and testosterone levels and renin concentrations.
Hydrocortisone therapy should be initiated (12–15 mg/m2 body surface; e.g. 2–1– 1 mg/day) together with Astonin H therapy (0.1 mg tablets;
e.g. ½ – ¼ – ½). Postnatal genetic confirmation of the prenatal diagnosis should be
attempted (possibly through umbilical cord blood sampling).
6.1 Maternal safety
There are numerous studies on prenatal therapy [2 ], [4 ], [7 ], [17 ], [18 ], [19 ], [20 ], [21 ], [22 ]. The study group working with Maria New in New York has the most extensive experience
[18 ], [20 ], [23 ], [24 ], [25 ]. Maternal side effects such as increased weight gain and/or striae and edema have
been reported in individual cases; these effects were found to be reversible after
dexamethasone was discontinued. Neither arterial hypertension nor diabetes mellitus
were noted during dexamethasone therapy [20 ], [26 ].
In a survey done by questionnaire of dexamethasone-treated mothers in the USA (n = 22),
almost all of them (n = 20) were positive about the benefits of prenatal therapy,
stating that they would undergo dexamethasone treatment again in a subsequent pregnancy
[27 ]. These results are in contrast to results reported from Sweden [28 ]. Only 70 % of women (n = 23) surveyed by questionnaire were prepared to undergo
prenatal therapy again in a subsequent pregnancy.
6.2 Fetal and pediatric safety
Length at birth, head circumference and birthweight were within normal ranges for
all of the neonates who received prenatal therapy. To date, there have been no reports
of malformations such as orofacial cleft. Postnatal growth of treated children was
normal [26 ]. The long-term data, collected with the help of questionnaires sent to the parents
(174 children treated prenatally compared with 313 untreated children, age range:
1 month to 12 years), showed no differences in cognitive, social or psychomotor development
[29 ]. A follow-up study was done of 140 children aged between 5 and 12 years, 25 of whom
were girls with CAH who had received prenatal treatment. The study showed that girls
with CAH treated prenatally were less masculine in their behavior compared to girls
with CAH who did not receive prenatal therapy [30 ]. Using standardized neuropsychological tests, Hirvikoski et al. found deficits in
verbal working memory in children with CAH treated prenatally [31 ]. A meta-analysis of studies published to date found no significant differences in
the behavior of prenatally treated children [32 ]. A follow-up of female patients with CAH treated prenatally (n = 8) found a trend
to cognitive deficits compared to a control group (n = 15), but the difference was
not statistically significant [33 ]. One study group in Warsaw also subsequently carried out neuropsychological examinations
of a small number of girls treated prenatally (9 with CAH vs. 8 without CAH) and found
that the girls with CAH treated prenatally performed better in all cognitive tests
[34 ].
6.3 Dexamethasone in animal experiments
Malformations such as orofacial clefts, pulmonary hypoplasia and anencephalus have
been reported in experiments on animals treated with dexamethasone [22 ]. Fatty degeneration of the liver (rats, sheep, primates) and changes in glomerular
filtration rates have also been noted [35 ]. There are also reports of disorders of brain development and behavioral changes
in treated animals [36 ]. Adult rodents had arterial hypertension and hyperglycemia with increased insulin
concentrations after prenatal glucocorticoid therapy [37 ], [38 ]. The offspring of non-human primates treated during pregnancy with high doses of
dexamethasone (120 or 200 µg/kg BW per day) had increased cortisol levels after experiencing
only mild stress as well as hypertension at the age of 12 months [39 ].
6.4 Documentation of prenatal therapy in Germany
Already in 1990, the working group/section for pediatric endocrinology (Arbeitsgemeinschaft/Sektion
für Pädiatrische Endokrinologie [APE/SPE]) proposed that cases known to pediatric
endocrinologists should be recorded in a central registry (Hospital for Children and
Adolescents of Erlangen University, Prof. Dr. H.-G. Dörr). There was no plan to provide
financial support for the project. A questionnaire was developed and initially sent
to all pediatric endocrinologists based on the assumption that families (with an index
case) would inform their pediatric endocrinologist of future pregnancies. The questionnaire
was recently revised; one version was developed for the affected mother/family and
another version was developed for the treating physician; the physiciansʼ version
should be completed by the treating gynecologist. The questionnaires can be obtained
from the homepages of DGKED (www.paediatrische-endokrinologie.de ) and the German CAH self-help group (https://www.ags-initiative.de/ ) or are available on request.
Questionnaires are completed on a voluntary basis. It has not been possible to carry
out any detailed analysis of the documented data in Germany as the questionnaires
have either not been completed at all or were returned incomplete.
7 Conclusion and Prospects
Prenatal CAH therapy is still an experimental therapy. The experience to date has
shown that prenatal therapy is effective. Female neonates with CAH who received prenatal
therapy had externally unremarkable genitalia or genitalia with only mild virilization
(Prader score 1). No serious maternal complications have been recorded; no malformations
were reported for any of the neonates [40 ]. Up to now, the ethical dilemma was that 7 of 8 fetuses (4 males and 3 females)
were treated unnecessarily with dexamethasone. With new procedures for prenatal diagnosis
based on an analysis of cell-free DNA obtained from maternal blood samples it will
be possible in future to offer targeted therapy which will only treat female fetuses
or even only homozygous or compound heterozygous female fetuses with CAH.
The data on the potential negative emotional and cognitive effects on children with
CAH who received prenatal treatment must be taken seriously. However, these data are
from studies with small case numbers. Larger studies and follow-up studies of all
children treated prenatally are therefore urgently needed to establish or exclude
side effects such as fetal programming from prenatal dexamethasone. Standardized protocols
for prenatal diagnosis and therapy should be developed and implemented. This also
applies to the long-term follow-up of women and children treated prenatally with dexamethasone.
If long-term follow-up of the children cannot be guaranteed, then they should not
be treated prenatally.
All prenatal CAH therapies should be documented and recorded in a central registry.
The registry should also include those pregnancies where therapy was terminated early
after receiving the results of the prenatal diagnostic procedure [6 ].
The medical societies involved should agree on a protocol for therapy and follow-up
which should then be assessed and confirmed by an ethics committee.
Guideline Program
Editors Leading Professional Medical Associations
German Society of Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie
und Geburtshilfe e. V. [DGGG])
Head Office of DGGG and Professional Societies Hausvogteiplatz 12 DE-10117 Berlin
info@dggg.de
http://www.dggg.de/
President of DGGG
Prof. Dr. med. Diethelm Wallwiener Universitätsfrauenklinik Tübingen Calwerstraße 7 DE-72076 Tübingen
DGGG Guidelines Representative
Prof. Dr. med. Matthias W. Beckmann Universitätsklinikum Erlangen Frauenklinik Universitätsstraße 21–23 DE-91054 Erlangen
Guidelines Coordination
Dr. med. Paul Gaß, Tobias Brodkorb, Marion Gebhardt Universitätsklinikum Erlangen Frauenklinik Universitätsstraße 21–23 DE-91054 Erlangen
fk-dggg-leitlinien@uk-erlangen.de
http://www.dggg.de/leitlinienstellungnahmen
Austrian Society of Gynecology and Obstetrics (Österreichische Gesellschaft für Gynäkologie
und Geburtshilfe [OEGGG])
Innrain 66A AT-6020 Innsbruck
stephanie.leutgeb@oeggg.at
http://www.oeggg.at
President of OEGGG
Prof. Dr. med. Uwe Lang Universitätsklinik für Frauenheilkunde und Geburtshilfe Graz Auenbruggerplatz 14 AT-8036 Graz
OEGGG Guidelines Representative
Prof. Dr. med. Karl Tamussino Universitätsklinik für Frauenheilkunde und Geburtshilfe Graz Auenbruggerplatz 14 AT-8036 Graz
Swiss Society of Gynecology and Obstetrics (Schweizerische Gesellschaft für Gynäkologie
und Geburtshilfe [SGGG])
Gynécologie Suisse SGGG Altenbergstraße 29 Postfach 6 CH-3000 Bern 8
sekretariat@sggg.ch
http://www.sggg.ch/
President of SGGG
Dr. med. David Ehm FMH für Geburtshilfe und Gynäkologie Nägeligasse 13 CH-3011 Bern
SGGG Guidelines Representative
Prof. Dr. med. Daniel Surbek Universitätsklinik für Frauenheilkunde Geburtshilfe und feto-maternale Medizin Inselspital Bern Effingerstraße 102 CH-3010 Bern