Repeated spontaneous pregnancies in 45,X Turner syndrome.

Abstract

Spontaneous pregnancy rarely occurs in women with Turner syndrome, and poor maternal outcomes are prominent in these women.
We report two women with 45,X Turner syndrome who had a total of four spontaneous pregnancies. Maternal and fetal outcomes were good despite maternal comorbidities. Cesarean deliveries were performed in two of the pregnancies because of aortic dilatation and fetopelvic disproportion. Both cases were initially diagnosed as primary amenorrhea (absent pubarche and menarche with serological hypogonadism).
Repeated spontaneous pregnancies occur in women with 45,X Turner syndrome. Poor maternal outcome is not the rule.

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Repeated Spontaneous
Pregnancies in 45 X Turner
Syndrome
Kristian Havmand Mortensen, MD,
Marianne Daniel Rohde, MD,
Niels Uldbjerg, MD, PhD, MedSci, Professor,
and Claus Højbjerg Gravholt, MD, PhD, MedSci
BACKGROUND: Spontaneous pregnancy rarely occurs
in women with Turner syndrome, and poor maternal
outcomes are prominent in these women.
CASES:
We report two women with 45 X Turner syn-
drome who had a total of four spontaneous pregnancies.
Maternal and fetal outcomes were good despite maternal
comorbidities. Cesarean deliveries were performed in
two of the pregnancies because of aortic dilatation and
fetopelvic disproportion. Both cases were initially diag-
nosed as primary amenorrhea (absent pubarche and
menarche with serological hypogonadism). Ovarian fol-
licles were only visualized in one woman.
CONCLUSION: Repeated spontaneous pregnancies oc-
cur in women with 45 X Turner syndrome. Poor maternal
outcome is not the rule.
(Obstet Gynecol 2010;115:1–1)
S
ure, is a cardinal trait. Spontaneous conceptions and the
ensuing pregnancies in Turner syndrome are sparingly
investigated. Regardless of the assisted or unassisted
nature of conception, the mother and fetus face in-
creased risk of poor outcome. This includes endocrine
and cardiovascular maternal morbidity as well as mis-
carriage, stillbirth, and congenital abnormalities.1
We report two cases of spontaneous pregnancies
in Turner syndrome. The aim is to shed further light
on the significance of karyotype and gynecologic phe-
notype to unassisted conception. Furthermore, maternal
pontaneous pregnancy is rare in Turner syndrome
where infertility, because of premature ovarian fail-
and fetal outcome is discussed with particular reference
to cardiovascular morbidity and mortality.
CASES
Our first patient was 28 years old at first spontaneous
conception. She was diagnosed with Turner syndrome at
the age of 10 because of absent growth spurt. Growth
hormone therapy was given for 4 years; she reached a final
height of 160 cm. Other syndrome associated characteris-
tics were (1) recurrent childhood middle-ear infections with
conductive hearing loss, (2) insulin-dependent diabetes
mellitus (diagnosed at the age of 8), and (3) hypothyreosis
substituted with levothyroxine (diagnosed at the age of 18).
Estrogen therapy was started at the age of 14 because of
absent pubarche and menarche. Development of second-
ary sex characteristics and a normal menstrual cycle re-
sulted. Four years later, hormone therapy was started (an
orally administrated low-dose monophase gestagen and
estrogen). Because of a desire to bear children, hormone
therapy was suspended at the age of 26 when a laparoscopy
showed bilateral ovarian follicles. The menstrual cycle
became irregular, and amenorrhea resulted over a period of
months. Conception was not achieved over a period of 24
months. Analyses of sex hormones then led to the conclu-
sion that spontaneous pregnancy was not possible: folli-
tropin and lutropin were elevated while estradiol was low.
Hormone therapy was not reinitiated, and 3 months later
conception did result. An uncomplicated pregnancy fol-
lowed with no maternal or fetal complications. The preg-
nancy was followed with short intervals by appointments
with obstetricians (repetitive fetal ultrasounds and fetal
echocardiographies). Amniocentesis showed a normal fetal
karyotype. Endocrinologists kept strict diabetic and thyroid
control. First- and third-trimester maternal echocardio-
graphies showed mild ascending aortic dilatation (the di-
ameter was 26 mm with a suspicion of slight progression on
the third-trimester echocardiography). To reduce possible
hemodynamic stress on the aorta associated with vaginal
delivery, an elective cesarean delivery was performed at
gestational age 37 4/7 weeks. A healthy male newborn was
delivered (weight 3.750 g). Hormone therapy was reiniti-
ated after the pregnancy, and 24 months later the patient
became pregnant while taking this drug. The second preg-
nancy was uncomplicated; the ascending aortic diameter
was stationary (repeat echocardiographies). No prenatal
karyotype was performed, but several normal nucheal
translucency scans were performed. A healthy normal-
weight male newborn was delivered by cesarean at gesta-
tional age 39 weeks, which was chosen because of a
suspicion of fetopelvine disproportion and the previously
diagnosed aortic dilation.
Karyotype determination on peripheral blood lympho-
cytes showed 45 X (10 cells), whereas fluorescent in situ
hybridization analysis found 45 X in 199 of 200 metaphases
with 47 XXX in one metaphase. The patient declined an
ovarian biopsy at the cesarean delivery. Hormone analyses
after 1 month of suspended anticontraceptive treatment
From the Medical Department M (Diabetes and Endocrinology) and Research
Laboratories, Aarhus University Hospital, Aarhus Hospital; and Department of
Obstetrics and Gynecology, Aarhus University Hospital, Skejby, Denmark.
Corresponding author: Kristian Havmand Mortensen, MD, Medical Depart-
ment M (Diabetes and Endocrinology) and Research Laboratories, Nørrebrogade
44, Aarhus University Hospital, Aarhus Hospital NBG, DK–8000 Aarhus C;
e-mail: kristian.havmand@ki.au.dk.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2010 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/10
VOL. 115, NO. 2, PART 2, FEBRUARY 2010 OBSTETRICS & GYNECOLOGY
1
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(postpregnancy) showed inhibin-A 52 pg/mL and ummea-
surably low inhibin-B. The other sex hormones were (nor-
mative ranges): follitropin 13.3 international units/L (follicular
phase: 2.4–11.0 IU/L), lutropin 11.4 international units/L
(1–10 international units/L), E2 0.36 nmol/L (follicular phase:
0.1–0.5 nmol/L), and sex hormone binding globulin 60
nmol/L (20–145 nmol/L). A transvaginal ultrasonography was
performed (postpregnancy) showing (1) few visible follicles
bilaterally, (2) smooth ovarian surface, and (3) right and left
ovary volume 3.0 cm
The second patient was 23 years old at first pregnancy.
She was diagnosed with Turner syndrome because of
absent growth at the age of 7. Oxandrolone treatment was
given for 10 months at the age of 12 according to guidelines
for growth stimulation in Turner syndrome, followed by
growth hormone therapy for 1 year at the age of 14 resulting
in a final height of 144 cm. Other syndrome related traits
were (1) recurrent middle ear infections complicated by
cholesteatoma with a conductive hearing loss and (2)
multiple dental extractions due to a narrow jaw. Absence of
pubarche and menarche resulted in estrogen therapy from
the age of 15. Pubertal development and a normal men-
strual cycle resulted. Traditional hormone therapy was
initiated at the age of 19. At the age of 22 the patient
experienced breast tenderness, tiredness, and the absence
of periods. A pregnancy was confirmed, and the hormone
therapy was stopped in the sixth to seventh gestational
week. The pregnancy was uneventful except for mild
glucosuria in the second trimester without outright gesta-
tional diabetes mellitus. A fetal karyotype was not carried
out, but a normal postnatal karyotype was found in a
healthy female newborn of birth weight 3,000 g. She was
delivered vaginally after stimulation therapy initiated at the
gestational age of 38 2/7 weeks because of suspicion of
fetopelvic disproportion. Hormone therapy was reinitiated
after the pregnancy. Two years later another unassisted
conception resulted while taking this medication. The
patient delivered vaginally at term. The newborn was male
and of normal birth weight and normal postnatal karyotype.
Chromosome analysis on peripheral lymphocytes (10
cells) showed monosomy 45 X, which was confirmed by
fluorescent in situ hybridization analysis in 200 met-
aphases. The patient declined an ovarian biopsy. Sex
hormone analysis after a 3-month withdrawal of hormone
therapy (with complete amenorrhea) showed (1) immeasur-
ably low inhibin-A and inhibin-B, (2) follitropin: 42 interna-
tional units/L, and (3) lutropin: 24 international units/L. A
transvaginal ultrasonography was performed (postpregnancy)
showing (1) no visible follicles, (2) smooth ovarian surface,
and (3) right and left ovary volume 1.2 cm3and 1.4 cm3,
respectively.
3and 1.3 cm3, respectively.
COMMENT
We report repeat spontaneous pregnancies in two
patients with classical X-chromosomal monosomy.
They illustrate the complexity of determining ovarian
status and fertility planning in Turner syndrome and
that the gynecologic phenotype and genotype can be
discordant. Karyotype determination and fluorescent
in situ hybridization analysis confirmed the previous
findings in one while the other was monosomy 45 X
in 199 of 200 metaphases with triple X found in one.
The clinical significance of this last metaphase is
debatable, and the patient is still classified as mono-
somic rather than mosaic. But it is likely, and in line
with spontaneous pregnancies occurring more com-
monly in mosaics, that ovarian tissue biopsies would
have revealed cell lines with both X chromosomes
intact. Such ovarian biopsy–aided karyotype is, how-
ever, a rarity. Advice in the clinical setting will
therefore rely on a karyotype derived from peripheral
blood lymphocytes. The most recent Turner Syn-
drome Study Group guideline concurs with the
American College of Medical Genetics recommenda-
tion. It recommends less intensive karyotype analysis
(30 cells) than used in the present cases and that at
least 10% of another cell line should be present to call
it a mosaic.2Therefore, patients as the two presented
here, will be viewed as classic 45 X females at the
fertility or gynecology clinic. As a result, advice will
be given on the reasonable assumption that the
patients have fetal-life onset gonadal demise with
classical premature ovarian failure on a back-drop of
total or partial absence of pubarche and menarche
(depending on the rate of ovarian failure).
Although originally diagnosed as premature
ovarian failure, due to the presence of 45 X and
amenorrhea, the ensuing history clearly shows that
both cases could indeed should not be classified as
such. The ovarian reserve declines regardless of
karyotype in Turner syndrome.3The variable pres-
ence of ovarian follicles on ultrasound with hypogo-
nadism and amenorrhea in our patients could reflect
different but (compared with most normal women)
accelerated ovarian follicle apoptosis toward a mini-
mal reproductive potential (as reflected by immeasur-
able inhibin-B in both).4Estimation of the probability
of achieving unassisted pregnancy is therefore not
always straight forward, and considering occurrences
like the present are important. This is especially the
case with emerging possibilities for fertility preserva-
tion with cryopreservation of ovarian tissue or oo-
cytes. The use of current criteria for identification of
candidates for fertility preservation, such as karyotype
or spontaneous menarche, will clearly exclude some
with reasonable potential for fruitful preservation.3
This is supported by a recent study in which sponta-
neous puberty, mosaicism, and normal hormone con-
centrations were positive but not exclusive prognostic
2
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factors for ovarian follicles in a young patient with
Turner syndrome.3Further research is necessary to
aid correct identification of young girls with Turner
syndrome as candidates for fertility preserving initia-
tives because the currently introduced criteria are not
optimal.3
Thorough investigation is necessary in patients
with Turner syndrome desiring pregnancy. The most
recent American Society for Reproductive Medicine
recommendation should guide fertility evaluation
with emphasis on ovulatory function.5Because of the
complexity of ovarian failure and widespread thyroid
disease, baseline evaluation should include follitropin,
thyroid-stimulating hormone, and evaluation of the
ovarian reserve. As our patients demonstrate, all
advice should also state that traditional hormone
therapy offers no protection against pregnancy (in
patients with an ovarian reserve). Only contraceptive
therapy protects from unwanted pregnancy, and de-
pending on the agent it can fully suffice in preventing
osteoporosis as well as cardiovascular disease in es-
trogen-deficient patients withTurner syndrome.
The risk of pregnancy-related maternal death
may be increased 100-fold in patients withTurner
syndrome. The main cause of this excess mortality is
cardiovascular with a 2% risk of aortic dissection.
Further contributors are (1) hypertension, (2) or non–
insulin-dependent diabetes mellitus or gestational di-
abetes mellitus, and (3) dysregulation of the com-
monly encountered thyroid disease.2,6As a result, no
pregnancy should be planned without careful screen-
ing, involving complete endocrine and cardiac assess-
ment. Furthermore, all pregnancies should be re-
gardedashigh risk. Thorough
unfortunately not the rule in Turner syndrome. A
third of adult patients never go through an adequate
cardiovascular assessment, a point perfectly illus-
trated by our two petients going through pregnancy
without such investigations performed beforehand.
Gynecologists may even diagnose a number of pa-
tients with Turner syndrome because considerable
diagnostic delay exists, and an estimated third of
patients are diagnosed due to absent pubarche or
menarche or even infertility.7It is therefore essential
that gynecologists and obstetricians ensure that endo-
crinologists and cardiologists regularly monitor all
patients. They should also be familiar with the guide-
lines for monitoring cardiovascular disease in Turner
Syndrome to make sure that the standards are met
and to give advice accordingly (Table 1).2,8
All patients should be informed that (1) the risk of
morbidity and mortality is considerable, and (2) par-
ticular caution is advised in certain cardiovascular
assessment is
phenotypes because of an especially increased risk of
aortic dissection. The most important risk factors for
aortic dissection (bicuspid aortic valve, aortic coarc-
tation, and aortic dilatation), and recommendations
on aortic size from other high-risk aortic dissection
populations are not to be extrapolated to this patient
group; the small body size should always be taken
into account with a resulting lower limit for the
pathological aortic dilatation (and thus contraindica-
tion to pregnancy). This is shown by the concerns
regarding aortic size in one of our patients. When it
comes to defining the precise limits much remains to
be resolved, and cardiovascular assessment is best left
to cardiologists experienced with Turner syndrome
(tertiary centers). Pregnancy should be regarded as
relatively contraindicated in the presence of risk
factors, but dissection is not the rule in these patients.
Conversely, adverse events may occur in the absence
of acknowledged risk factors. As an illustration of the
blurred picture, we strongly advised a young mosaic
patient with aortic dilatation secondary to a bicuspid
aortic valve against pregnancy, but a strong desire for
motherhood lead her through an uncomplicated preg-
nancy. By extension, there is an unresolved question
of vaginal compared with cesarean delivery. It is an
important issue because hemodynamic stress (such as
Table 1. Gold Standard Cardiovascular
Assessment in Turner Syndrome*
Additional Concerns
Before fertility planning
• Echocardiography
• Magnetic resonance
imaging of the heart
and great vessels
• Twenty-four-hour
ambulatory blood
pressure measurement
• Electrocardiogram
During pregnancy
• Echocardiography (early
in first trimester, repeat
often as necessary)
• Repeat consultation or
24-hour ambulatory
blood pressure
• Electrocardiogram
An endocrinologist
experienced with Turner
syndrome should be
involved before and during
pregnancy to coordinate
the multidisciplinary efforts
and to regularly test for
other major morbidity in
Turner syndrome. This
should in relation to
pregnancy include:
• Oral glucose tolerance test
• Fasting blood sugar
• Urine glucose test
• Thyroid-stimulating
hormone
* Gold standard for cardiovascular assessment in Turner syndrome
derived from: 1) combined guidelines of the American Society
for Reproductive Medicine and the Turner Syndrome Study
Group,2,8and 2) our clinical experience and research activities
in the gynecologic, obstetric, cardiovascular, and endocrine
complications to Turner syndrome.
VOL. 115, NO. 2, PART 2, FEBRUARY 2010 Mortensen et alSpontaneous Pregnancy in Turner Syndrome
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with extreme physical activity) has been known pro-
voke dissection in predisposed individuals. Hypothet-
ically, a cesarean delivery may pose less of a hemo-
dynamic burden compared with vaginal delivery, but
there is no evidence to this.
Our patients are in line with a large register study
where 75% of spontaneous pregnancies had a normal
fetal karyotype with no correlation with specific ma-
ternal karyotype and with a high rate of healthy
offspring. Some studies indicate high likelihood of
carriage to term.2Other studies report increased risk
of miscarriage, stillbirth, and malformation secondary
to an abnormal fetal karyotype.1,4A prenatal karyo-
type could foresee such complications, but it will not
identify the total fetal risk because undetermined
uterine factors contribute to poor outcome, which is
also evident in oocyte donations. These fetal compli-
cations are difficult to change, but the obstetrician
should focus particularly on the risk of fetopelvine
disproportion secondary to small body size of the
mother as one way of improving outcome. Despite
recommendations on the use of growth hormone
treatment, the population cannot be expected to
reach normal height, and maternal pelvic size will
continue to pose a potential issue.
Spontaneous pregnancy occurs even in hypogo-
nadal 45 X Turner syndrome. The clinical indices of
successful spontaneous pregnancy are not straight
forward. This complicates both the choice of estrogen
substitution therapy and fertility preservation initia-
tives. Joint existing guidelines from the American
Society for Reproductive Medicine and the Turner
Syndrome Study Group can prevent complications.
Because these are high-risk pregnancies, it is pivotal
that no fertility planning precedes thorough endo-
crine and cardiovascular characterization to minimize
pregnancy-related morbidity and mortality.
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000Repeated Spontaneous Pregnancies in 45 X Turner Syndrome
Repeated spontaneous pregnancies with good maternal and fetal outcomes may occur in
women with amenorrheal hypogonadal 45 X Turner syndrome.
Kristian Havmand Mortensen, Marianne Daniel Rohde,
Niels Uldbjerg, MedSci, Professor, Claus Højbjerg Gravholt, MedSci

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