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2010 Exploracion de 11 - 13 Ss - DX de Holopros - Exomphalos - Megavejiga
2010 Exploracion de 11 - 13 Ss - DX de Holopros - Exomphalos - Megavejiga
K E Y W O R D S: chromosomal defect; exomphalos; free β-hCG; holoprosencephaly; megacystis; nuchal translucency; PAPP-A
Correspondence to: Prof. K. H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, Denmark Hill,
London SE5 9RS, UK (e-mail: fmf@fetalmedicine.com)
Accepted: 12 March 2010
Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER
Holoprosencephaly, exomphalos and megacystis at 11–13 weeks 11
estimated risk for trisomies 21, 18 and 13 in the chro- Table 1 Characteristics of the study population
mosomally abnormal and euploid fetuses with these
defects, and, third, to determine the outcome of affected Median (range)
pregnancies. Characteristic or n (%)
Maternal characteristics
METHODS Age (years) 35.3 (14.1–52.5)
Weight (kg) 63.6 (34–165)
This was a prospective screening study for trisomy 21 in Spontaneous conception 54 456 (95.3)
singleton pregnancies, using a combination of maternal Smoker 2583 (4.5)
Ethnicity
age, fetal NT thickness and maternal serum-free β- Caucasian 51 025 (89.3)
hCG and PAPP-A in a one-stop-clinic for first-trimester Afro-Caribbean 2443 (4.3)
assessment of risk (OSCAR) at 11 + 0 to 13 + 6 weeks East Asian 644 (1.1)
of gestation7,8 . Transabdominal ultrasound examination South Asian 2229 (3.9)
was performed to diagnose any major fetal defects and Mixed 778 (1.4)
Gestational age
to measure the fetal crown–rump length (CRL), NT 11 + 0 to 11 + 6 weeks 5677 (9.9)
thickness and FHR. Automated machines that provide 12 + 0 to 12 + 6 weeks 32 037 (56.1)
reproducible results within 30 minutes were used to 13 + 0 to 13 + 6 weeks 19 405 (34.0)
measure PAPP-A and free β-hCG (Delfia Express System; Crown–rump length (mm) 62.8 (45.0–84.0)
Perkin Elmer, Waltham, USA and Kryptor System; Karyotype
Normal 56 376 (98.7)
Brahms, Berlin, Germany). Trisomy 21 395 (0.7)
Maternal demographic characteristics, ultrasono- Trisomy 18 122 (0.2)
graphic measurements and biochemical results were Trisomy 13 61 (0.1)
recorded in a computer database. Karyotype results and Turner syndrome 38 (0.07)
details on pregnancy outcomes were added to the database Other 127 (0.2)
Total 57 119
as soon as they became available. A search of the database
was performed to identify all singleton pregnancies in
which first-trimester combined screening was carried out
characteristics of the study population are summarized in
from July 1999 to April 2007.
Table 1.
The diagnosis of alobar holoprosencephaly was based
According to the maternal age distribution of our
on the fusion of the anterior horns of the lateral ventricles
population and the gestational age at the time of screening
and the absence of the butterfly sign in a cross-sectional
we would have expected 367 (95% prediction interval
view of the fetal brain9 . Exomphalos was diagnosed if
329–405) cases with trisomy 21, 112 (95% prediction
there was herniation of bowel or liver in the base of the
interval 91–133) cases with trisomy 18 and 50 (95%
umbilical cord and if the CRL was ≥ 45 mm. Megacystis
prediction interval 36–64) cases with trisomy 1310,11 .
was defined as enlarged bladder with a diameter of
≥ 7 mm3 .
Holoprosencephaly
Statistical analysis The prevalence of holoprosencephaly was 1 : 1298 (44 of
We estimated the risk for trisomy 21, trisomy 18 and 57 119). The fetal karyotype was normal in 15 (34.1%)
trisomy 13 by the combined test based on maternal age, and abnormal in 29 (65.9%), including 25 cases of
fetal NT, FHR, free β-hCG and PAPP-A, and used the sum trisomy 13 (Table 2).
of all three risks to calculate detection and false-positive In the chromosomally abnormal fetuses, compared with
rates by taking the proportions with risks above a given the euploid group, median maternal age, fetal NT and
risk threshold.6 FHR were higher, and free hCG and PAPP-A were lower
(Table 3). The estimated risk for trisomies based on mater-
nal age, fetal NT, FHR, free β-hCG and PAPP-A was
RESULTS above 1 : 100 in 28 of the 29 (96.7%) chromosomally
abnormal fetuses and in one of the 15 (6.7%) euploid
Study population fetuses.
The search of the database identified 60 172 singleton In all cases with holoprosencephaly the pregnancy was
pregnancies. In 3053 (5.1%) cases, the outcome or terminated at the request of the parents.
one of the covariates was not available. Thus, our
study population consisted of 57 119 pregnancies: 56 376 Exomphalos
pregnancies with a normal karyotype or delivery of
a phenotypically normal baby (unaffected group), 395 In the study population of 57 119 pregnancies, there were
cases of trisomy 21, 122 cases of trisomy 18, 61 cases 150 (0.08%) cases with exomphalos, giving a preva-
of trisomy 13, 38 cases with Turner syndrome and lence of 1 : 381. However, the prevalence was dependent
127 cases with other chromosomal abnormalities. The on the fetal CRL and the content of the exomphalos.
Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 10–14.
12 Kagan et al.
Table 2 Incidence of holoprosencephaly, exomphalos and megacystis in chromosomally normal and abnormal fetuses
Chromosomal abnormality
Data are expressed as n or n (%). *Two cases of triploidy and one of 46,XX, add(6)(q26). †Three cases of triploidy and one of
46,XY, add(21)(p11.1).
Table 3 Characteristics of first-trimester combined test in euploid and aneuploid fetuses with holoprosencephaly, exomphalos and
megacystis
Maternal age 33.1 (30.2–36.6) 37.8 (35.3–40.4) 34.7 (31.8–37.0) 39.0** (36.0–40.8) 33.9 (30.7–36.1) 37.0 (35.6–39.0)
(years)
Delta NT (mm) 0.0 (−0.3 to 0.3) 2.7** (0.5–4.3) 0.1 (−0.1 to 0.7) 3.6** (1.4–5.2) 0.0 (−0.3 to 0.2) 1.3* (0.3–3.0)
Delta fetal heart 0.6 (−4.9 to 4.4) 15.5** (10.6–21.1) 1.6 (−3.4 to 5.2) 1.7 (−5.6 to 15.5) 0.1 (−1.9 to 4.8) 11.2* (6.3–16.3)
rate (bpm)
PAPP-A (MoM) 0.90 (0.66–1.28) 0.21** (0.15–0.36) 0.96 (0.70–1.38) 0.29** (0.15–0.46) 0.99 (0.60–1.34) 0.19** (0.10–0.46)
Free β-hCG 0.94 (0.61–1.55) 0.40* (0.28–0.59) 1.04 (0.63–1.63) 0.32* (0.18–0.57) 0.86 (0.59–1.15) 0.41* (0.18–0.41)
(MoM)
Median risk for 1 : 3433 1:2 1 : 2840 1:2 1 : 4800 1:4
trisomies
Risk for 1 (6.7) 28† (96.7) 11 (16.4) 80‡ (96.4) 1 (4.2) 11 (100)
trisomies
> 1 : 100
Data are presented as median (interquartile range), ratio or n (%). Differences between aneuploid and euploid fetuses were tested using a
t-test, and significant differences are indicated: *P < 0.05; **P < 0.001. †One case missed: 46,XX, add(6)(q26). ‡Three cases missed: two
cases of triploidy and one case of 46,XY, add(21)(p11.1). hCG, human chorionic gonadotropin; MoM, multiples of the median; NT, nuchal
translucency; PAPP-A, pregnancy-associated plasma protein-A.
For an exomphalos containing bowel only, the preva- the pregnancies were terminated because of large fetal
lence was 1 : 98 for a CRL of 45.0–54.9 mm, 1 : 798 NT and generalized hydrops. In the remaining 53
for a CRL of 55–64.9 mm and 1 : 2073 for a CRL continuing pregnancies, there were 49 (92.5%) cases with
of 65.0–84.0 mm. The prevalence for an exomphalos spontaneous resolution of the exomphalos by 20 weeks
containing liver was 1 : 3360. The fetal karyotype was and the subsequent birth of healthy infants, and four cases
abnormal in nine (52.9%) of 17 cases with an exompha- where the condition persisted until delivery.
los containing liver and in 74 (55.6%) of 133 cases with
an exomphalos containing bowel only (Table 2).
Megacystis
In the chromosomally abnormal fetuses, compared with
the euploid group, median maternal age, fetal NT and The prevalence of megacystis was 1 : 1632 (35 of 57 119).
FHR were higher, and free β-hCG and PAPP-A were The fetal karyotype was normal in 24 (68.6%) cases and
lower (Table 3). The estimated risk for trisomies based abnormal in 11 (31.4%) cases, including six with trisomy
on maternal age, fetal NT, FHR, free β-hCG and PAPP-A 13 and four with trisomy 18 (Table 2). In 31 of the cases
was above 1 : 100 in 80 of the 83 (96.4%) chromosomally with megacystis the bladder length was 7–15 mm and in
abnormal fetuses and in 11 of the 67 (16.4%) euploid four cases it was > 15 mm.
fetuses. In the chromosomally abnormal fetuses, compared
There were eight euploid fetuses with exomphalos with the euploid group, median maternal age, fetal NT
containing liver, and in the four where the parents and FHR were higher, and free hCG and PAPP-A were
chose to continue with the pregnancy the condition lower (Table 3). The estimated risk for trisomies based on
persisted until delivery. There were 59 euploid fetuses maternal age, fetal NT, FHR, free β-hCG and PAPP-A,
with exomphalos containing only bowel. In three cases was > 1 : 100 in all 11 chromosomally abnormal fetuses
there was spontaneous miscarriage and in another three and in one of the 24 (4.2%) euploid fetuses.
Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 10–14.
Holoprosencephaly, exomphalos and megacystis at 11–13 weeks 13
In one of the 21 euploid cases with bladder length combining the three risk algorithms for trisomies 21,
of ≤ 15 mm there was spontaneous miscarriage; in 18 and 13, the detection rate for trisomy 21 is about
the remaining 20 cases there were 18 (90%) with 90% and for trisomies 18 and 13 it is > 95%, for an
spontaneous resolution of the megacystis by 16 weeks overall false-positive rate of 3.1%6 . As demonstrated
and the subsequent birth of healthy infants and two in our study, these algorithms will identify the vast
where there was evolution to obstructive uropathy (and majority of the chromosomally abnormal fetuses with
these pregnancies were terminated). In the four cases holoprosencephaly, exomphalos or megacystis.
with fetal megacystis of > 15 mm the pregnancies were The outcome for fetuses with holoprosencephaly is fatal
terminated. and only a few children survive the neonatal period, all
of whom have a major developmental disability. In this
respect, fetal karyotyping will not influence the common
DISCUSSION decision of parents in favor of pregnancy termination.
The findings of the study demonstrate that at The main aim of karyotyping is to define the risk of
11–13 weeks of gestation, first, the prevalence of holo- recurrence, which is < 1% if the karyotype is normal
prosencephaly, exomphalos and megacystis is about 1 in and > 10% if the karyotype is abnormal. The high risk
1300, 1 in 400 and 1 in 1600, respectively; second, these of recurrence of holoprosencephaly in euploid fetuses is
defects are associated with a high incidence of chromoso- caused by the common association with several genetic
mal abnormalities (mainly trisomies 18 and 13), found in syndromes, including Pallister Hall, Smith-Lemli–Opitz
about 65% of fetuses with holoprosencephaly, 55% with and CHARGE syndrome16 – 18 .
exomphalos and 30% with megacystis; and, third, in the In contrast to holoprosencephaly, exomphalos contain-
majority of cases, exomphalos and megacystis represent ing liver and megacystis with bladder length > 15 mm
temporary abnormalities that resolve spontaneously. (which are irreversible anatomical defects), megacystis
Our results on the prevalence of exomphalos and with bladder length ≤ 15 mm and exomphalos contain-
megacystis at 11–13 weeks of gestation and the pro- ing only bowel are transient abnormalities. In such cases
portion with chromosomal abnormalities are consistent the parents can be reassured that once the fetal kary-
with the results of previous smaller studies2 – 4 . Mann et al. otype is found to be normal the conditions are likely
reported on a postnatal prevalence of exomphalos of 1 to resolve spontaneously over the subsequent few weeks
in 300012 . In our study, the prevalence of exomphalos without any residual damage. Because in normal devel-
containing only bowel varied between 1 in 98 and 1 in opment exomphalos containing bowel only is observed
2073, according to the CRL and in cases containing liver in all fetuses at 8 weeks of gestation and subsequently
it was 1 in 3360. With respect to the aneuploidy rate and resolves by 11 weeks, persistence at 11–13 weeks can be
the high loss-rate of trisomic fetuses, our figures are in considered to be a delay in the recovery of physiological
concordance with the reported postnatal incidence of 1 in herniation of the bowel and such delay is more common
300012,13 . in aneuploid than euploid fetuses. Similarly, megacystis at
In the case of holoprosencephaly there are no 11–13 weeks can be the consequence of developmental
previous screening studies at 11–13 weeks of gestation. delay. The presence of smooth muscle in the bladder and
A study from a population-based register of congenital autonomic innervation occur only after 13 weeks, and
abnormalities, involving 531 686 births between 1985 and before this gestation time the bladder wall consists of
1998, estimated that the prevalence of holoprosencephaly epithelium and connective tissue with no contractile ele-
in second-trimester pregnancies is about 1 in 8000, ments. It is therefore likely that in the majority of fetuses
which is six times lower than in our study14 . Possible with megacystis there is no underlying urethral obstruc-
explanations for this apparent discrepancy are poor tion but a temporary malfunction of the bladder during a
ascertainment and under-reporting of affected cases in critical stage in its development19 .
the registry and the high rate of intrauterine lethality
during the early second-trimester of affected fetuses
ACKNOWLEDGMENT
with trisomy 1311 . A study involving pathological
examination of 36 380 conceptuses, obtained through The study was supported by a grant from The Fetal
induced abortion before 10 weeks of gestation during the Medicine Foundation (UK Charity no. 1037116).
time-period 1962–1974, reported that the prevalence of
holoprosencephaly was 1 in 24015 .
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