Chapter 4
CHROMOSOMAL DEFECTS IN MULTIPLE PREGNANCIES
In multiple pregnancies compared to singletons, prenatal diagnosis of
chromosomal abnormalities is complicated because, firstly, the techniques
of invasive testing may provide uncertain results or may be associated
with higher risks of miscarriage and, secondly, the fetuses may be discordant
for an abnormality, in which case one of the options for the subsequent
management of the pregnancy is selective fetocide.
Selective fetocide can result in spontaneous abortion or severe preterm
delivery, which may occur several months after the procedure. The risk
for these complications is related to the gestation at fetocide. Selective
fetocide after 16 weeks is associated with a three-fold increase in risk
compared to reduction before 16 weeks (about 5%), and there is an inverse
correlation between the gestational age at fetocide with the gestation
at delivery.
Amniocentesis in twins is effective in providing a reliable karyotype
for both fetuses and the procedure-related fetal loss rate is about 2%.
In the case of chorionic villus sampling, the procedure-related fetal
loss rate is about 1%, but in about 1% of cases there may be a diagnostic
error, either due to sampling the same placenta twice or cross-contamination.
The main advantage of chorionic villus sampling is that it provides results
sufficiently early to allow for safer selective fetocide.
Screening by maternal age
In dizygotic pregnancies, the maternal age-related risk for chromosomal
abnormalities for each twin may be the same as in singleton pregnancies
and therefore the chance that at least one fetus is affected by a chromosomal
defect is twice as high as in singleton pregnancies. Furthermore, since
the rate of dizygotic twinning increases with maternal age the proportion
of twin pregnancies with chromosomal abnormalities is higher than in singleton
pregnancies. In monozygotic twins, the risk for chromosomal abnormalities
is the same as in singleton pregnancies and in the vast majority of cases
both fetuses are affected. The relative proportion of spontaneous dizygotic
to monozygotic twins in Caucasian populations is about two-to-one and
therefore the prevalence of chromosomal abnormalities affecting at least
one fetus in twin pregnancies would be expected to be about 1.6 times
higher than in singletons.
In counselling parents it is possible to give more specific estimates
of one and/or both fetuses being affected depending on chorionicity. Thus
in monochorionic twins the parents can be counseled that both fetuses
would be affected and this risk is similar to that in singleton pregnancies.
If the pregnancy is dichorionic, then the parents can be counseled that
the risk of discordancy for a chromosomal abnormality is about twice that
in singleton pregnancies whereas the risk that both fetuses would be affected
can be derived by squaring the singleton risk ratio. For example, in a
40 year old woman with a risk for Trisomy 21 of about 1 in 100 based on
maternal age, in a dizygotic twin pregnancy the risk that one fetus would
be affected would be 1 in 50 (1 in 100 plus 1 in 100), whereas the risk
that both fetuses would be affected is 1 in 10,000 (1 in 100 x 1 in 100).
This is in reality an oversimplification, since, unlike monochorionic
pregnancies that are always monozygotic, only about 90% of dichorionic
pregnancies are dizygotic.
Screening by second trimester maternal serum biochemistry
In singleton pregnancies, screening for trisomy 21 by a combination of
maternal age and second trimester maternal serum biochemistry can detect
50-70% of trisomy 21 cases for a 5% false positive rate. In twin pregnancies,
the median value for maternal serum markers, such as AFP, hCG, free β-hCG
and inhibin-A are about twice those for singleton pregnancies. When this
is taken into account in the mathematical modeling for calculation of
risks it was estimated that serum screening in twins may identify about
45% of affected fetuses for a 5% false positive rate. Even if prospective
studies demonstrate that serum testing in twins is effective, the following
problems would still need to be addressed; (a) the detection rate for
an acceptable low false positive rate, especially since invasive testing
in multiple pregnancies is technically more demanding, (b) in the presence
of a ‘screen positive’ result, there is no feature to suggest
which fetus may be affected, and (c) if the pregnancy is discordant for
chromosomal defect, further management by way of selective termination
carries increased risk in the second compared to the first trimester.
Screening by fetal nuchal translucency thickness
In dichorionic twin pregnancies, the detection rate (75-80%) and false
positive rate (5% per fetus or 10% per pregnancy) of fetal NT in screening
for trisomy 21 are similar to those in singleton pregnancies. Patient
specific-risks for trisomy 21 are calculated for each fetus based on maternal
age and fetal NT. Effective screening and diagnosis of major chromosomal
abnormalities can be achieved in the first trimester, allowing the possibility
of earlier and therefore safer selective fetocide for those parents that
choose this option. An important advantage of screening by fetal NT in
dichorionic twins is that when there is discordancy for a chromosomal
abnormality, the presence of a sonographically detectable marker helps
to ensure the correct identification of the abnormal twin should the parents
choose selective termination.
In monochorionic pregnancies, the false-positive rate of NT screening
(8% per fetus or 14% per pregnancy) is higher than in singletons, because
increased NT is an early manifestation of TTTS. The number of cases examined
is still too small to draw definite conclusions as to whether, in the
calculation of risk of trisomy 21 in monochorionic pregnancies, the NT
of the fetus with the largest or the smallest measurement (or the average
of the two) should be considered.
Screening by fetal nuchal translucency thickness and maternal serum biochemistry
In normal twin pregnancies, compared to singletons, the median maternal
serum free β-hCG and PAPP-A, adjusted for maternal weight, are about 2.0
MoM. In trisomy 21 twin pregnancies the median level of free β-hCG is
significantly higher and PAPP-A lower than than in normal twins. At a
false positive rate of 10% (compared to 5% in singletons) screening by
a combination of fetal NT and maternal serum biochemistry could identify
85-90% of trisomy 21 pregnancies. Therefore, in twins to achieve the same
detection rate as in singletons it is necessary to do twice as many invasive
tests.
Management of twin pregnancies with chromosomal abnormalities
When both fetuses are chromosomally abnormal the parents usually chose
termination of pregnancy. In pregnancies discordant for chromosomal abnormalities
the main options are either selective fetocide or expectant management.
In such cases the decision is essentially based on the relative risk of
selective fetocide causing miscarriage and hence death of the normal baby,
compared to the potential burden of caring for a handicapped child.
Selective fetocide can result in spontaneous abortion or early preterm
delivery, which may occur several months after the procedure. The risk
for these complications is related to the gestation at fetocide (about
5% at 12 weeks and 15% after 16 weeks). It is possible that the resorbing
dead fetoplacental tissue triggers an intrauterine inflammatory process
that is proportional to the amount of dead tissue and therefore the gestation
at fetocide. Such an inflammatory process could result in the release
of cytokines and prostaglandins which would in turn induce uterine activity
with consequent miscarriage / preterm labour.
In pregnancies discordant for trisomy 21 the usual choice is selective
fetocide, because with expectant management the majority of affected babies
would survive. In the case of more lethal defects, such as trisomy 18
about 85% of affected fetuses die in-utero and those that are live born
usually die within the first year of life. In this respect, expectant
management may be the preferred option; this would certainly avoid the
procedure-related complications from selective fetocide. The alternative
view is that the amount of dead fetoplacental tissue (and therefore the
risk for consequent miscarriage or preterm labour) would be less after
fetocide at 12 weeks rather than spontaneous death of the trisomy 18 fetus
at a latter stage of pregnancy. |