Interpretation
Mastroiacovo and Li previously analyzed the incidence of BDs, and found
that it is significantly higher in twins than in
singletons.26 In the present study, we also found that
the incidence of BD associated with multiple pregnancies is more than
four times higher than that associated with singletons. The previous
study also showed higher incidences of a number of types of BD, such as
CHD, congenital hydrocephalus, and cleft lip with or without cleft
palate. Table 1 also shows that mothers of children with BDs that were
derived from multiple pregnancies were more likely to be older, to live
in an urban environment, to have a college education or above, and to be
multiparous, than mothers who gave birth to singletons. This may be
explained by the use of ARTs. Although we could not collect information
regarding the use of ARTs in the present study, previous studies have
shown that the age of women who are using ARTs in China is increasing,
and that children born as a result of the use of some ARTs are at higher
risk of BD than those that result from natural
conception.27, 28
There was also a significantly lower prenatal diagnosis rate for BDs
that were associated with multiple pregnancies than for those that were
associated with singletons, and this applied to 10 specific types of BD.
Eight of these were structural malformations that are normally
identified in the second or third trimester. Shielding of one fetus by
another in multiple pregnancies might account for this lower prenatal
diagnosis rate. The study by Razavi et al . yielded consistent
results, because they found that the accuracies of the prenatal
diagnosis of congenital clubfoot in fetuses that were singletons or part
of multiple pregnancies were 68.8% and 35%, respectively.
With regard to chromosomal malformations, the accuracy of screening was
also lower for multiple pregnancies, despite the government of Zhejiang
Province providing free serological tests as part of prenatal healthcare
during the first or second trimester. At present, nuchal translucency
thickness (NT) in combination with NIPT is the most effective
non-invasive method of screening for Down syndrome in multiple
pregnancies,29 but this must be performed by
physicians experienced in maternal and fetal care. Invasive prenatal
methods of screening for chromosomal malformations in multiple
pregnancies, which include CVS or amniocentesis, should also be
performed by an experienced physician, because of the difficulty and
risks associated.
There are few centers in Zhejiang Province where prenatal diagnosis can
be performed for multiple pregnancies, but the Prenatal Diagnosis
division of the China Ultrasound Association has generated standards for
the prenatal ultrasonographic diagnosis of six types of BD and trained
ultrasonographers for this purpose. This probably explains why there
were no significant differences in the prenatal diagnosis rates of spina
bifida, encephalocele, anencephaly, gastroschisis, or omphalocele
between singletons and multiple pregnancies. However, owing to the
limitations of the available methods of screening, the prenatal
diagnosis rates for anal atresia, microtia, and esophageal atresia are
extremely low: these defects can only be diagnosed using non-specific
signs, with or without magnetic resonance imaging
(MRI).30, 31 Consequently, there
were no significant differences in the prenatal detection rates for
these three defects between singleton and multiple pregnancies. Given
the greater technical challenge in prenatally diagnosing BDs in multiple
pregnancies, we suggest that women with multiple pregnancies should be
cared for from as early a date as possible in institutions in which the
staff are capable of performing accurate prenatal diagnosis in women
with multiple pregnancies. In addition, physicians should be more
cautious when discussing prenatal diagnoses for women with multiple
pregnancies and choose the most accurate non-invasive prenatal screening
methods to avoid misdiagnoses. Finally, multiple methods of screening
should be used for multiple pregnancies, such as ultrasonography, MRI,
and genetic testing, as described for a combination of neurological and
cardiac defects32 to improve the prenatal diagnosis
rate for BDs.
Of all the BDs diagnosed prenatally, the proportion diagnosed before 28
weeks of gestation was significantly lower in multiple pregnancies than
in singleton pregnancies, and the same finding was also made for cleft
lip with cleft palate, trisomy 21 syndrome, and congenital malformation
of the urinary system. Congenital urinary system malformations, such as
hydronephrosis, duplication of the kidney, or genital abnormalities,
normally become apparent during the second or third trimester and are
identified during the third trimester.33 However,
orofacial cleft may be difficult to confirm in multiple pregnancy
because of the fetal position. Therefore, women with multiple
pregnancies should be informed of the limitations of prenatal
ultrasonographic screening for structural malformations of the fetus
during the first and second trimesters, and should be made aware of the
importance of screening for structural malformations during the third
trimester, even if such screening was negative during the first. With
respect to euploidy, a previous study found no significant difference in
the incidence of trisomy 21 between singletons and multiple
births.34 We speculate that the limitations of NIPT,
the lack of experienced personnel in many centers, sampling error,
and/or cross-contamination of samples collected during invasive prenatal
diagnostic procedures may be responsible for delays in diagnoses.
The high incidence of structural malformations associated with multiple
pregnancies can be explained not only by of the larger number of
fetuses, but also by the existence of specific complications associated
with multiple births, especially in monochorionic twins. With the
development of ultrasonographic methods of examination and the
increasing availability of various diagnostic techniques, increasing
numbers of reports have been published regarding BDs in association with
multiple pregnancies. Table 5 shows that the methods used for the
prenatal diagnosis of defects in multiple pregnancies mainly comprise
ultrasonography, clinical history or physical examination, genetic
testing, and biochemical testing. We found that the prenatal
ultrasonographic diagnosis rates for CHD and hydrocephalus were very
high, and indeed, in recent years, the methods of prenatal diagnosis,
such as ultrasonography, serum biochemical screening, CVS, and
amniocentesis, have improved substantially. More recently, great
advances have been made in NT, NIPT, and ultrasonographic screening for
structural defects in early pregnancy. The improvements in these
techniques, accompanied by improvements in prenatal healthcare, account
for the declining incidences of BDs and chromosomal anomalies. However,
we should also be aware that the prenatal diagnosis of structural
malformations is more difficult in multiple pregnancies, because one
fetus may obscure another. Therefore, obstetricians should inform
pregnant women that the prenatal diagnosis of defects is not always
highly accurate, especially in multiple pregnancies.