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.