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The Role of Cell-Free DNA-Based Prenatal Testing in Twin Pregnancy
Introduction
Due to an increasing trend of advancing maternal age at conception, and the increased use of assisted reproductive technologies (ART), the number of twin and higher order multiple pregnancies is increasing in many countries, despite the introduction of the single embryo transfer policy .
Compared to singletons, twin pregnancies are at increased relative risk of many obstetric complications, including aneuploidy . This is probably the indirect consequence of the fact that older women not only have a higher risk of aneuploidy pregnancies, but also a higher risk of naturally conceiving twin pregnancies. Additionally, older women are more likely to need ART to conceive, and ART is a risk factor for twin pregnancies as well as for fetal aneuploidy .
Risks of prenatal invasive testing are higher in twins than in singletons and accurate noninvasive prenatal testing (NIPT) would therefore be welcomed by mothers of twin pregnancies, particularly by those women who had difficulties conceiving. Additionally, in twin pregnancies, there is also a greater potential for sampling errors at chorionic villous sampling (CVS) as well as at amniocentesis . The currently used conventional prenatal screening strategies: the first trimester combined test and the second trimester serum screening test have a high false positive rate that surpasses that in singleton pregnancies and may be even higher in pregnancies conceived by ART .
Data from published studies informing the use of cell-free DNA-based noninvasive prenatal testing (cfDNA NIPT) in twins are relatively small compared to that of singleton pregnancies. There is debate as to whether the diagnostic accuracy of cfDNA NIPT in twin pregnancy is equivalent to that of singletons, and what role cfDNA NIPT should have in routine clinical care. This is against the backdrop of the increasing use in clinical practice of cfDNA testing both in state-run and private healthcare systems.
In this chapter, we will outline the evidence and the current opinions of the professional bodies, review the differences in cfDNA NIPT accuracy between twins and singletons, and stratify the available evidence on impact of chorionicity.
Zygosity, Chorionicity, and Amnionicity
Twin pregnancies can be classified according to zygosity, chorionicity, and amnionicity, all of which have implications on prenatal diagnosis and subsequent management. Zygosity refers to the number of zygotes. Monozygotic (MZ) twins originate from one zygote (one sperm and one oocyte), and dizygotic (DZ) twins originate from two zygotes (two sperm and two oocytes). Consequently, MZ twins are genetically “identical” although there are rare exceptions reported of heterokaryotypic MZ twins . It is assumed that a third of twins are monozygous. DZ twins are genetically nonidentical. In MZ twins, it can be assumed that the cfDNA NIPT result will reflect the genetic makeup of both twins, whereas in DZ twins it is more complicated as, in case of an anomaly, the twins are most likely to be discordant, that is, one twin will be affected but the other twin will not.
However, in clinical practice, the prenatal risk is allocated by the chorionicity (placental type) and amnionicity. Chorionicity refers to the number of placentas: monochorionic (MC) twins share one placenta and have interfetal vascular placental anastomoses, whereas dichorionic (DC) twins have two individual placental masses. Up to 15% of twins are MC and 85%–90% are DC. Amnionicity refers to the number of amniotic fluid sacs: monoamniotic (MA) twins have one sac; diamniotic (DA) twins have two sacs. The chorionicity and amnionicity should be determined in all twin pregnancies at the first trimester ultrasound scan , as each combination (DCDA, MCDA, MCMA) is managed differently antenatally due to different perinatal/fetal risks and complications including: twin-twin transfusion syndrome, selective intrauterine growth restriction, intrauterine death, and cord entanglement . The sensitivity and specificity of “correct” first trimester ultrasound chorionicity allocation is > 99%. Clinically, zygosity cannot be assumed from chorionicity and/or amnionicity. Although all DZ twins are DC, and all MC twins are MZ, not all DC twins are DZ, and not all MZ twins are MC. Fifteen percent of DC twins are MZ; of the MZ twins 33% are DCDA, 66% MCDA, and 1% MCMA. Consequently, this adds a layer of complexity to cfDNA NIPT in twins, particularly in cases of DC twins which although most likely to be DZ and thus discordant for aneuploidy, may be MZ. Table 1 outlines the theoretical genetic risks in twin pregnancies.
Table 1
Genetic Risks in Twin Pregnancies, Based on One-Third of Twins Being Monozygous
Table amended from Harper P. Twins and prenatal diagnosis. In: Practical Genetic Counselling. 7th ed: CRC Press; 2010. p. 132.
| Chromosome Abnormality | X-Linked (Fetal Sexing Only) | X-Linked (Specific Diagnostic Test) | Autosomal Recessive | |
|---|---|---|---|---|
| Risk for singleton pregnancy | Y a | 1/2 | 1/4 | 1/4 |
| Risk of at least one twin being affected | 5/3 Y | 2/3 | 3/8 | 3/8 |
| Risk of both twins being affected | ~ 1/3 Y | 1/3 | 1/8 | 1/8 |
Vanishing Twins
An increasingly recognized problem of twinning is the “vanishing twin,” whereby single twin demise is noted on ultrasound prior to 14 weeks’ gestation. In such cases, the “vanishing twin” may be “reabsorbed” and difficult to visualize on ultrasound later in pregnancy. A vanishing twin has little consequence to the surviving cotwin. It may though have consequences for false positive rates in cfDNA NIPT (of a presumed singleton pregnancy).
Higher Order Multiple Pregnancies
There is little data from cohort studies on cfDNA NIPT in higher order multiples (triplets, quadruplets, etc.), including the effect that selective reduction has on cfDNA NIPT results of the surviving fetuses . Therefore, conclusions on test accuracy in higher order multiple pregnancies cannot be confidently drawn and are not covered in this chapter.
Role of CELL-FREE DNA NIPT in Twin Pregnancies
The majority of research on cfDNA NIPT in twin pregnancies has investigated detecting aneuploidy, with few studies looking at fetal Rhesus status, or fetal sexing. The focus of this section will be on autosomal and sex chromosome aneuploidy testing, but we will briefly cover the other areas as well. Again, it is essential to emphasize that the clinical efficacy has to be assessed separately for both DC and MC twin pregnancies.
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