Trisomy 21 in both fetuses in a DCDA twin pregnancy

Abstract

A woman’s chances of having a child with Down syndrome increases with age. By age 40, the risk of conceiving a child with Down syndrome is about 1 in 100. We report a rare case of dizygotic dichorionic diamniotic twin pregnancy conceived via in vitro fertilisation, with both twins having trisomy 21. Both fetuses were independently detected to be at high risk of autosomal trisomy, initially via first-trimester screening and subsequently via invasive definitive diagnostic tests (ie, chorionic villus sampling and amniocentesis).

Diagnosis of trisomy 21 has to be made via initial non-invasive prenatal screening, followed by further rigorous and accurate invasive pregnancy testing for confirmation. The gravity of the results necessitates high detection rates and high specificity of prenatal screening tests. Management of the patient must be multidisciplinary and supportive in nature, involving extensive and non-directive pregnancy counselling and management, genetic counselling and management of psychological distress.

Background

A woman’s chances of having a child with Down syndrome increases with age. By age 40, the risk of conceiving a child with Down syndrome is about 1 in 100. However, it is extremely rare to have Down syndrome in both fetuses in case of a dichorionic diamniotic (DCDA) twin pregnancy. We report a case of dizygotic DCDA twin pregnancy conceived via in vitro fertilisation intracytoplasmic sperm injection (IVF-ICSI) with a transfer of two embryos and had both twins with trisomy 21.

Case presentation

Our patient is a 38-year-old Chinese primigravida who had conceived by IVF-ICSI and transfer of two embryos.

This pregnancy was preceded by two previous first trimester miscarriages, of which the causes were unknown. She had no significant medical, surgical and family history.

Investigations

All her routine antenatal blood tests were normal. Her first trimester combined screening done at 12 weeks was reported as high risks of trisomy 21 in both twins. This was followed up with a non-invasive pregnancy test which was also reported to be high risk for trisomy 21 for both fetuses. Chorionic villus sampling (CVS) on both placentas were done which confirmed that the male twin had trisomy 21 and the female twin had the possibility of mosaicism.

After counselling, the couple underwent amniocentesis for both sacs, and the samples were sent for karyotyping. The karyotyping reported trisomy 21 in both male and female twins.

Treatment

In this case report, we discuss the efficacy of available prenatal screening and diagnostic tests in multiple pregnancies. The process of prenatal screening and diagnosis in twin pregnancies is complex. These tests are useful for imparting non-directive counselling to couples and helping them in deciding on the options like termination of pregnancy and selective fetal reduction or aid specialist input for women who are keen to continue pregnancies.

First trimester combined screening

The first trimester screening is currently the first-line prenatal screening offered to all pregnant women in Singapore. It involves the biochemical markers pregnancy-associated plasma protein A and free beta human chorionic gonadotropin and the ultrasound measurement of fetal nuchal translucency (NT). NT measurement alone has a 76.8% detection rate with a false positive rate of 4.2%, whereas the combination with biochemical markers brings the detection rate up to 87.0% with a 5.0% false positive rate.¹

Down syndrome screening dependent on multiple maternal serum markers is less sensitive in twin pregnancies than singleton pregnancies. A study showed that 73% of monozygotic twin pregnancies and 43% of dizygotic twin pregnancies can be detected, with a 5% false positive rate.² Usually, there is limited value in the first trimester screen for dizygotic twin pregnancies due to the masking effect of abnormal serum results by the unaffected twin.³ However, in this rare case scenario, this masking effect does not exist due to both twins being affected, and we are unable to establish a relative detection rate based on this single case scenario.

Additionally, a retrospective study of twin pregnancies has shown that the supplementation of nuchal thickness by the nasal bone assessment increased the detection rate of Down syndrome from 75% to 87%, and the addition of serum analytes to the above further increases the detection rate to 89%.⁴ This is an adjunctive assessment that can be considered in circumstances as such. The Down syndrome screening in IVF-ICSI pregnancies are often complicated by higher maternal age, a high multiple pregnancy rate, a high risk of a vanishing twin and an increased risk of chromosomal abnormalities.⁵ Such calculations are not been fully elucidated for twins, and few studies show high false positive rates.⁶

Patients with twins should be made aware that the detection rate is less than that of singleton pregnancies.

Non-invasive prenatal screening

After deemed high risk on the first trimester screening, this patient chose to have a non-invasive prenatal screening (NIPS) test. A single-centre study done in 2016 with 516 cases of twin pregnancies from assisted reproductive technologies identified 4 cases of T21 via non-invasive prenatal testing which were confirmed via karyotyping.⁷ This gives a 100% positive predictive value, with a 95% CI of 39.8% to 100%. There were also no false negative results reported in the remaining patients. A prospective study reports that in twin pregnancies undergoing first trimester screening for trisomies by cell-free fetal DNA analysis referred to as NIPS, the fetal fraction of the total DNA in the blood sample retrieved is lower, and the failure rate is higher compared with the singletons.⁸

However in a meta-analysis, NIPS for trisomy 21 screening in twin pregnancies showed a pooled sensitivity of 0.99 (95% CI 0.92 to 1.00), a specificity of 1.00 (95% CI 0.99 to 1.00) and particularly proved the accuracy of NIPS for detecting trisomy 21 for DCDA twin pregnancies.⁹

CVS and amniocentesis

This case exemplifies the most common indications for prenatal cytogenetic diagnosis: advanced maternal age and increased risk as estimated from non-invasive screening results. For this particular case scenario, CVS and amniocentesis were both done.

Chorionic villus sampling

When CVS is performed in non-monochorionic multiple pregnancies, the transabdominal approach or a combination of transabdominal and transcervical techniques are recommended to minimise the chance of sampling errors.¹⁰ In our patient, both placentae were distinctly visible and quite accessible by transabdominal approach. Early fetal loss and perinatal mortality post-CVS in twin pregnancies were comparable with that of twin pregnancies with prenatal diagnosis.¹¹ For DCDA pregnancies, karyotyping for each fetus is necessary.

Amniocentesis

Amniocentesis for genetic diagnosis is generally performed after 15 weeks of gestational age. In dichorionic twin gestations, amniotic fluid from both sacs was sampled. It is crucial to assess the chorionicity, each gestational sac, placental location, fetal anatomy, viability and gender. Injection of 2–3 mL of indigo carmine can be done after aspiration of amniotic fluid from the first sac, without removing the needle to aid identification and prevent the same sac from being sampled twice. A second amniocentesis can then be done after visualising the two separate sacs.¹² Alternatively, there is the single puncture sampling technique¹³ or the simultaneous visualisation of two needles on each side of the separating membrane.¹⁴ In this case, the samples from the amniocentesis were sent for karyotyping and quantitative fluorescent PCR (QF-PCR), and both samples were reported positive for Down syndrome with different sexes. Diagnostic accuracy of amniocentesis is proven. There are case reports of monochorionic diamniotic twin pregnancy with a discordant trisomy 21 detected by amniocentesis although they develop from single zygote.¹⁵

Outcome and follow-up

For our patient, in particular, the couple subsequently opted for termination of pregnancy and had second trimester termination at 18 weeks. Our patient had five remaining frozen embryos stored and was keen for preimplantation genetic diagnosis before considering future embryo transfers.

Discussion

Rarity of the case

It is known that there is an increased risk of autosomal trisomy and chromosomal abnormalities as maternal age advances.¹⁶ The risk of Down syndrome is estimated to be 1:173 at 38 years old and 1:136 at 39 years old.¹⁷ In this case, the DCDA twin pregnancy occurred after the implantation of two separate embryos during in vitro fertilisation. Both fetuses were independently detected to be at high risk of autosomal trisomy, initially via first trimester screening as well as non-invasive cell-free fetal DNA testing and subsequently confirmed via invasive diagnostic tests (ie, CVS and amniocentesis). This case scenario is thus extremely rare. There are many case reports with discordant structural abnormality or chromosomal abnormality in MC and DC pregnancies. However, case reports with both fetuses of dizygotic pregnancy having Down syndrome were very rare, and we only came across one case series done by Nicolaides that reported two cases of both fetal trisomies.¹⁸

Learning points.

• In the last three decades, the incidence rate of twins has increased, especially for that of dizygotic twins largely due to the use of assisted reproductive techniques (ART) and advanced maternal age. Due to the rarity of this case scenario, there are no prior statistics available as to the rates of concomitant Down syndrome in dichorionic diamniotic twins during pregnancy.

• Screening for trisomy 21 has to be made via initial combined first trimester test and then non-invasive prenatal screening after counselling if they decline invasive testing. If the risk is reported to be, high then an invasive diagnostic test has to be proposed for confirmation, all of which should be done by a trained practitioner. The decision making that depends on the results of the tests necessitates high detection rates and high specificity of prenatal screening tests. Management of the patient must be multidisciplinary and supportive in nature, involving extensive and non-directive pregnancy counselling and management, genetic counselling, management of psychological distress. Counselling throughout the pregnancy must be non-directive and the woman’s right to accept or decline any or all of the testing or options offered at any point in the process must be respected.