The Journal of Pediatrics
Volume 146, Issue 4 , Pages 450-452, April 2005

Pediatricians beware: The age of ARTs is upon us

  • Judith G. Hall, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Judith G. Hall, OC, MD, UBC and Children's and Women's Health Centre of BC, Department of Pediatrics, BC's Children's Hospital, 4480 Oak St, Room L408, Vancouver, BC, V6H 3V4.

Department of Pediatrics, UBC & Children's and Women's Health Centre of BC, Vancouver, BC V6H3V4, Canada

See related article, p 565.

Article Outline

ARTs, Assisted reproductive technologies, DZ, Dizygotic twinning, ICSI, Intracytoplasmic sperm injection, MZ, Monozygotic twinning

 

Assisted reproductive technologies (ARTs) have made a huge difference for infertile couples. However, in North American culture, perhaps to a lesser degree in Europe and Australia, infertility carries with it embarrassment and even shame, so there is still an aspect of secrecy about the utilization of ARTs. Once babies are conceived by ARTs, the families often do not tell their pediatrician or even their obstetrician that this pregnancy is the product of ARTs. Thus, if you, the pediatrician, do not ask, you may not find out and consequently not be suspicious of possible complications. The article by Yoon et al1 in this issue of The Journal brings to light many of the potential issues.

A recent review of published articles on ARTs, by a combined committee of the American Academy of Pediatrics and the American Society for Reproductive Medicine and sponsored by the Genetics and Public Policy Center at Johns Hopkins University aimed to determine whether there was an increased risk to mother and child(ren) with ARTs. The conclusion of that review was that no studies have been properly done to be able to actually assess the risk, but if there is an increased risk for congenital anomalies, neurologic abnormalities, learning defects, and so forth, it is primarily related to the increase in multiples births (ie, twins, triplets, and so forth).2 It is well known that twins have more complications than singletons and tend to be small for dates and born prematurely; however, the products of ARTs have even more intrauterine growth restriction for their gestational age.3 There does not appear to be a marked increase in congenital anomalies or handicaps beyond that which might be expected as related to the products of a “multiples” pregnancy. The concern in North America is that more than 1% of conceptions are now the products of ARTs, leading to a remarkable increase in multiple births that have a major effect on special care nurseries and on the costs of pregnancies. However, the pediatrician should be aware that there is also likely to be an increase in rare complications, highlighted in the excellent case report by Yoon et al. Single case reports can be extremely important to identify rare pathogenic events. In the case described by Yoon et al, there is a conjunction of the rare complications that can be seen in ARTs.

In addition to the increased number of dizygotic twins expected because of the replacement of multiple fertilized eggs during the procedure of ARTs, there has been an observed increase in monozygotic twinning (MZ) with ARTs.4 This increase rate of MZ twinning is 3 to 5 times the spontaneous background rate of MZ twinning. It is not clear whether these are true monozygotic twins or whether, as reported in Yoon's case report, it is because they have a monochorionic placenta and therefore are assumed to be MZ twins. Normally, dizygotic twins (DZ) have completely separate placentas. Rarely, there can be implantation of their placentas close enough together to consider them fused. However, it is extremely rare, or at least it has been thought to be extremely rare, for dizygotic twins to have a single chorion.

There are now two reports of DZ twins with a monochorionic placenta, that is, the current report by Yoon et al1 and the report by Souter et al,5 both associated with ARTs, and it is rumored that there are at least two more monochorionic DZ twins that were products of ARTs.

The case of DZ twins reported by Souter et al and the case reported by Yoon et al were both the product of intracytoplasmic sperm injection (ICSI). ICSI appears to improve fertilization when there is oligospermia. ICSI is often combined with allowing the zygote to grow to the blastocoele stage before returning the zygote to the uterus for reimplantation. Neither of these reports1, 5 indicate whether the embryos were placed in the uterus immediately or allowed to grow to blastocoele stage. It may be that placing two zygotes back into the uterus in a particular way or at a particular stage of development influences whether or not they will implant so close to each other that they can have a monochorionic placenta. Spontaneous dizygotic twins are likely to be ovulated and fertilized at slightly different times, whereas ARTs twins are replaced within minutes of each other. Unfortunately, the details of the ARTs procedures as to medium, culture conditions, difficulty with ICSI, and so forth are rarely reported and may be difficult to obtain because of privacy issues. Nor is the procedure concerning replacing the zygotes and the timing of replacement usually reported (as seen in these two cases).

Most pediatricians are well aware that monochorionic twins are usually MZ.6 In fact, the presence of a single chorion is traditionally the way to identify MZ twins. 70% to 75% of MZ twins are monochorionic. However, there is less awareness that 25% to 30% of MZ twins have separate placentas and are dichorionic diamniotic, just like DZ twins. Those MZ twins who are monochorionic are thought to undergo formation/separation into twins later (4 to 8 days of embryonic development) than dichorionic MZ twins, who are thought to separate in the first 4 days of embryonic development.7

Because MZ twins share a single placenta, they have an increased risk for complications that include vascular connections, twin-twin transfusions, and vascular compromise, which can then lead to limb reduction anomalies, gastroschisis, central nervous system destructive lesions, and so on.8 The pediatrician needs to be aware of the increased risk for MZ monochorionic twins to have these types of vascular problems that predispose to disruptive types of congenital anomalies. It is the monochorionic status that gives this increased risk, and thus the DZ twins who are monochorionic have the same risk.

What is also important about the recognition of DZ monochorionic twins is that because they share vascular connections, their bone marrow can be expected to be chimeric (a mixture of the white blood cells from each twin) or may be taken over completely by one of the twins. Thus, looking at white blood cell DNA to establish dizygosity may not work in monochorionic DZ twins. It may be necessary to do fibroblast or buccal smear DNA to determine whether the twins are MZ or DZ.

There appears to be a small increase in imprinting defects among the products of ARTs. This has not yet been sorted out completely, but several registries of Beckwith-Wiedemann patients indicate a marked increase in cases among the products of ARTs.9 Also, in the case of Angelman syndrome, there appears to be an increase in a very rare type of imprinting defect.10 Interestingly, Beckwith-Wiedemann syndrome has been reported for years to be increased in one of MZ twins, usually female twins. This phenomenon appears to be related to the failure to maintain normal imprinting on chromosome 11 in one of the MZ twins.11 Weksberg has suggested that this failure to maintain imprinting may actually produce the MZ twinning. In Yoon's report, there are DZ twins who are the product of ARTs utilizing ICSI, and the source of the imprinting defect leading to Beckwith-Wiedemann syndrome has not been elucidated. Thus, it seems likely that the presence of Beckwith-Wiedemann syndrome in one of these twins is related to ARTs rather than to the MZ twinning process and the failure of maintaining imprinting usually seen with discordant MZ Beckwith-Weidemann twins.

An increase in aneuploidy is seen in the offspring of ARTS.12 This probably primarily relates to the infertility in the parents that brings them to use ARTs. For instance, men with Klinefelter syndrome have produced children with Klinefelter syndrome, and men with a Y deletion have produced children with Y deletion. In Yoon's report, we would have suspected that the father of this child might have Klinefelter syndrome and that he was the source of the extra chromosome; however, analysis of the child's sex chromosomes have demonstrated that the extra X came from mother.

Because of the cost of chromosome analysis, many couples with infertility do not have a proper workup for the cause of their infertility before using ARTs (eg, careful parental chromosome studies to rule out small deletions or translocations). This can then lead to the production of chromosomal abnormalities in their children derived from their own chromosomal abnormalities, which could also be the cause of their infertility. In general, there has not appeared to be an increased occurrence of chromosome abnormalities other than those associated with advanced maternal age or those producing the infertility problems in the parents.

Nevertheless, it has been suggested for some time that when there are dizygotic twins and one twin has aneuploidy, the pregnancy of the aneuploid twin could be maintained rather than miscarried, by the presence of the normal twin. Half of Down syndrome pregnancies and 99% of Turner syndrome pregnancies miscarry. However, the presence of a normal dizygotic twin appears to maintain discordant twin pregnancies. In Yoon's case, Klinefelter syndrome is not a situation that would be expected to miscarry, but it does raise the issue of the presence of aneuploidy being increased and maintained by the presence of a normal twin in ARTs when multiples are produced.

The pediatrician needs to be aware of the possibility of rare complications when ARTs is used. Pediatricians are undoubtedly aware of the increased incidence of twinning related to ARTs because of the presence of so many twins, triplets, and quadruplets in the special care nurseries. It appears that the problems related to multiple births increases the true cost of ARTs, that is, the overall cost to the health care system. Because each attempt to attain a pregnancy by using ARTs is expensive, families tend to opt to put more fertilized ovum into the uterus than are necessary. It appears that in young women younger than 35 years of age, it is not necessary to put back multiple ovum to achieve a pregnancy.2 In addition, it is best to work up the infertility of the couple before using ARTs. Interestingly, if only one zygote had been replaced in the case presented by Yoon et al, as was appropriate because the mother was younger 35 years old, we would not have learned about these many complications from this remarkable case report.

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References 

  1. Yoon G, Beischel LS, Johnson JP, Jones MC. Dizygotic twin pregnancy conceived with assisted reproductive technology associated with chromosomal anomaly, imprinting disorder, and monochorionic placentation. J Pediatr. 2005;146:565–567
  2. Hudson KL, Robinson KA, Ananthakrishnan A, Pritchard DE, Goodman S. A comprehensive review of the health and developmental outcomes of children conceived through assisted reproductive technologies (ART). Abstracts of The American Society of Human Genetics 54th Annual Meeting. 2004:18.
  3. Nassar AH, Usta IM, Rechdan JB, Harb TS, Adra AM, Abu-Musa AA. Pregnancy outcome in spontaneous twins versus twins who were conceived through in vitro fertilization. Am J Obstet Gynecol. 2003;189:513–518
  4. Edwards RG, Mettler L, Walters DE. Identical twins and in vitro fertilization. J In Vitro Fertil Embryo Trans. 1986;3:114–117
  5. Souter VL, Kapur RP, Nyhold DR, Skogerboe K, Myerson D, Ton CC, et al. A report of dizygous monochorionic twins. N Engl J Med. 2003;349:154–158
  6. Hall JG. Twinning. Lancet. 2003;362:735–743
  7. Benirschke K, Kim CK. Multiple pregnancy. N Engl J Med. 1973;288:1329–1336
  8. Hall JG. Twins and twinning. In: Rimoin DL, Connor JM, Pyeritz RE, eds. Emery and Rimoin's Principles and Practice of Medical Genetics. Vol 1, 4th ed. New York: Churchill-Livingstone; p. 501-13.
  9. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet. 2003;72:156–160
  10. Ostravik KH, Eiklid K, van der Hagen CB, Spetalen S, Kierulf K, Skjeldal O, et al. Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. Am J Hum Genet. 2003;72:218–219
  11. Weksberg R, Shuman C, Caluseriu O, Smith AC, Fei YL, Nishikawa J, et al. Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet. 2002;11:1317–1325
  12. Devroey P, Van Steirteghem A. A review of ten years' experience of ICSI. Hum Reprod Update. 2004;10:19–28

PII: S0022-3476(05)00084-3

doi:10.1016/j.jpeds.2005.01.041

Refers to article:

  • Dizygotic twin pregnancy conceived with assisted reproductive technology associated with chromosomal anomaly, imprinting disorder, and monochorionic placentation

    Grace Yoon, Linda S. Beischel, John P. Johnson, Marilyn C. Jones
    The Journal of Pediatrics April 2005 (Vol. 146, Issue 4, Pages 565-567)

The Journal of Pediatrics
Volume 146, Issue 4 , Pages 450-452, April 2005

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