Neurological sequelae in twins born after assisted conception: controlled national cohort study
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.38156.715694.3A (Published 05 August 2004) Cite this as: BMJ 2004;329:311All rapid responses
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In a recent study (ref 1) twins born in Denmark between 1995 and 2000
as a result of IVF/ICSI were found to be no more likely than naturally-
conceived twins to suffer from neurological morbidity. This is a very
important result which will go some way to allaying the fears of parents
of IVF/ICSI parents and clinicians. Nonetheless, as the editorial points
out (ref 2), the issue of multiplicity and it’s associated morbidity
remains.
Using data from the year 2000, we estimate that around 930 twin
babies were born alive in Denmark following IVF/ICSI treatment (ref 3),
representing 37% of the total 2540 twin babies born alive that year (ref
4). Using a risk estimate of 9.6 per 1000 for neurological morbidity in
any twin, the estimated number of cases of neurological morbidity in all
Danish twins born alive in 2000 is 25, approximately 9 (37%) of whom would
have been conceived by IVF/ISCI. Some of these 9 cases could have been
prevented if the IVF/ICSI twins had been born as singletons. The exact
number of "saveable" cases will depend on the risk in IVF/ICSI singleton
babies compared to naturally conceived singleton babies, an issue which
requires further clarification, but the fact remains that at least some
cases could be avoided each year.
The message is simple: high rates of multiplicity in babies resulting
from assisted conception continue to drive an excess health burden in the
population which is preventable. As long ago as 1990, multiplicity was
highlighted as the primary adverse health outcome in a study of the first
1500 babies born following IVF in the UK (ref 5). While there is evidence
that the frequency of higher order births (triplets and above) has now
started to decline in the UK (ref 6),there is as yet no similar evidence
for twinning rates.The excess morbidity associated with assisted
conception through multiplicity alone is thus likely to continue for some
time.
1 Pinborg A, Loft A, Schmidt L, Greisen G, Rasmussen S, Andersen AN.
Neurological sequelae in twins born after assisted conception: controlled
national cohort study. BMJ 2004;329(7461):311.
2 Keirse MJNC, Helmerhorst FM. How many eggs? BMJ 2004;329:302-3.
3 Nyboe Andersen A, Gianaroli L, Nygren KG; European IVF-monitoring
programme; European Society of Human Reproduction and Embryology. Assisted
reproductive technology in Europe, 2000. Results generated from European
registers by ESHRE. Hum Reprod 2004;19(3):490-503.
4. Data from Danish National Board of Health, Copenhagen.
5 Beral V, Doyle P. Births in Great Britain resulting from in-vitro
fertilization 1978-87. BMJ 1990;300:1229-1233.
6 Simmons R, Doyle P, Maconochie N. Dramatic reduction in triplet and
higher order births in England and Wales. BJOG 2004;111(8):856-8.
Competing interests:
None declared
Competing interests: No competing interests
Neurological sequelae in babies born after assisted conception
Raymond D Lambert
Raymond D Lambert is a professor in the Department of Obstetrics and
Gynaecology at Laval University, Québec, Canada, G1V 4G2
Correspondance: ray.lambert@crchul.ulaval .ca
The recently published paper by Pinborg et al 1show interesting, but
surprising data related to the health of children born from infertility
treatment procedures, since they go against the main stream in the field.
Shortly, the Pinborg's study suggests that twins and singletons born after
IVF/ICSI (in vitro fertilisation/intracytoplasmic sperm injection) have
similar risks of neurological problems. These data are intriguing because
the current paradigm is that multiple pregnancy is an at risk pregnancy
and therefore, according to that paradigm, there should be some
differences between the outcome of twins either from IVF/ICSI or
"naturally" conceived twins on one hand and singletons on the other hand.
Early in year 2002 several population-based study have shown the
increased risks of health problems in babies born from IVF/ICSI, the main
risk factor being multiple pregnancy. 2-5 Multiple pregnancies, either
from IVF/ICSI, ovarian stimulation with or without artificial insemination
(AI), or naturally conceived, result in a higher frequency of perinatal
mortality, 6-11 morbidity, 6 10 12 13 and psychological sequelae. 14-16
Obstetrical and perinatal costs are also considerably higher for twins and
triplets than for singletons. 15 17-19 These data were expected since a
long time ago. 20 The prudent attitude recommended in the Pinborg's paper
1regarding the number of embryos to be transferred after an IVF/ICSI is
therefore fully justified.
However, the absence of differences in terms of neurological sequelae
in IVF/ICSI twins, as compared to IVF/ICSI singletons, 1 is intriguing and
needs further clarification. Stromberg has shown that the whole population
of children born from IVF has an increased risk of cerebral palsy of 3.7,
and IVF singletons of 2.8, no differences being found between IVF and
spontaneously conceived twins. 5 This suggests that treatment of
infertility per se is an important risk factor for singletons. Supporting
this interpretation, singleton IVF/ICSI pregnancies are at higher risks of
low and very low birth weights as compared to a matched group of
spontaneous gestations. 3 21 22
It has been suggested that the causal factor of the adverse outcomes
of IVF pregnancies could be intrinsically related to the health status of
the infertile woman. 23 24 The true question is therefore what is the
frequency of neurological sequelae in singleton babies born from IVF/ICSI
pregnancies as compared to spontaneous pregnancies in mothers aged of 33.8
years (mean maternal age at delivery in the Pinborg's study) and with the
same social profile?
Data on the frequency of neurological sequelae in control matched
spontaneous singleton pregnancies would help to resolve the contradictory
issue raised in the Pinborg's paper, and, furthermore, decryption of the
data might help to identify the criteria for screening at-risk infertile
women of giving birth of a health-compromised child.
1. Pinborg A, Loft A, Schmidt L, Greisen G, Rasmussen S, Nyboe
Andersen A. Neurological sequelae in twins born after assisted conception:
controlled national cohort study. Br Med J 2004;329(7461):311-317.
2. Hansen M, Kurinczuk JJ, Bower C, Webb S. The Risk of Major Birth
Defects after Intracytoplasmic Sperm Injection and in Vitro Fertilization.
New Engl J Med 2002;346(10):725-730.
3. Koivurova S, Hartikainen A-L, Gissler M, Hemmenki E, Sovio U, Jarvelin
M-R. Neonatal outcome and congenital malformations in children born after
in-vitro fertilization. Hum Reprod 2002;17(5):1391-1398.
4. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and
Very Low Birth Weight in Infants Conceived with Use of Assisted
Reproductive Technology. New Engl J Med 2002;346(10):731-737.
5. Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist
K. Neurological sequelae in children born after in-vitro fertilisation: a
population-based study. The Lancet 2002;359(9305):461-465.
6. Luke B, Keith LG. The contribution of singletons, twins and triplets to
low birth weight, infant mortality and handicap in the United States. J
Reprod Med 1992;37:661-666.
7. Gissler M, Silverio MM, Hemminki E. In-vitro fertilization pregnancies
and perinatal health in Finland 1991-1993. Hum Reprod 1995;10:1856-1861.
8. Tarin JJ, Cano A. Effects of manipulations in vitro of human oocytes
and embryos on the birthweight of the resultant babies. Hum Reprod
1995;10:1322-1324.
9. Lieberman B. An embryo too many? Hum Reprod 1998;13:2664-2666.
10. Murdoch AP. How many embryos should be transferred? Hum Reprod
1998;13:2666-2669.
11. Russell RB, Petrini JR, Damus K, Mattison DR, Schwarz RH. The changing
epidemiology of multiple births in the United States. Obstet Gynecol
2003;101:129-135.
12. Seamark RF, Robinson JS. Potential health problems stemming from
assisted reproduction programmes. Hum Reprod 1995;10:1321-1322.
13. Keith LG, Oleszczuk JJ, Keith DM. Multiple gestation:reflections on
epidemiology, causes, and consequences. Int J Fertil Womens Med
2000;45(3):206-214.
14. Olivennes F, Mannaerts B, Struijs M, Bonduelle M, Devroey P. Perinatal
oputcome of pregnancy after GnRH antagonist (ganirelix) treatment during
ovarian stimulation for conventional IVF or ICSI: a preliminary report.
Hum Reprod 2001;16(8):1588-1591.
15. White GB, Leuthner SR. Infertility treatment and neonatal care: The
ethical obligation to transcend specialty practice in the interest of
reducing multiple birth. J Clin Ethics 2001;12(3):223-230.
16. Pinborg A, Loft A, Schmidt L, Nyboe Andersen A. Morbidity in a Danish
National cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634
IVF/ICSI singletons: health-related and social implications for the
children and their families. Hum Reprod 2003;18(6):1234-1243.
17. Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF, Crowley
WFJ. The economic impact of multiple-gestation pregnancies and the
contribution of assisted-reproduction techniques to their incidence. N
Engl J Med 1994;331:244-249.
18. Souter I, Murphy Goodwin T. Decision making in multifetal pregnancy
reduction for triplets. Am J Perinatol 1998;15:63-71.
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children of assisted reproduction confront the responsible conduct of
assisted reproductive technologies. Hum Reprod 2002;17(12):3011-3015.
21. Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal
outcome of pregnancies after assisted reproduction: a case-control study.
Am J Obstet Gynecol 1999;181(3):688-695.
22. Perri T, Chen R, Yoeli R, Merlob P, Orvieto R, Shalev Y, et al. Are
singleton assisted reproductive technology pregnancies at risk of
prematurity? Assist Reprod Genet 2001;18(5):245-249.
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Perinatal outcome and developmental studies on children born after IVF.
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24. Lambert RD. Aetiology of the health problems in singleton ARTs babies.
Hum reprod 2003;18(10):1983-1986.
Competing interests:
None declared
Competing interests: No competing interests
Fewer twins died after assisted conception than after natural
conception. This may be play of chance (p = 0.04), or a real difference.
Do the authors think, that assisted conception makes the difference, or is
a counfounding mechanism more likely ?
Competing interests:
None declared
Competing interests: No competing interests
Sir:
Both the editorial [1] and the related study [2] make a very
interesting reading and are further thought provoking. The editorialists
suggested strongly that one nest and one egg is ideal for one offspring
and medically strongly compatible. We further add that one egg and one
nest should have one natural human young couple in order to avoid most but
not all adverse consequences of assisted conceptions by in vitro
fertilization [IVF] and intracytoplasmatic sperm injection [ICSI].
This controlled study informed the readers about two major findings;
twins from assisted conception have a similar risk of neurological
sequelae as their naturally conceived peers and singletons from assisted
conception and children born after ICSI have the same risk of neurological
sequelae as children born after IVF. However, low birth weight and preterm
birth were insignificantly more common among twins born after assisted
conception than the naturally born twins. Hospital stay was longer in
assisted conception born twins. Surprisingly and unexpectedly, perinatal
infant and infant mortality was more common among naturally born twins
than the assisted conception born twins and singletons.
These findings have some implications; the females would further
delay natural pregnancies or even marriages in order to enjoy their life,
knowing that twins or singletons born after assisted conception which can
be realized at any time in life are not vulnerable to and rather safe from
developing any neurological complications and sequelae; and IVF and ICSI
clinics would boom in future, which if run most by private sector will
result in huge financial burden to the couple including infertile ones.
Finally, one egg, one nest and one offspring from one natural young
couple is ideal and highly recommended.
References:
1. Marc J N C Keirse and Frans M Helmerhorst.How many eggs?. BMJ 2004
329: 302-303.
2.Anja Pinborg, Anne Loft, Lone Schmidt, Gorm Greisen, Steen
Rasmussen, and Anders Nyboe Andersen. Neurological sequelae in twins born
after assisted conception: controlled national cohort study. BMJ 2004;
329: 311-0.
Competing interests:
None declared
Competing interests: No competing interests
Does the high rate for singletons mean that one embryo transfer is not preferable?
The finding that the rate of neurological sequelae and cerebral palsy
was not higher amongst twins born after assisted conception compared to
naturally compared twins is reassuring. It suggests that assisted
conception does not lead to a higher rate of neurological sequelae per se.
The rate of neurological sequelae and cerbral palsy amongst
singletons after assisted conception may not be a good guide as how many
eggs should be transferred. Although the paper by Pinborg et al (1) does
not give information on how many embryos were transferred to the mothers
in their study, it is reasonable to assume that it was usual for at least
two embryos to be transferred. The women who gave birth to singletons
will be different from those women who gave birth to twins in that only
one embryo developed. It may well be that the chances of only having a
singleton rather than twins is sometimes a reflection of the health of the
woman or that one of the twins died early. This could well explain the
higher rate in singletons resulting from assisted conception, compared to
naturally conceived singletons, of neurological sequelae and cerebral
palsy as naturally conceived singletons are likely to be usually the
result of only one egg being fertilised.
Studies show that there is a higher rate of cerebral palsy in twins
compared to singletons (2-3). The comparisons given, by Pinborg et al,
for the crude rates of cerebral palsy in all births are higher than the
rates for singletons. For example, the rate of cerebral palsy amongst
singletons in a European multicentre study, which included East Denmark,
was 1.8 per 1,000 live births in 1984-90(4).
The epidemiological evidence indicates that it is safest to transfer
only one embryo. A randomised controlled trial, comparing one versus two
embryo transfer, could provide a more definitive answer but this would
need to recruit tens of thousands of couples to have sufficient
statistical power. In the absence of such a trial, it will be necessary
to make a judgement using all the evidence available.
(1) Pinborg A, Loft A, Schmidt L, Griesen G, Rasmussen S, Andersen
AN, Neurological sequaelae in twins born after assisted conception:
Controlled national cohort study, BMJ, 2004; 329: 311-7
(2) Luke B, Keith LG, The contribution of singletons, twins and
triplets to low birth weight, infant mortality and handicap in the United
States. J Reprod Med 1992: 37: 661-6
(3) Petterson B, Nelson KB, Watson L, Stanley F, Twins, triplets and
cerebral palsy in births in Western Australia in the 1980s, BMJ, 1993,
307: 1239-43
(4) Topp M, Huusom LD, Langhoff-Roos J, Delhumeau C, Hutton JL, Dolk
H on behalf of the SCPE Collaborative Group, Multiple birth and cerebral
palsy in Europe: a multicenter study, Acta Obstet Gynecol Scand, 2004; 83:
548-53
Competing interests:
None declared
Competing interests: No competing interests