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Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 1
WHO IS AFRAID OF TRIPLET PREGNANCIES ?
Isaac Blickstein, MD
Dept. of Obstetrics and Gynecology, Kaplan Medical Center, Rehovot,
Israel
Introduction
Before the introduction of effective infertility treatment triplet births were very rare, and
until the era of modern neonatology, their likelihood to survive into adult life was quite low.
For this reason, limited historical references to triplet pregnancy and birth exist. [1] The
Hellin-Zeleny approximation – a quasi-mathematical relationship describing the frequencies
of singletons, twins, triplets, and quadruplets in a large population – remained satisfactory for
describing spontaneous conceptions, but the observed frequency was 27% above the expected
value when the triplet epidemic started in the late 80’s, and more than double the expected
value at the high-point of the epidemic at the mid-90’s. [2,3] These changes reflect the current
frequencies of high order multiple births in most developed countries which amount to 400 to
800% over the “spontaneous” rates observed in the late 1970’s.
In the past, few obstetricians could accrue much personal experience in managing
triplet pregnancies, and small hospital-based series collected over a wide time span were
unanimous about their dismal outcomes. However, such studies were obviously of inadequate
statistical power to draw meaningful conclusions. More importantly, they could not delineate
the tremendous changes that had occurred in neonatal management of premature and low birth
weight (LBW) infants. Despite this change, large datasets remained either incomplete or few
and far between. In fact, and perhaps ironically, more large-scale studies on multifetal
pregnancy reduction (MFPR) have been published than on outcome of non-reduced triplets.
Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 2
Outcome related to maternal age
The reduced fecundity of older age significantly increases the need for infertility
treatment.[2] In terms of triplet pregnancies, a stepwise increase could be demonstrated up to
a 10-fold increase for the group of patients aged over 35 years, and vastly exaggerated in
women over 44 years of age. In contrast to the pattern seen with singleton births, a study by
the National Institute of Child Health and Human Development (NICHD) found that triplets
born to older mothers actually fare better than triplets born to younger mothers. [4] This
finding is encouraging for the typical infertile patient because it indicates that multiples born
to older mothers do not have any excess risk of poor outcomes. Women who conceive
through the use of assisted reproduction are likely to receive good prenatal care, and their
infants are likely to receive a high standard of care as newborns, explaining the speculation
that women who use assisted reproduction may have better health care coverage and lesser
need to work during pregnancy. The inevitable conclusion might be that better outcomes
among triplets mothers appear to be a prerogative of women of the affluent social class. [5]
Does specialized antenatal care improve outcome?
The comparison of United States data to the data collected by the Women’s Health
Division of Matria Healthcare, Inc. (Marietta, GA), a company that specializes in providing
outpatient surveillance to women with high-risk pregnancies, mostly financed with private
insurance, revealed that: (1) in the Matria group, there were 50% fewer extremely premature
triplets (<28 weeks), (2) Matria triplets were delivered at more advanced gestational ages,
thus, there were 17.7% more deliveries at 28-32 and 33-36 weeks compared with the overall
USA figures in these gestational age ranges.[6]
It is clear now that one should aim for a realistic gestational age at which neonatal
mortality is lowest. (Papiernik E. The 13th Workshop on Multiple Pregnancy, Porto, Portugal,
June 2000, unpublished) It is reasonable to propose that efforts should not be focused in
Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 3
postponing triplet births until “term” or until the average gestational age, and that specialized
care may, in fact, reduce the frequency of extremely premature deliveries.
The risk of premature birth in triplets
The analysis of Alexander et al [7] and the more recent population-based data of
Ventura et al [8] demonstrate the axiomatic concept that singletons fare better than twins, and
that twins fare better than triplets, both in terms of gestational duration and birth weight. The
over-representation of multiples among LBW infants is accentuated for triplets, whereby the
risk of delivering extremely LBW (less than 1000 g) infants is 10 times higher than that it is
in the general population. [9] The odds of having at least one extremely LBW was 1:9, with
significantly higher odds among nulliparas (1:8) than among multiparas (1:14). [10] The
significance of these observations is highlighted by large series reporting 24 to 25 % major
neurological abnormalities among extremely LBW infants. [11]
Are very LBW triplets doing worse than very LBW twins and singletons?
A recent population-based study examined data from the Israel National very LBW
Infant Database. [12] The OR for RDS was without significant difference between triplets and
twins as were the OR for adverse neurological findings. The only significant complication
among triplets was the higher odds ratio for neonatal death – 1.5 vs. 1.1 in twins. The bottom
line of this study shows that plurality per se does not significantly influence short-term
outcome of very LBW infants, except for increased mortality rates among triplets.
The evidence for increased risk of cerebral palsy among triplets
Triplets have been associated with increased rates of cerebral palsy primarily because
they were over-represnted among premature and LBW infants.[13] The prevalence of cerebral
palsy in triplets exceeds that of twins and of singletons – 28 vs. 7.3 vs. 1.6 per 1000 survivors
to 1 year, and 44.8 vs. 12.6 vs. 2.3 per 1000 survivors. The data therefore indicate that the
Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 4
higher the plurality, the greater the prevalence of cerebral palsy. Moreover, the increase in
cerebral palsy with the number of fetuses bears a significant exponential relationship. [13]
However, these population-based data were accumulated over a very long time interval and
date to the mid 80’s. Thus, the true risk of CP in triplets under modern perinatal conditions is
expected to be lower.
Is there a difference in intrauterine growth of triplets?
A recent study examined individual as well as the total triplet growth patterns. The
relationships found support a model of two distinct growth periods for triplets: an age- and
growth-promoting period (until 33 weeks), and an age-promoting but growth-restricting
period thereafter. [14] The most important factor affecting the growth of triplets is maternal
parity. [14] The effect of parity on birth weight suggests that the uterine milieu of the
nullipara is less efficient in accommodating triplets than that of the multipara, a phenomenon
seen in twins as well. Another important factor affecting growth, independent of maternal
body mass index, was that taller mothers were more likely to deliver heavier triplets and were
at lower risk of delivering very low birth weight triplets. [15]
Finally, recent observations [16] suggest that birth weight discordance in triplets is more
frequent and of significantly greater severity compared with discordant twins. The high rate of
severe discordance may imply a physiological phenomenon and pertain to the different
individual growth pattern of triplets.
Outcomes of triplets
Few large-scale datasets include sufficient cases to draw meaningful conclusions about
outcome of triplets. Among these is a Canadian study [17] on triplets’ birth, which compared
the periods 1985-90 vs. 1991-1996. The stillbirth rate did not change significantly whereas
the infant mortality declined from 113 to 74 / 1000 live births, suggesting a temporal
Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 5
reduction in mortality associated with improved perinatal care. Newman compiled data from
12 studies published in the 1980’s and 1990’s from 471 pregnancies including 1413 triplets.
[18] The stillbirth rate was 32 /1000 and the neonatal mortality rate was 79/1000 for a
perinatal mortality of 109/1000. The perinatal mortality rate for triplets corresponds well with
a recent single-center experience of 100 consecutive triplet births. [19]
Conclusion
It goes without saying that triplets do worse than twins, and twins do worse than
singletons. [20] In such a construct, better results are expected after MFPR. However, given
the improved outcome and the declining perinatal mortality for triplets with modern perinatal
care – it is not anymore certain that MFPR is absolutely indicated in triplet gestations.
The arguments against MFPR in triplets are:
1. At the same time that the risk for delivering ELBW is much increased, there is still a
90% chance of delivering infants weighing >1000 g, for which survival is almost
granted by modern NICUs.
2. Despite the fact that the frequency of mothers over 40 with triplets is skyrocketing,
recent data clearly show that these mothers, in fact, do better than their matched-forparity young controls.
3. Data from the Israeli Neonatal Network of infants weighing <1500 g, definitely show
that triplets do not do worse than twins in terms of RDS, CLD, and adverse
neurological findings.
4. Data demonstrated that with close HRP observation, the frequency of “dangerously”
preterm birth (<28 weeks) can be significantly reduced.
5. Psychological morbidity associated with MFPR is a significant variable that cannot be
overlooked.
Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 6
6. Data from recent series on outcomes of triplets do not support an obstetrical reasoning
for MFPR
7. There are no randomized controlled trials to suggest that the overall risk of having
triplets is higher than the combined risk of MFPR and having twins.
In summary, MFPR in triplets cannot be recommended light-headedly. At this time, there
is no absolute proof that the risks associated with triplets outweigh the combined risks
associated with MFPR. Regrettably, triplets are undoubtedly at high risk for perinatal
complications. The future may be related to better understand maternal characteristics that
favor better outcomes of triplets in whom MFPR may not be indicated. [20]
Whereas contemporary neonatalogy and its interventions can save the lives of extremely
LBW and premature infants, no sure measures exist to prevent a significant proportion of
these babies from potential neurological morbidity. It is axiomatic that all triplets are highrisk pregnancies thus deserve optimal perinatal care irrespective of the mode of conception.
Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 7
References
1. Blickstein I. Spontaneous and induced triplets. In: Keith LG, Blickstein I.
Triplet pregnancies and their consequences. New York: The Parthenon
Publishing Group; 2002. pp.9-16.
2. Blickstein I, Keith LG. The epidemic of multiple pregnancies. Postgrad
Obstet Gynecol 2001; 21:1-7.
3. Blickstein I, Keith LG. Outcome of triplets and higher order multiple
pregnancies. Curr Opin Obstet Gynecol 2003; 15:113-7.
4. Zhang J, Meikle S, Grainger DA, Trumble A. Multifetal pregnancy in
older women and perinatal outcome. Fertil Steril 2002; 78:562-8.
5. Blickstein I, Keith LG. Aging, twinning, and perinatal outcome. Fertil
Steril, 2003; 79:661.
6. Blickstein I, Jacques DL. The Matria triplet database: 1988-2000. In:
Keith LG, Blickstein I. Triplet pregnancies and their consequences. New
York: The Parthenon Publishing Group; 2002. pp.267-291.
7. Alexander GR, Kogan M, Martin J, Papiernik E. What are the fetal
growth patterns of singletons, twins, and triplets in the United States?
Clin Obstet Gynecol 1998;41:114-25.
8. Ventura SJ, Martin JA, Curtin SC, Mathews TJ, Park MM. Births: final
data for 1998. Natl Vital Stat Rep 2000;28:1-100.
9. Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and
functional outcomes of extremely low birth weight infants in the National
Isaac Blickstein, MD – COGI5 – Who’s afraid of triplets ? 8
Institute of Child Health and Human Development Neonatal Research
Network, 1993-1994. Pediatrics, 2000; 105:1216-26.
10. Blickstein I, Jacques DL, Keith LG. The odds of delivering one, two or
three extremely low birth weight (<1000 g) triplet infants. J Perinat Med
2002; 30: 359-63.
11. Hack M, Willson-Costello D, Friedman H, et al. Neurodevelopment and
predictors of outcomes of children with birth weights of less than 1000 g.
Arch Pediatr Adolesc Med 2000; 154:725-31.
12. Shinwell ES, Blickstein I, Lusky A, Reichman B. Excess risk of mortality
in very low birth weight triplets: a national, population-based study. Arch
Dis Child Fetal Neonatal Ed 2003; 88:F36-F40
13. Blickstein I. Cerebral palsy in mutifetal pregnancies. Dev Med Child
Neurol 2002; 44:352-355.
14. Blickstein I, Jacques DL, Keith LG. Total and individual triplet birth
weigh as a function of gestational age. Am J Obstet Gynecol 2002;
186:1372-5.
15. Blickstein I, Jacques DL, Keith LG. The effect of maternal height on
gestational age and birth weight in nulliparous mothers of triplets with
normal pre-gravid body mass index, J Reprod Med 2003: 48:335-8.
16. Blickstein I, Jacques DL, Keith LG. A novel approach to intertriplet birth
weight discordance. Am J Obstet Gynecol 2003; 188:172-176.
17. Joseph KS, Marcoux S, Ohlsson A, et al. Preterm birth, stillbirth and
infant mortality among triplet births in Canada, 1985-96. Paediatr Perinat
Epidemiol 2002; 16:141-8.
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18. Newman RB. Management of triplets and other high order multiples. In:
Newman RB, Luke B. Multifetal pregnancy. Philadelphia: Lippincott
Williams & Wilkins; 2000. pp.192-219.
19. Devine PC, Malone FD, Athanassiou A, et al. Maternal and neonatal
outcome of 100 consecutive triplet pregnancies. Am J Perinatol
2001;18:225-35.
20. Blickstein I, Jacques DL, Keith LG. The likelihood of adverse outcomes
in triplet pregnancies estimated by pre-gravid maternal characteristics.
Fertil Steril; 2004; in press