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Isaac Blickstein, MD COGI5 Whos afraid of triplets ?

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For this reason, limited historical references to triplet pregnancy and birth exist.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 80s, and more than double the expected

value at the high-point of the epidemic at the mid-90s. [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 1970s.

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 Whos 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 Womens 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 Whos 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 Whos 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 80s. 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 reduction in
Isaac Blickstein, MD COGI5 Whos afraid of triplets ? 5

mortality associated with improved perinatal care. Newman compiled data from 12 studies

published in the 1980s and 1990s 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-for-

parity 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.
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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 high-risk

pregnancies thus deserve optimal perinatal care irrespective of the mode of conception.
Isaac Blickstein, MD COGI5 Whos 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 Institute of Child
Isaac Blickstein, MD COGI5 Whos afraid of triplets ? 8

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.
Isaac Blickstein, MD COGI5 Whos afraid of triplets ? 9

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

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