Since the birth of Louise Brown in 1978, more than 1 million infants have been born as a result of in vitro fertilization (IVF). Severalfold more infants have resulted from less aggressive treatments. The price of use of assisted reproductive technologies (ARTs) has been a virtual epidemic of multifetal pregnancies. The twin pregnancy rate, historically accurate for generations as 1 in 90, has doubled to more than 1 in 45. In the 1990s, twin pregnancies rose 20% and triplets or more rose greater than 100% (Table 1).¹ Only since 2000 has the incidence of triplets begun to decrease slightly. The ratio of observed to naturally expected multifetal pregnancies shows that twins are more than double the expected rate. Quintuplets occur more than 1000-fold over expected numbers without infertility therapies (Table 2).

TABLE 1. Multiple Births in the United States

TABLE 2. Multiple Births in the United States^*

There continues to be controversy over the inherent risks of multifetal pregnancies. The major criteria for the extent of appreciated pregnancy losses relates to the gestational age at which one starts counting. There have been optimistic reports by some perinatologists who do not start counting until they begin to see patients at nearly 20 weeks. By that time, most of the losses already have occurred.² We previously estimated losses before viability from attempting to carry twins at 10%, triplets at 15%, quadruplets at greater than 25%, and quintuplets at 50%.² Serious morbidity rates also correlate with starting numbers, which directly relates to the incidence of premature deliveries.³

In the 1980s, in about 75% of patients with multifetal pregnancies seeking reduction, the pregnancies were initiated with ovulation induction agents, such as menotropins (Pergonal).⁴ We have seen even quintuplets, however, from the first month of the lowest dose of clomiphene citrate (Clomid). There has been a gradual shift to cases induced by ARTs, such as IVF. Currently, about 70% of cases of multifetal pregnancies are generated by ARTs.

Despite the increase in the use of ARTs,⁵ the proportion of cases that are badly hyperstimulated, resulting in quintuplets or more, has decreased dramatically to less than 10% risk. For cases of ovulation stimulation, however, particularly using urofollitropin (Metrodin), the proportion of cases that are quintuplets or more has decreased but not as dramatically. There has been no dramatic improvement in recent years. Such data continue to speak strongly toward the need to have significant vigilance in the monitoring of infertility therapies. Belief in this concept varies apparently from religious dogma to lip service. The conversion of apparent hyperstimulated induction cycles to IVF has been used by some centers to minimize the risk of multifetal pregnancies. Although most multifetal cases seem to be occurring to physicians with the best equipment and with the best of intentions, who have a reasonably unpredictable or unpreventable maloccurrence, there are some cases that might have been prevented if increased vigilance had been used.

Public fascination with multifetal pregnancies extends back more than 70 years, with the Dionne quintuplets in Ontario, Canada.⁶ In the 1980s, quintuplets piqued national interest, but now the bar continually rises higher and higher for lay press interest. In the early 1990s, sextuplets, such as the Dilly family in Indiana, drew several rounds of national media attention and got help from diaper companies, formula companies, crib companies, and the support of neighbors in their small town. The ultimate example of that was the MacCaughy septuplets in Iowa, where virtually the entire town of Carlyle, Iowa, was enlisted to help the family deal with the rigors of so many children at once. The family was given a van by a local automotive dealer, and the state of Iowa contributed a house. Miraculously, that pregnancy lasted until about 31 weeks, and the national media reported that all were doing well. Closer inspection revealed, however, that the presenting fetus was transverse, whose lie blocked the cervix from opening, rather than acting as the usual wedge to cause dilatation. Media reports of the children at age 4 reveal that two of them have been diagnosed with cerebral palsy, a fact that has been glossed over and explicitly ignored by the media, and a third is said to have epilepsy. Three children have required feeding tubes for nearly their entire life. The Houston octuplets in 1988 received much less attention. Whether this lack of attention was due to saturation of the concept of multifetal pregnancies, or (more likely) to the African origin of the couple is open for speculation. One of these infants died shortly after birth, and the other seven were said to be doing reasonably well at 3 years of age.

As a clinical procedure, multifetal pregnancy reduction (MFPR) began in the mid-1980s when a few centers in the United States and Europe attempted to ameliorate the usual, tremendously adverse sequelae of multifetal pregnancies by selectively reducing the number of fetuses to a more manageable number. The first European report by Dumez and Oury⁷ and the first American report by Evans and colleagues⁸ followed by reports by Berkowitz and associates⁹ and Wapner and coworkers¹⁰ laid out for physicians a possible dramatic surgical approach to improve the outcome in multifetal pregnancies. These early reports recognized, however, the ethical conundrum faced by couples and physicians under such difficult circumstances.⁸ In the mid-1980s, needles were inserted transabdominally and maneuvered into the thorax of the fetus despite relatively mediocre ultrasound visualization with mechanical destruction, air embolization, or potassium chloride injections. Transcervical aspirations also were tried, with little success. Some centers also used transvaginal mechanical disruption, but more recent data suggest a significantly higher loss rate than with the transabdominal route.¹¹

Today virtually all experienced operators perform the procedure inserting needles transabdominally under ultrasound guidance. We find it best to line up the needle with the thorax first in the longitudinal plane. Under transverse visualization, the needle is thrust carefully into the thorax, and a syringe is attached to the needle. Potassium chloride is injected slowly so as not to dislodge the needle tip. A pleural effusion should be seen and asystole.

Several centers with the world’s largest experience with MFPR have collaborated to leverage the power of their data. In 1993, the first collaborative report showed a 16% pregnancy loss rate through 24 completed weeks.¹² This rate was a major improvement compared with expectations of higher order multiple pregnancies, particularly of quadruplets and more. In 1994, 1996, and 2001, multicenter reports showed continued dramatic improvements in the overall outcomes of such pregnancies (Table 3).^13,14,15 The 2001 collaborative data show that the outcomes of triplets reduced to twins and quadruplets reduced to twins are essentially as if they started as twins (Fig. 1).¹ Even with the tremendous advances in neonatal care for premature infants, the 95% take-home baby rate for triplets and the 92% take-home baby rate for quadruplets are dramatic improvements over natural statistics. The pregnancy loss rate and the rate of very early prematurity have been reduced substantially. The loss and the prematurity rates continue to be a direct function of the starting number. There still is a price to be paid for overaggressive infertility therapies.

TABLE 3. Multifetal Pregnancy Reduction—Losses by Years

Most observers except those completely opposed to intervention on religious grounds accepted MFPR with quadruplets or more and saw no need at twins.¹⁶ The debate concerns triplets. Although there are conflicting data in the literature, our experience suggests that triplets reduced to twins do much better in terms of loss and prematurity than unreduced triplets. We believe that if a patient’s primary goal is to maximize the chances of healthy children, reduction of triplets to twins achieves the best results.

Several previous articles argued whether triplets have better outcomes, “reduced” or not. Yaron and colleagues¹⁷ looked at triplets reduced to twins and compared these data with unreduced triplets and with two large cohorts of twins. The data showed substantial improvement of reduced twins compared with triplets. The data from the most recent collaborative series suggest that pregnancy outcomes for cases starting at triplets or quadruplets reduced to twins do fundamentally as well as starting at twins and support some cautious aggressiveness in infertility treatments to achieve pregnancy in difficult situations. When higher numbers occur, good outcomes clearly diminish. A 2001 study suggested that reduced tiplets did worse than continuing ones. Analysis of that series showed, however, a loss rate after MFPR twice that seen in our collaborative series¹⁸ and worse outcome data in every other category for remaining triplets. One must use extreme caution in choosing comparison groups. Many other reports have compared reduced versus unreducedtriplets. The data show better outcomes with reduction (Table 4).

TABLE 4. Reduced Versus Unreduced Triplets Comparison

Pregnancy loss is not the only poor outcome. Very early premature delivery correlates with the starting number. The data on diminishing birth weight percentile in singletons and discordancy in twins are of concern, consistent with a belief that there is perhaps a fundamental “imprinting” of the uterus early in pregnancy that is not completely undone by MFPR.15,18

The subset of patients in the 2001 collaborative report reduced from two to one (not for fetal anomalies) included 154 patients. Nine patients lost their pregnancies before 24 weeks, and two delivered between 25 and 28 weeks. Although, in absolute terms, the numbers are not large compared with other categories, they suggest a loss rate comparable to 3 to 2. In an earlier series, in about one third of the two reduced to one cases, there was a medical indication for the procedure (e.g., maternal cardiac disease, prior twin pregnancy with severe prematurity, or uterine abnormality).¹⁴ In more recent years, most such cases are from women in their 40s or 50s who are using donor eggs, who, more for personal reasons than medical, want only a singleton pregnancy.¹⁹ The effect of maternal age per se is negligible, however, explaining only 3.5% of the variance, suggesting that with reduction, “older” gravidas do nearly as well as their younger counterparts.^14,19

The characteristics of patients seeking MFPR evolved in the 1990s.¹⁹ Particularly with the availability of donor eggs, the number of women older than age 40 seeking MFPR has increased dramatically. In several programs, more than 10% of all patients seeking MFPR are older than age 40, and most are using donor eggs. As a consequence of the shift to older patients, many of whom already had previous relationships and children, there is an increased desire by these patients to have only one child. The number of experienced centers willing to do two to one reductions is still limited, but we believe it can be justified in the appropriate circumstances.

Likewise, for patients who are older and using their own eggs, the issue of genetic diagnosis comes into play.²⁰ In the 1980s and early 1990s, the most common approach was to offer amniocentesis at 16 to 17 weeks on the remaining twins. One report suggested an 11% loss rate in these cases, which caused considerable concern.²⁴ A much larger collaborative series then settled the question, however, by showing that loss rates were no higher than comparable controls of MFPR patients who did not have amniocentesis.²⁵ The collaborative data shared a loss rate of 5%, which was no higher than the group of patients post-MFPR who did not have genetic studies.

Given that the centers with the most MFPR experience also happened to be the ones that had the same accomplishments with chorionic villus sampling (CVS), combinations of the procedures were logical. There have been two principal schools of thought as to the best approach to first-trimester genetic diagnosis: Should it be before or after the performance of MFPR? Published data in the early 1990s doing the CVS first followed by reduction suggested a 1% to 2% error rate as to which fetus was which, particularly if the entire karyotype is obtained before going on to reduction.²⁶ For the first 10 to 15 years, the approach that one of us used was to prefer generally to do the reduction first at approximately 10.5 weeks in patients reducing down to twins or triplets, followed by CVS approximately 1 week later. In patients going to a singleton pregnancy, however, we believed the best approach was to perform testing before reducing the other embryos.^15,19 In these cases, we did a CVS on usually all the fetuses or one more than the intended stopping number and performed a fluorescent in situ hybridization (FISH) analysis with probes for chromosomes 13, 18, 21, X, and Y. Although we have published about 30% of anomalies seen on karyotype that would not be detectable by FISH with these probes,²⁷ the absolute risk given a normal FISH and a normal ultrasound is about 1/500. We believe that risk is lower than the increased risk from the 2-week wait necessary to get the full karyotype. We commonly have extended this approach to all patients who are appropriate candidates for prenatal diagnosis regardless of the fetal number.

The other approach used by the Philadelphia group was to perform the CVS and complete karotype first and have the patient come back for the reduction. Although “mistakes” were common in the 1990s, the chance of error has been reduced considerably, and these investigators believed the benefits of the full karyotype justified the wait. The issue as to the better of these two approaches is currently unsettled.

MFPR continues to be controversial. In our experience, opinions about MFPR have not ever followed the classic “pro-choice/pro-life” dichotomy. Back in the mid to late 1980s, opinions about MFPR were highly varied. Even then, when much less was known about the subject, opinions did not always parallel the usual pro-choice/pro-life boundaries.^28,29,30,31 We believe that the real debate over the next 5 to 10 years will not be whether or not MFPR should be performed with triplets or more; the fact is that MFPR does improve those outcomes. A serious debate will emerge over whether or not it would be appropriate to offer MFPR routinely for twins, even natural ones for whom the outcome is commonly considered “good enough.” Our data suggest that reduction of twins to a singleton improves the outcome of the remaining fetus. No consensus on appropriateness of routine twin to singleton reductions is ever likely to emerge, however.

The ethical issues surrounding MFPR always will be controversial. Much has been written on the subject. Opinions always will vary substantially from outraged condemnation to complete acceptance. No short paragraph could do justice to the subject other than to state that most proponents do not believe MFPR is a frivolous procedure but do believe in the principle of proportionality (i.e., therapy to achieve the most good for the least harm).^{8,27,28,29,30,31}

Since the mid-1980s, MFPR has become a well-established and integral part of infertility therapy and attempts to deal with the sequelae of aggressive infertility management. In the mid-1980s, the risks and benefits of the procedure could only be guessed.^8,9,10 We now have clear, precise data on the risks and benefits of the procedure and an understanding that the risks increase substantially with the starting and finishing number of fetuses in multifetal pregnancies. The collaborative loss rate numbers—4.5% for triplets, 8% for quadruplets, 11% for quintuplets, and 15% for sextuplets or more—seem reasonable ones to present to patients for the procedure performed by an experienced operator. Our own experience and anecdotal experiences from other groups suggest that less experienced operators have worse outcomes.

Pregnancy loss is not the only poor outcome. The other main issue with which to be concerned is very early premature delivery.³² There is an increasing rate of poor outcomes correlated with the starting number. The finishing numbers also are crucial, with twins having the best outcomes for cases starting with three or more.¹⁵ Triplets and singletons do not do as well. We continue to hope, however, that MFPR will become obsolete as better control of ovulation agents and ARTs make multifetal pregnancies uncommon.

1. National Vital Statistics Report. 50:19, 2002

2. Evans MI, Rodeck CH, Stewart KS, et al: Multiple gestation: Genetic issues, selective termination, and fetal reduction. In Gleisher N, Buttino L Jr, Elkayam U, et al (eds): Principles and Practices of Medical Therapy in Pregnancy. pp 235, 242 3rd ed.. Norwalk, CT, Appleton & Lange, 1998

3. Shankaran S, Papile LA, Wright LL, et al: Neurodevelopmental outcome of premature infants after antenatal phenobarbital exposure. Am J Obstet Gynecol 187:171, 2002

4. Evans MI, Dommergues M, Wapner RJ, et al: Efficacy of transabdominal multifetal pregnancy reduction: Collaborative experience among the world’s largest centers. Obstet Gynecol 82:61, 1993

5. Evans MI, Littman L, St Louis L, et al: Evolving patterns of iatrogenic multifetal pregnancy generation: Implications for aggressiveness of infertility treatments. Am J Obstet Gynecol 172:1750, 1995

6. Evans MI, Fletcher JC: Multifetal pregnancy reduction. In Reece EA, Hobbins JC, Mahoney MJ, Petrie R (eds): Medicine of the Fetus and Its Mother. pp 1345, 1362 Philadelphia, Lippincott Harper Publishing, 1992

7. Dumez Y, Oury JF: Method for first trimester selective abortion in multiple pregnancy. Contrib Gynecol Obstet 15:50, 1986

8. Evans MI, Fletcher JC, Zador IE, et al: Selective first trimester termination in octuplet and quadruplet pregnancies: clinical and ethical issues. Obstet Gynecol 71:289, 1988

9. Berkowitz RL, Lynch L, Chitkara U, et al: Selective reduction of multiple pregnancies in the first trimester. N Engl J Med 318:1043, 1988

10. Wapner RJ, Davis GH, Johnson A: Selective reduction of multifetal pregnancies. Lancet 335:90, 1990

11. Timor-Tritsch IE, Peisner DB, Monteagudo A, et al: Multifetal pregnancy reduction by transvaginal puncture: Evaluation of the technique used in 134 cases. Am J Obstet Gynecol 168:799, 1993

12. Evans MI, Dommergues M, Wapner RJ, et al: Efficacy of transabdominal multifetal pregnancy reduction: Collaborative experience among the world’s largest centers. Obstet Gynecol 82:61, 1993

13. Evans MI, Dommergues M, Timor-Tritsch I, et al: Transabdominal versus transcervical and transvaginal multifetal pregnancy reduction: International collaborative experience of more than one thousand cases. Am J Obstet Gynecol 170:902, 1994

14. Evans MI, Dommergues M, Wapner RJ, et al: International collaborative experience of 1789 patients having multifetal pregnancy reduction: A plateauing of risks and outcomes. J Soc Gynecol Invest 3:23, 1996

15. Evans MI, Berkowitz R, Wapner R, et al: Multifetal pregnancy reduction (MFPR): Improved outcomes with increased experience. Am J Obstet Gynecol 184:97, 2001

16. Evans MI, Drugan A, Fletcher JC, et al: Attitudes on the ethics of abortion, sex selection and selective termination among health care professionals, ethicists and clergy likely to encounter such situations. Am J Obstet Gynecol 164:1092, 1991

17. Yaron Y, Bryant-Greenwood PK, Dave N, et al: Multifetal pregnancy reduction (MFPR) of triplets to twins: Comparison with non-reduced triplets and twins. Am J Obstet Gynecol 180:1268, 1999

18. Torok O, Lapinski R, Salafia CM, et al: Multifetal pregnancy reduction is not associated with an increased risk of intrauterine growth restriction, except for very high order multiples. Am J Obstet Gynecol 179:221, 1998

19. Evans MI, Hume RF, Polak S, et al: The geriatric gravida: Multifetal pregnancy reduction (MFPR) donor eggs and aggressive infertility treatments. Am J Obstet Gynecol 177:875, 1997

20. Baker C, Feldman B, Shalhoub AG, et al: Demographic determinants on the utilization of invasive genetic testing after multifetal pregnancy reduction (MFPR). Fetal Diagn Ther (in press)

21. Leondires MP, Ernst SD, Miller BT, et al: Triplets: Outcomes of expectant management versus multifetalreduction for 127 pregnancies. Am J Obstet Gynecol 72:257, 1999

22. Angel JL, Kalter CS, Morales WJ, et al: Aggressive perinatal care for high-order multiplegestations: Does good perinatal outcome justify aggressive assistedreproductive techniques? Am J Obstet Gynecol 181:253, 1999

23. Lipitz S, Shulman A, Achiron R, et al: A comparative study of multifetal pregnancy reduction fromtriplets to twins in the first versus early second trimesters afterdetailed fetal screening. Ultrasound Obstet Gynecol 18:35, 2001

24. Tabsh KM, Theroux NL: Genetic amniocentesis following multifetal pregnancy reduction twins: Assessing the risk. Prenat Diagn 15:221, 1995

25. McLean LK, Evans MI, Carpenter RJ, et al: Genetic amniocentesis (AMN) following multifetal pregnancy reduction (MFPR) does not increase the risk of pregnancy loss. Prenat Diagn 18:186, 1998

26. Brambati B, Tului L, Baldi M, Guercilena S: Genetic analysis prior to selective termination in multiple pregnancy: Technical aspects and clinical outcome. Hum Reprod 10:818, 1995

27. Evans MI, Henry GP, Miller WA, et al: International, collaborative assessment of 146,000 prenatal karyotypes: Expected limitations if only chromosome-specific probes and fluorescent in situ hybridization wereused. Hum Reprod 14:1213, 1999

28. Evans MI, Fletcher JC, Rodeck C: Ethical problems in multiple gestations: Selective termination. In Evans MI, Fletcher JC, Dixler AO, Schulman JD (eds): Fetal Diagnosis and Therapy: Science, Ethics, and the Law. pp 266, 276 Philadelphia, Lippincott Harper Publishing, 1989

29. ACOG Ethics Statement: Multifetal pregnancy reduction and selective fetal termination. The Committee onEthics, American College of Obstetricians and Gynecologists, November 1990

30. Chervenak FA, McCullough LB, Wapner R: Three ethically justified indications for selective termination in multifetal pregnancy: A practical and comprehensive management strategy. J Assist Reprod Med 12:531, 1995

31. Evans MI, Drugan A, Fletcher JC, et al: Attitudes on the ethics of abortion, sex selection and selective termination among health care professionals, ethicists and clergy likely to encounter such situations. Am J Obstet Gynecol 164:1092, 1991

32. ACOG practice: bulletin: Clinical Management Guidelines forObstetrician-Gynecologists: Number 38, September 2002. Perinatal careat the threshold of viability Obstet Gynecol 100:617, 2002