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Impact of multifetal pregnancy reduction; review of history of the clinical procedure and discussion of dramatic decrease in loss and prematurity rates.
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A pioneer in the field says that MFPR clearly improves higher-order pregnancy outcomes. But despite the clinical benefit, ethical concerns remain.
Modern infertility therapies have enabled tens of thousands of previously infertile women to have their own children. However, a virtual epidemic of multifetal pregnancies has been a by-product of this remarkable success. For generations, the rate of twin pregnancies had commonly been quoted as 1 in 90. That rate has now doubled to essentially 1 in 45. In the last 10 years alone, twin pregnancies have risen 20%, and triplets or higher-order births have increased well over 100% (Table 1). The ratio of observed-to-expected numbers of multifetal pregnancies shows that twins are being born at approximately twice the expected rate. Worse yet, the number of quintuplets now being born is more than 1,000-fold over numbers that would be expected without infertility therapies (Table 2).
|Year||Twins||Triplets||Quadruplets||Quintuplets and higher-order multiples|
|Quintuplets and higher-order multiples||79||0.06||1,316.7:1|
This paper tries to clarify some misperceptions about the outcomes of multiple pregnancies and traces the advent of the multifetal pregnancy reduction (MFPR) procedure for the purpose of dramatically improving outcomes in higher-order multiple pregnancies. While some conflicting data are still found in the literature with regard to triplets, our data on this controversial issue based on recent findings from collaborative studiesshow clear improvements with reduction.
Public fascination with multifetal pregnancies extends back to the 1930s, with the Dionne quintuplets in Ontario, Canada, and has not abated in the more than 60 years since. But whereas in the 1980s, a quintuplet birth would make the national news, the bar keeps getting set higher and higher for generating lay press interest.
The McCaughey septuplets of Iowa are the ultimate example of media attention to multiple births. In 1997, virtually the entire town of Carlisle, Iowa, was marshaled to help the family deal with the rigors of coping with so many children at once. A local automotive dealer donated a van 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 a different story, however. The presenting fetus was, in fact, a transverse lie, a position that fundamentally blocked the cervix from opening, rather than acting as the usual wedge to cause dilation. The media has glossed over and ignored unpublished assessments of the children at age 2, which reveal that two have cerebral palsy and a third is said to have a behavioral disorder.
A year later, the Houston octuplets received much less attention, due perhaps to saturation of the concept of multifetal pregnancies or that their parents' African roots were less appealing to the media. One of these fetuses died very shortly after birth; the other seven are said to be doing reasonably well.
Multifetal pregnancy reduction is a clinical procedure dating back to the mid-1980s. At that time, a handful of centers in both Europe and the United States were looking for a way to ameliorate the seriously adverse complications of many multifetal pregnancies. The approach they tried was to selectively terminate, or reduce, the number of fetuses to a more manageable number. Oury and colleagues published the initial European reports. The first American reports by my colleagues and me, as well as another study by Berkowitz and colleagues, laid out for physicians a possible dramatic approach to improving outcomes in higher-order multiple pregnancies. At the same time, we all recognized the ethical conundrum faced by couples and physicians under such difficult circumstances.
In the mid-1980s, despite relatively mediocre ultrasound visualization, needles were inserted transabdominally and maneuvered into the thorax of the fetus. That was then followed by either mechanical destruction, air embolization, or potassium chloride injections. Transcervical aspirations were also tried, without much success. Today, virtually all experienced centers perform transabdominal potassium chloride injections into the fetal thorax.
Outcomes improve dramatically. To leverage the power of their data, several centers with the world's largest experience began collaborating. The first collaborative report, published in 1993, showed a 16% pregnancy loss rate up through 24 completed weeks, which represented a big improvement compared with expectations of higher-order multiple pregnancies, particularly for quadruplets and above. Further collaborative efforts published in 1994, 1996, and 1999 have revealed continued dramatic improvements in the overall outcomes of such pregnancies (Table 3).
|Losses (%)||Deliveries (%)|
|Total (No.)||> 24 wks||2528 wks||2932 wks||3336 wks||37+ wks|
Overall outcomes of higher-order multiple pregnancies continue to improve dramatically.
Source: Adapted from Miller VL, et al. Multifetal pregnancy reduction: perinatal and fiscal outcomes. Am J Obstet Gynecol. 2000;182:1577.
A recent paper by Leondires and colleagues stated their data suggest that MFPR "does not have a significant impact on the probability of live birth or on gestational age at delivery for women with triplets conceived with ART." However, in their report, the rate of pregnancy loss following MFPR was substantially higher than in experienced centers, rendering the conclusions of this paper completely backwards, in our opinion. We believe that the real conclusion of this paper is that MFPR should be performed only by experienced operators.
The most recently presented collaborative datasummarized in Figure 1show that the outcomes of both triplets reduced to twins and quadruplets reduced to twins are now essentially as good as if the fetuses had started as twins. The 95% take-home baby rate for triplets and the 92% take-home baby rate for quadruplets are clearly dramatic improvements over natural statistics, even with tremendous advances in neonatal care. There have been substantial reductions in rates not only of pregnancy loss, but also of very early prematurity. Both the pregnancy loss and prematurity rates continue to be a function of the starting number, showing that there still is a real price to be paid for overaggressive infertility therapies (Figure 1). Pregnancy loss prior to viability is one of the two possible types of poor outcomes. The other is delivery in the 24- to 28-week windowa period in which there is an increasing likelihood of survival, but a significant risk of serious morbidity. MFPR has been shown to reduce both risks.
Analyzed further, the data suggest that improvements in MFPR outcomes are a function of extensive operator experience, combined with improved U/S. Historically, most observersexcept those completely opposed to intervention on religious groundsaccepted MFPR with quadruplets or more and saw no need to extend this approach to twins. The debate was over triplets. While conflicting data are reported in the literature, our experience suggests that triplets reduced to twins do much better in terms of loss and prematurity than do unreduced triplets. We believe that if a patient's primary goal is to maximize outcome, then reduction of triplets to twins is the safest course.
Changing demographics, different desires. The demographics of patients seeking multifetal pregnancy reduction have also changed over the past decade. Particularly with the availability of donor eggs, the number of "older" women seeking MFPR has grown dramatically. In several programs, more than 10% of all patients seeking MFPR are now over 40 years old and using donor eggs. Because of this shift to older patients, many more of these women have had previous relationships and children, and therefore increasingly desire to have only one more child. The number of experienced centers willing to do 2 to 1 reductions is still very limited, but I believe it can be justified in the appropriate circumstances. Likewise, for patients who are "older" using their own eggs, the issue of genetic diagnosis comes into play.
Timing of genetic diagnosis. There are two schools of thought on the best approach to genetic diagnosis: Should it be done before or after the performance of MFPR? The approach we have generally preferred at our institution over the years is to do the reduction first at approximately 10 1/2 weeks in patients reducing down to twins or triplets, followed by chorionic villus sampling (CVS) approximately 1 week later. Published data on doing the CVS firstfollowed by reductionhave suggested an error rate of between 1% and 2% of mistaking which fetus was which, particularly with the 2-week delay to get the entire karyotype before proceeding to reduction. However, particularly for patients reducing to a singleton pregnancy, who are therefore putting "all their eggs in one basket," we believe the best approach is to know what is in the basket before reducing the other embryos. We have also been increasingly willing to do CVS first in patients going to twins, because of greater numbers of "older" patients using their own eggs. For such patients, we usually do a CVS on all fetuses (Figure 2), and perform a fluorescent in situ hybridization (FISH) analysis with probes for chromosomes 13, 18, 21, X, and Y. While it is true that about 30% of anomalies seen on karyotype would not be detectable by FISH with these probes, the absolute risk given a normal FISH and a normal U/S is about 1 in 500. We believe that risk is lower than the increased risk from the 2-week wait necessary to get the full karyotype.
An ongoing controversy. MFPR continues to be controversial. In our experience, feelings about MFPR do not follow the classic "pro-choice/pro-life" dichotomy. Nevertheless, we believe that the real debate over the next 5 to 10 years will not be whether MFPR should be performed with triplets or higher-order births because MFPR does, in fact, clearly improve outcomes. The debate will be whether it would be appropriate to routinely offer MFPR for twins, for whom the outcome is generally considered "good enough." Our data suggest that reduction of twins to a singleton actually improves the outcome of the remaining fetus. No consensus on this point is likely to emerge.
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