Multifetal pregnancy reduction and selective termination

Clin Perinatol 30 (2003) 623 – 641

Multifetal pregnancy reduction and selective termination Melissa C. Bush, MD, Keith A. Eddleman, MD* Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai School of Medicine, 5 East 98th Street, Box 1171, New York, NY 10029, USA

The incidence of multifetal pregnancies has increased markedly over the past 20 years because of advancements in assisted reproductive techniques. Despite efforts to avoid multifetal pregnancies, data from the National Center for Health Statistics indicates that from 1971 to 1998 the rate of twins increased from 1.8% to 2.8%, the rate of triplets increased 5.9-fold, and the rate of quadruplets increased 11-fold [1]. This dramatic increase in the number of multifetal pregnancies has driven physicians to develop techniques to deal with complications that arise as a result of these pregnancies. Multifetal pregnancy reduction (MPR) and selective termination (ST) are ultrasound-guided procedures that have evolved over the past 20 years [2,3]. While the technical aspects of the procedures are similar, the purpose and the long-term outcomes are different. MPR is the nonselective reduction of one or more fetuses in a multifetal pregnancy. The purpose is to reduce the number of fetuses in an attempt to prolong the pregnancy to a point at which it is likely to result in a term or near-term birth of the remaining fetus or fetuses, obviating the complications of extreme prematurity. ST is offered when a multifetal pregnancy has one or more fetuses that have a karyotypic, structural, or genetic abnormality. While the procedure was originally performed for major anomalies that result in survival of a severely impaired fetus, it also can be performed for a lethal anomaly. The purpose of ST is to continue the pregnancy with only a nonanomalous fetus or fetuses. This article discusses the natural history of multifetal pregnancies and the indications, techniques, risks, benefits, and alternatives for MPR and ST procedures. The psychological impact of MPR and ST is also addressed.

* Corresponding author. E-mail address: [email protected] (K.A. Eddleman). 0095-5108/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0095-5108(03)00055-1

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Natural history of multifetal gestations Prematurity Neonatal morbidity in a preterm delivery is generally inversely proportional to gestational age (GA) at delivery. In the majority of cases, a woman carrying two or more fetuses who delivers prematurely delivers all of her fetuses at the same time. Therefore, a patient carrying triplets or quadruplets who delivers significantly preterm has the potential of having three or even four infants that have major permanent disabilities including cerebral palsy, mental retardation, chronic seizure disorders, short gut syndrome, or blindness. While it is commonly known that perinatal and maternal morbidity and mortality increase with increasing numbers of fetuses, most published series contain small numbers of patients and lack data on long-term outcome. Most of the perinatal morbidity and mortality associated with a multiple pregnancy is related to prematurity, specifically to GA at delivery and birth weight. Table 1 illustrates the relationship between the number of fetuses and the rate of spontaneous loss before viability. The inverse relationship of GA at delivery and birth weight is also demonstrated [4]. Maternal complications and costs Maternal risks of higher-order multiple gestations can be significant. In a recent series of 100 patients carrying triplets from a single institution 96% had antepartum complications and 44% had postpartum complications including symptoms of preterm labor (PTL) (78%), pre-eclampsia (26%), preterm premature rupture of membranes (PPROM) (24%), anemia (24%), severe pre-eclampsia (19%), Hemolysis, elevated liver enzymes and low platelets (HELLP) (9%), acute fatty liver of pregnancy (4%), and eclampsia (1%) [5]. The median hospital stay was 11 days (range 1 – 110 days). The median GA at delivery was 33 weeks with 14% of pregnancies delivering before 28 weeks’ gestation. Although data are limited, the rate of maternal complications is presumed to be higher with an increasing numbers of fetuses.

Table 1 Mean spontaneous loss rates, gestational ages at delivery, and birthweights of twins, triplets, quadruplets, and quintuplets Type of fetuses

Spontaneous loss rate (%)

Mean gestational age at delivery (wk)

Mean birthweight (g)

Twins Triplets Quadruplets Quintuplets

6 11 Not available 16.7

35.3 33.5 30 28.9

2473 1666 1414 Not available

Twin, triplet, and quadruplet data from Stone J, Eddleman K. Multifetal pregnancy reduction. Curr Opin Obstet Gynecol 2000;12:491 – 6; quintuplet data from Francois K, Alperin A, Elliot J. Outcomes of quintuplet pregnancies. J Repro Med 2001;46:1047 – 51.

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Furthermore, the neonatal intensive care costs associated with triplets are significant. A 1994 study revealed that charges related to delivering a singleton were $9845. For twins the cost was $37,947 ($18,974 per baby) and for triplets the cost was $109,765 ($36,588 per baby). This study excluded charges associated with physicians’ services, treatment of infertility, outpatient management of highrisk pregnancies, loss of time from work for bed rest, or antepartum admissions [6].

Multifetal pregnancy reduction Historical aspects At the authors’ institution in 1981 Kerenyi and Chitkara performed the first ‘‘selective birth’’ in the United States by terminating the abnormal fetus in a twin pregnancy that was discordant for Down syndrome [7]. Dumez and Oury subsequently described a series of ‘‘selective abortions’’ on 15 women who had multifetal pregnancies and demonstrated the potential for reducing the risk of severe prematurity [8]. In that series the determining factor for selection was physical accessibility as opposed to anything intrinsic to the fetuses themselves. In 1988 Berkowitz et al reported the first series of ultrasound-guided transabdominal MPR [9]. The initial three procedures in that series were performed by suction aspiration using an 8-mm catheter according to the technique described by Dumez and Oury [8]. Although the first two procedures were uneventful, the third patient had a placental separation with vaginal bleeding during the procedure that was severe enough to require termination of the pregnancy. As a result of that experience physicians at the authors’ institution began using transabdominal intrathoracic injection of potassium chloride exclusively and currently continue to use that approach. Among the initial 12 patients there were four losses (33%). The term ‘‘selective reduction’’ was used initially to describe this procedure [9]. After reflecting on the psychological stress imparted to couples with the implication that they had to ‘‘select’’ which fetus or fetuses to terminate, the terminology was changed to ‘‘multifetal pregnancy reduction,’’ thus distinguishing this procedure from ‘‘selective termination’’ [10]. The most recent American College of Obstetricians and Gynecologists Committee Opinion endorses this terminology [11]. Technical aspects Transabdominal potassium chloride injection—Mount Sinai experience The technical aspects of the procedure have been reviewed in detail elsewhere, but they will be reviewed here briefly [2]. At Mount Sinai each patient undergoes an extensive consultation with the physician who will perform the procedure, at which time the risks and benefits of MPR are discussed in detail. Before the session, patients watch a 30-minute videotape outlining the natural history of multifetal pregnancies and the institution-specific statistics on expected outcomes.

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Whenever possible, the MPR is performed on a day other than the day of counseling to give couples sufficient time to process the wealth of information that is discussed. In cases of travel from great distances, however, exceptions are made. Not all patients who undergo counseling for MPR end up having the procedure performed. The authors feel, however, that all patients carrying a higher-order multifetal pregnancy should undergo rigorous counseling about the risks involved and about the option of MPR so that they can make an informed decision about how to manage their pregnancies. The procedure is performed in the ultrasound unit with an intravenous line for a single dose of cefazolin (1 g) or clindamycin (600 mg). Local anesthesia is used on the skin. Under ultrasonographic visualization using a free-hand technique a 22-gauge spinal needle is inserted into the thorax of the fetus to be terminated. Potassium chloride (2 mEq/mL) is injected in aliquots of 2 to 3 mEq until asystole achieved. Asystole is observed for at least 2 minutes before removal of the needle. The procedure is repeated for each fetus to be terminated. Unless significant discrepancies in the sizes of the fetuses or gross anomalies are noted, the selection of the fetuses to be terminated is based on the technical ease with which the procedure can be performed. The fetus in the sac over the internal cervical os is left alone unless abnormalities are noted in that fetus or none of the other fetuses is approachable technically. After the procedure the patient is observed in the waiting area for 1 hour to monitor for evidence of progressive uterine cramping, vaginal bleeding, or leakage of fluid. An ultrasound is then repeated to confirm normal cardiac activity in the nonreduced fetuses and the absence of cardiac activity in the reduced fetuses. The patient is then discharged to home and instructed to watch for nonspecific signs of infection such as fever, malaise, or abdominal pain. Patients are advised to maintain a period of reduced activity for 2 to 3 days and to follow up with their physicians 2 weeks after the procedure. MPR is typically performed between 10 and 14 weeks’ gestation. Before 10 weeks it is technically more difficult to perform transabdominal procedures because of the small fetal size and greater distance from the maternal abdominal wall to the fetuses when the uterus is confined to the pelvis. Another advantage of waiting until 10 weeks is that before that time spontaneous loss of a fetus could occur, which would obviate the need to perform MPR. In addition, waiting increases the chances of detecting an intrinsic growth delay in one of the fetuses so that fetus can be targeted for reduction if such a difference exists. Pregnancy loss—Mount Sinai. MPR is an invasive procedure and, as such, carries an intrinsic risk for pregnancy loss. When analyzing complete pregnancy loss rates it is important to consider background losses that would have occurred regardless of whether or not MPR was performed. Aggregate data since 1991 from 10 studies on 332 patients who had triplets reveal a mean spontaneous loss rate before 24 weeks of 11% (Table 1) [3]. In 1999 Yaron et al reported a 6% loss rate in reduced and nonreduced twins compared with a 25% loss rate in 12 sets of nonreduced triplets (Table 2) [12]. This study suggests that the procedure-related component of the overall pregnancy loss rates after MPR is small.

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Table 2 Pregnancy outcomes in nonreduced triplets, in triplets reduced to twins, and in two groups of nonreduced twins Group

No.

Miscarriage rate (%)

Duration of gestation (wk)

Delivery at 25 – 28 wk (%)

Birthweight (g)

Nonreduced triplets MPR twins Twins (Quest) Twin (WSU)

12 143 207 605

25 6.0 5.8 6.3

32.9 35.6 35.8 34.4

25 4.9 7.7 8.4

1636 2381 2254 2123

Adapted from Yaron Y, Bryant-Greenwood PK, Dave N, Moldenhauer JS, Kramer RL, Johnson MP, et al. Multifetal pregnancy reductions of triplets to twins: comparison with nonreduced triplets and twins. Am J Obstet Gynecol 1999;180(5):1268 – 71.

In a recently published series of 1000 MPR procedures performed at Mount Sinai, the unintended pregnancy loss rate was 5.4% [13]. The unintended pregnancy loss rate in the first 4 weeks postprocedure was 0.8% (Table 3). Thirty of 54 (55.6%) of the losses in that series occurred more than 8 weeks postMPR, a time when many spontaneous losses occur in twins. The overall loss rate is similar to that associated with other needle-guided procedures (ie, amniocentesis and chorionic villus sampling [CVS]) and might reflect the procedurerelated risks of MPR more accurately. It is impossible to determine whether these later losses were caused by the MPR procedure itself or related to the spontaneous loss rate in twins because the majority of patients in that series reduced to twins. Loss rates after MPR have been shown to decrease with increasing operator experience. In the first 200 cases at Mount Sinai the loss rate was 9.5% [14], but it fell to and remaining stable at 4.5% to 6.0% over the next 800 cases. The loss rate was lowest with a starting number of two fetuses (2.5%), it remained stable for three, four, and five fetuses, then it increased to 12.9% with a starting number of six or more fetuses (Table 4). Loss rates were similar with a finishing number of one or two fetuses (3.5% and 5.5%, respectively) but were highest with a finishing number of three fetuses (16.7%; Table 5). To determine risk factors for loss the authors compared patients who had pregnancy loss after MPR matched by starting and finishing numbers of fetuses to patients underwent MPR but did not sustain a pregnancy loss [15]. Bleeding

Table 3 Gestational age at unintended pregnancy loss Weeks postprocedure

No. (%) of losses

% total

<4 4–8 >8

8/54 (14.8) 16/54 (29.6) 30/54 (55.6)

0.8 1.6 3.0

From Stone J, Eddleman K, Lynch L, Berkowitz RL. A single center experience with 1000 consecutive cases of multifetal pregnancy reduction. Am J Obstet Gynecol 2002;187(5):1163 – 7; with permission.

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Table 4 Unintended loss rate by starting number of fetuses Starting number of fetuses (n)

Unintended loss rate (%)

2 (40) 3 (549) 4 (294) 5 (86) 6 + (31)

2.5 5.3 5.4 4.7 12.9

From Stone J, Eddleman K, Lynch L, Berkowitz RL. A single center experience with 1000 consecutive cases of multifetal pregnancy reduction. Am J Obstet Gynecol 2002;187(5):1163 – 7; with permission.

within 2 weeks before consultation for MPR was the only independent risk factor for pregnancy loss that was identified. Nulliparity, history of preterm delivery, history of incompetent cervix, and uterine abnormalities were not risk factors. A history of a prior full-term delivery showed a trend toward a protective effect. Gestational age at delivery – Mount Sinai. In the authors’ series of 1000 consecutive MPRs, 941 of 1000 patients (94.1%) delivered at greater than or equal to 24 weeks with a mean GA at delivery of 35.6 weeks [13]. More than half (56.9%) delivered at greater than or equal to 36 weeks, and only 32 (3.4%) delivered between 24 and 28 weeks. No significant differences in this significantly early prematurity rate were seen with a starting number of three, four, five, or greater than or equal to six fetuses (Table 6). This finding is in contrast to Evans et al’s multicenter 1074 fetus series, which showed that significantly premature delivery was correlated with the starting number of fetuses [16]. Analysis of birth weights among the 1000 cases showed a linear decline with increasing starting (Fig. 1) and finishing numbers. The pathophysiology underlying this phenomenon is uncertain, but it has been suggested that there might be a fundamental ‘‘imprinting’’ of the uterus early in pregnancy that is not eliminated by MPR [17]. While patients who finished with two or three fetuses delivered at the same mean GA as that observed for nonreduced twins and triplets (ie, 35.3 and 33.5 weeks, respectively), patients reduced to a singleton delivered approximately 2 weeks earlier than anticipated for spontaneous singletons. No patient who ended with a singleton delivered before 28 weeks and only 4.5% delivered before 32 weeks.

Table 5 Unintended loss rate by finishing number of fetuses Finishing number of fetuses (n)

Loss rate (%)

1 (118) 2 (864) 3 (18)

3.4 5.5 16.7a

a P = 0.03 for one or two versus three fetuses. From Stone J, Eddleman K, Lynch L, Berkowitz RL. A single center experience with 1000 consecutive cases of multifetal pregnancy reduction. Am J Obstet Gynecol 2002;187(5):1163 – 7; with permission.

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Table 6 Gestational age at birth according to starting number of fetuses Starting No.

Mean (wk)

24 – 28 wk No. (%)

28 – 32 wk No. (%)

32 – 36 wk No. (%)

36+ wk No. (%)

2 (n = 39) 3 (n = 515) 4 (n = 278) 5 (n = 82) 6 + (n = 27) Total (n = 941)

38.1 35.8 35.3 34.7 34.6 35.6

0 16 10 5 1 32

1 40 28 8 3 80

2 153 90 36 13 294

36 306 150 33 10 535

(0) (3.1) (3.6) (6.1) (3.7) (3.4)

(2.6) (7.8) (10.1) (9.8) (11.1) (8.5)

(5.1) (29.7) (32.4) (43.9) (48.2) (31.2)

(92.3) (59.4) (54.0) (40.2) (37.0) (56.9)

From Stone J, Eddleman K, Lynch L, Berkowitz RL. A single center experience with 1000 consecutive cases of multifetal pregnancy reduction. Am J Obstet Gynecol 2002;187(5):1163 – 7; with permission.

Pregnancy loss: international experience. In the most recent international collaborative series Evans et al reported on 3513 MPRs (including those at Mount Sinai) from five countries [17]. All procedures were done by transabdominal potassium chloride (KCl) injection except 331 that were done transvaginally by one group. The overall loss rate was 9.6% with loss rates varying depending on the starting and finishing numbers of fetuses. Significantly early preterm delivery (25 – 28 weeks’ gestation) also correlated with the starting number of fetuses. Data by finishing number demonstrated that twins had the best outcomes. Although differences between twins and singletons were small, both groups had significantly lower loss rates than did the group ending with triplets. Loss rates with transabdominal procedures were lower than those done transvaginally (8.5%

Fig. 1. Mean birth weights according to starting number of fetuses. (From Stone J, Eddleman K, Lynch L, Berkowitz RL. A single center experience with 1000 consecutive cases of multifetal pregnancy reduction. Am J Obstet Gynecol 2002;187(5):1163 – 7; with permission.)

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versus 25.4%). The authors believe that the lower loss rates observed at Mount Sinai as compared with the international series is likely a result of having a small number of operators performing the procedure, strict adherence to an established protocol, and use of the transabdominal approach only. Transvaginal multifetal pregnancy reduction In 1993 Timor-Tritsch et al reported on 134 patients in whom MPR was accomplished with intrathoracic KCl by insertion of a needle attached to the transvaginal ultrasound probe or by an automatic spring-loaded device [18]. There were three clinically apparent infections, two of which responded to antibiotics. Uncontrolled infection in the third patient required uterine evacuation. The uncorrected loss rate in that series was 12.6%. There was no difference in the loss rate when the fetus in the sac overlying the internal os was terminated. In 1999 Mansour et al reported a modification of transvaginal MPR done under general anesthesia using propofol [19]. In their series the first 30 MPRs were performed by way of transvaginal KCl injection between 6 and 9 weeks’ gestation with a loss rate of 30%. The next 45 patients in their series underwent transvaginal suction aspiration with an ooctye retrieval needle and a 20-cc syringe until all (or most) of the fetal parts were aspirated. KCl was not used in those fetuses and the loss rate was 8.8%. While this is an interesting approach to early MPR, these findings are based on a small number of patients. In 2000 Ibe´rico et al reported on 149 cases of MPR performed at a mean GA of 7.8 weeks done by way of transvaginal puncture of the fetal heart [20]. The procedure was also done under general anesthesia using propofol. They also used a 30-cm-long, 1.8-mm outer diameter needle that was identical to those used for ovarian follicular puncture and punctured the heart until asystole was achieved without the injection of any substance. They specifically avoided any aspiration of embryonic tissues or amniotic fluid. The pregnancy loss rate in that series was 7.3%. Other complications included chorioamnionitis (1.3%) and transient spotting (11.4%). The ‘‘take-home baby’’ rate was 89.5% for twins and 80.0% for singletons. Paradoxically, the birth weight of singletons after MPR using this technique was lower than that of nonreduced singletons (2929 ± 160 versus 3291 ± 422 g). Does multifetal pregnancy reduction from three to two improve outcomes? The observed loss rate at Mount Sinai of 5.4% after MPR is similar to the 6% background loss rates in twins and lower than the 11% background loss rate in triplets. Thus, reducing to twins as opposed to carrying triplets appears to result in lower rates of pregnancy loss at less than 24 weeks’ gestation. Similarly, the mean GA at delivery of twins was 35.6 weeks in the authors’ series versus 33 weeks for triplet gestations [3]. The difference in the means of 2.5 weeks’ gestation is important, but to answer the question posed previously one needs to evaluate the rates of extreme prematurity in reduced and nonreduced triplets. Three early studies [21 –23] showed a decrease in the proportion of patients undergoing MPR who

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delivered before 32 weeks’ gestation. They also showed decreased perinatal mortality and respiratory distress syndrome (RDS). Two of the three showed decreased intraventricular hemorrhage (IVH). In a recent review Yaron et al compared 143 triplets who underwent MPR with groups of nonreduced triplets and twins [12]. They also found that twins after MPR had lower rates of severe prematurity, a longer mean GA, and higher birth weights compared with triplets that were managed expectantly. These favorable outcomes were comparable to those of nonreduced twins, so they concluded that MPR from triplets to twins is medically justifiable. Larger studies are needed, however, to resolve this question definitively. Intrauterine growth restriction It has been suggested that reduced twins are at a higher risk for intrauterine growth restriction (IUGR) than nonreduced twins [24 – 26]. A larger data set from the authors’ center using growth curve norms for twins suggests that rates of IUGR are increased in pregnancies that have a starting fetal number of five or more (23.1%) compared with pregnancies reduced from triplets or quadruplets (12.1%) [27]. This difference disappeared when these groups were compared with singleton norms. Depp et al also found that the incidence of IUGR (determined by a singleton curve) rose steadily from 19% in nonreduced twins to 50% in those reduced from greater than or equal to five fetuses [24]. These authors suggested that ‘‘crowding in utero’’ before MPR leads to subsequent limitation of placental expansion and growth, which leads to IUGR. Placental analysis to support this theory has not yet been done. Prenatal diagnosis and multifetal pregnancy reduction Because many women who conceive with assisted reproductive techniques (ARTs) spend a considerable number of years attempting to become pregnant, their age-related risk of aneuploidy is often significant. Furthermore, the numerical risk of aneuploidy (1:270 at term, a risk traditionally used for offering invasive testing) in at least one fetus in a 31-year-old white or African American woman carrying twins is similar to that of a 35-year-old woman carrying a singleton [28]. With higher-order multiples this age is expected to be even lower. There are two options available for prenatal diagnosis in patients contemplating MPR. One option is to undergo the MPR then 4 weeks later undergo amniocentesis on the remaining fetuses at 16 to 18 weeks’ gestation. Selam et al found that the pregnancy loss rate in patients at the authors’ center who underwent amniocentesis after MPR was 4 of 127 (3.1%) compared with 12 of 167 (7.2%) in those who did not undergo genetic amniocentesis [29], but this difference was not statistically significant. A multicenter group also found a 5.1% loss rate in the amniocentesis group versus 11.2% in those who underwent MPR without amniocentesis, a difference that was not statistically significant [30]. These studies suggest that genetic amniocentesis after MPR does not introduce an additional risk of pregnancy loss. The major drawback to amniocentesis after MPR is that if one

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of the remaining fetuses is found to be chromosomally abnormal, then the patient is forced to decide to either carry the abnormal fetus, terminate the pregnancy, or undergo yet another procedure to selectively terminate the abnormal fetus. The second option is to have CVS performed before the MPR, thereby assuring that karyotypically normal fetuses are left behind. In 1995 Brambati et al reported that 69 women who underwent CVS before MPR had no higher loss rates than women undergoing MPR without CVS [31]. They reported a sampling error rate of 1% to 2%, a rate consistent with other studies of CVS in multiple gestations. The authors recently reported the results of 86 patients undergoing CVS before MPR [32]. Placentas that were adjacent to each other were sampled by directing the catheter or needle tip to the portion of the placenta furthest from the adjacent placenta to minimize the chances of a sampling error. We waited for the long-term culture results before performing MPR, typically 1 week. In this series 165 of 166 fetuses were sampled successfully (99.4%). Three out of 164 fetuses (1.8%) had karyotypic abnormalities. Two out of 164 fetuses (1.2%) had probable sampling errors. The total loss rate (after the CVS and MPR) for these patients was 1.4%, which is significantly less than the overall loss rate for MPR at the authors’ center (5.4%) but based on a much smaller number of patients. This study demonstrated that CVS before MPR is technically feasible, reasonably accurate with acceptably low sampling error, and that pregnancy loss rates after MPR did not appear to be increased as a result of CVS. While at the beginning of the study only fetuses targeted to remain after the MPR were sampled, as it became apparent that CVS before MPR was safe sampling of additional fetuses was offered. The authors currently believe that CVS is the method of choice in patients undergoing invasive prenatal diagnosis and MPR. Because 1 to 2 weeks might elapse between the time of the CVS and the MPR, it is essential that the person performing the CVS draws a careful map of all fetuses and placentas so that they can be identified correctly should a karyotypic abnormality be found. For women who desire noninvasive screening the authors now offer nuchal translucency measurements. As part of a research protocol (a subset of the First and Second-Trimester Evaluation of Risk for aneuploidy, the FASTER trial [33]) patients are given a fetus-specific risk of aneuploidy based on singleton nuchal translucency (NT) norms for each fetal crown rump length. If one fetus has an increased risk that fetus is targeted for termination at the time of MPR. As part of this protocol first-trimester serum markers are measured, but they are not yet being used for risk calculation. Follow-up after multifetal pregnancy reduction Following MPR most patients return to their referring physicians for the remainder of their obstetrical care and delivery. They are advised not to undergo second-trimester multiple marker screening because there is no diagnostic value in these tests after MPR. Evidence for this recommendation is from the authors’ data showing that maternal serum a-fetoprotein (MSAFP) levels in 57 women

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who underwent MPR to twins were higher than would be expected for twins of the same GA [34]. The mean value obtained was 11.6 multiples of the median (MoM) (range 3.9 –47 MoM). A positive correlation was demonstrated between the MSAFP value and the number of reduced fetuses, which implies that the observed elevations do not necessarily reflect a morphologic abnormality in the surviving fetuses but the release of material from those that have been terminated. The authors therefore recommend that patients undergoing MPR have a comprehensive anatomic survey of the surviving fetuses in the mid-second trimester and that maternal multiple marker determinations are not performed. Psychological aspects The psychological impact of MPR is less well studied than other aspects of the procedure. Ninety-one of the first 100 MPR patients at the authors’ institution agreed to participate in a retrospective telephone survey to assess their emotional reactions and attitudes toward MPR. More than 65% recalled acute feelings of emotional pain, stress, and fear during the procedure. Seventy percent said they mourned for the lost fetuses, with a mean grieving period of 3.2 months. An anniversary grief reaction to the loss of the reduced fetuses was experienced by 37% of the patients [35]. The frequency of viewing the fetuses by ultrasound before MPR was significantly related to the intensity of the grief feelings that persisted at the time of the interview. Despite feelings of grief, 93% said they would make the decision to undergo MPR again. Garel et al prospectively compared psychological outcomes in MPR patients with women who delivered nonreduced triplets. MPR was experienced as stressful and distressing for a majority of those women [36]. Terminating one or more of the fetuses represented a dilemma that provoked intense feelings of sadness and guilt. Most of the women in that study were able to overcome the initial acute emotional pain and, in fact, reported better psychological health and relationships with their children 2 years later than did mothers of nonreduced triplets. A smaller study of 26 patients showed that none had depression and all but one believed they had made the right decision [37]. These studies are encouraging, but more data are needed to confirm these findings. The authors currently have several institutional review board-approved protocols to study these issues. Ethics Is it ethically acceptable to terminate presumably healthy fetuses to increase the potential for others in a multifetal pregnancy to survive and lead healthy lives? The medical justification for MPR is philosophically similar to the ‘‘lifeboat analogy,’’ which is that some drowning individuals can be legitimately denied access to an overcrowded lifeboat if bringing them aboard will cause it to sink and result in the loss of additional lives. Several reviews discussing the ethical justification for MPR have been published [38,39] offering the option that MPR is medically

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justifiable from the ethical perspective of supporting patients’ autonomy and respect for patients’ individual circumstances [12]. These arguments become more controversial when a smaller starting number of fetuses is considered. Controversies surrounding multifetal pregnancy reduction Multifetal pregnancy reduction to a singleton The majority of patients undergoing MPR reduce to a twin gestation, but some patients decide to reduce to a singleton for indicated or elective reasons. Examples of medically indicated reductions to a singleton are a prior history of incompetent cervix, uterine abnormalities, or a prior history of preterm delivery. When the authors first began performing the procedure, reduction to a singleton was performed only for medical indications. When information regarding the risks of the procedure became available the authors began offering it for purely elective reasons. Of the first 200 cases at Mount Sinai 3% chose reduction to a singleton versus 18.5% of the most recently published 200 cases [13]. While the authors’ series of 1000 MPR cases suggested that reduction to a singleton was associated with the lowest loss rates and lowest chances of preterm delivery, other series have not [16,17]. The authors do not believe there are enough data at this time to recommend that women opting for MPR should be routinely counseled to reduce to a singleton rather than twins. An exception to this opinion is patients who present with triplets in which there is a monochorionic twin gestation. Because of the increased risks inherent to monochorionicity, the authors advise these patients to consider reducing the monochorionic twins and continuing with a singleton gestation. Following cervical length after multifetal pregnancy reduction Several of the pregnancy losses many weeks after MPR have presented with signs and symptoms suggestive of an incompetent cervix. For that reason the authors have recommended that patients have an ultrasound assessment of the cervix every 2 weeks between 16 and 22 weeks’ gestation. It is unknown, however, whether or not this assessment can definitively affect rates of loss or preterm delivery. The authors’ group analyzed data from 104 patients who underwent cervical length assessment after MPR and found that 12.5% had funneling at the internal cervical os (Bush et al, manuscript in preparation). Funneling was associated with adverse perinatal outcome, which is defined as pregnancy loss or delivery before 28 weeks when present at 18 or 22 weeks. Patients who had adverse outcomes had a significantly shorter cervical length at 22 weeks (18 mm versus 38 mm; P = 0.02). A cervix of greater than or equal to 40 mm was predictive of delivery greater than or equal to 34 weeks, whereas a cervix less than or equal to 20 mm at 20 weeks was predictive of delivery at less than 34 weeks. Neither cervical length nor funneling was an independent predictor of pregnancy loss, but a power calculation demonstrated that 418 patients would have been required to demonstrate a 50% reduction in the rate of pregnancy loss from 6% to 3%.

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Avoiding multifetal pregnancy reduction on the presenting fetus Historically, the fetus in the sac overlying the internal os was typically not reduced because of the theoretical concern that material from the sac of the dead fetus could elicit an inflammatory response that might predispose the patient to pregnancy loss or preterm delivery. Analyses of placentas from MPRs done at Mount Sinai show that the majority of patients who underwent MPR did not develop a chronic inflammatory response to the process of resorbing the placental tissues of the reduced fetuses [40]. This concept of avoiding the reduction of fetus A is now being reconsidered because of ST data that will be presented in the next section.

Selective termination The rate of occurrence of a multifetal pregnancy in which one or more fetuses is abnormal has increased because the sheer number of multifetal pregnancies has increased. The likelihood of finding an anomaly in twins is more than twice the basic risk in a singleton pregnancy, and discordance for structural anomalies is common in both monozygotic and dizygotic twins. Twin gestations complicated by a single anomalous fetus show a significantly lower GA at delivery and birth weight and a higher rate of perinatal mortality and Cesarean delivery than normal twin pregnancies [41]. Patients with this problem have three options: (1) continue the pregnancy with both the normal and the abnormal fetuses, (2) terminate the pregnancy, or (3) selectively terminate the abnormal fetuses. Pregnancy loss Early series of patients undergoing ST in the1980s indicated high pregnancy loss and perinatal morbidity rates, which were probably related to the monochorionic pregnancies included in those series [42]. The first international collaborative experience of 183 cases revealed an 8.3% (13 of 156) loss rate by KCl injection and a 41.7% (10 of 24) loss rate by air embolization [43]. Three cases of ST in monochorionic twins resulted in pregnancy loss. A single center series of 100 consecutive cases of ST was published from the authors’ institution in 1997. That series showed that ST was associated with an unintended pregnancy loss rate of 3% [2]. The procedures were performed between 12 weeks and 23.3 weeks. Eighty-five percent of patients not experiencing a pregnancy loss delivered after 32 weeks. The 1999 international experience described 400 cases including patients from Mount Sinai. The overall spontaneous loss rate in that series was 7.5%, but it exceeded 12% when women started with three or more fetuses [42]. There was a progressive increase in loss rates in relation to the GA at which the ST was performed: 5.4%, 8.7%, 6.8%, and 9.1% for procedures performed between 9 to 12 weeks, 13 to 18 weeks, 19 to 24 weeks, and greater than or equal to 25 weeks, respectively, but these differences did not reach statistical significance. As

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expected, loss rates did not vary by indication. There were no instances of a clinically significant coagulopathy in mothers or ischemic damage or coagulopathy among surviving neonates caused by retention of a terminated fetus. Seventy-eight percent of all viable deliveries in that series occurred after 33 weeks and only 6% occurred at 25 to 28 weeks. Outcomes The authors recently published a single-center experience of ST in 200 patients between 1986 and 2000 [44]. There were 164 sets of twins, 32 triplets, and four quadruplets. The average GA at the time of ST was 19.2 weeks (range 12– 23.9 weeks). One hundred (50%) were performed on fetuses that had chromosomal abnormalities, most commonly Down syndrome. Eighty-seven (43.5%) had structural anomalies and 13 (6.5%) had other abnormalities. There were six cases in which two fetuses were terminated (three involving conjoined twins and three involving two fetuses that had anomalies). The presenting fetus was terminated in 91 (45.5%) cases. There were eight (4%) unintended pregnancy losses at less than 24 weeks, four of 164 (2.4%) in twins, four of 32 (12.5%) in triplets, and zero of four in quadruplets. Thus, the loss rate in patients carrying three or more fetuses was almost 5-fold higher than in patients carrying twins (11.1% versus 2.4%). The time of pregnancy loss averaged 3 weeks postprocedure (range 3 days – 5 weeks). The mean GA at delivery in the remaining 190 patients was 36.1 weeks. One hundred sixty (84.2%) patients delivered at or beyond 32 weeks’ gestation (Fig. 2). In that series there was a trend toward a higher rate of pregnancy loss in patients undergoing ST at less than or equal to 20 weeks (seven of 119; 5.9%)

Fig. 2. GA at delivery in 200 fetuses from gestations that underwent ST. (From Eddleman KA, Stone JL, Lynch L, Berkowitz RL. Selective termination of anomalous fetuses in multifetal pregnancies: 200 cases at a single center. Am J Obstet Gynecol 2002;185:1170; with permission.)

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compared with those who had their procedures performed at greater than 20 weeks (one of 79; 1.3%), but this difference failed to reach statistical significance. This finding serves to dispel a perception that performing the procedure after 20 weeks might increase the risk of pregnancy loss. The finding is also in contrast to a 1996 Mount Sinai study [45] reporting that patients who underwent ST after 20 weeks had a higher rate of preterm delivery than those who underwent the procedure at or before 20 weeks. The authors’ most recent data can reassure patients whose fetal abnormalities are not diagnosed until after 20 weeks’ gestation that their risk for loss after ST is not higher. Similar to what has been shown with MPR, this series concluded that smaller starting and finishing numbers of fetuses are associated with longer gestation. Patients presenting with twins delivered later than those presenting with triplets or quadruplets (36.6 weeks versus 33.6 weeks). There was also a significant difference in mean GA at delivery in patients ending with one fetus compared with those ending with two or more fetuses (36.5 weeks versus 33.5 weeks). Although the authors’ data revealed that loss rates are not affected by which fetus undergoes ST, GA at delivery might be earlier in those in whom the presenting fetus was terminated. A subanalysis of patients presenting with only twins (thus, all ending with a singleton) showed that 16 of 76 (21.5%) of those who had the presenting fetus terminated delivered before 32 weeks versus five of 82 (6.1%) of those who had the nonpresenting fetus terminated; however, this finding is of limited relevance because the ST must be performed on the fetus that has an abnormality regardless of its location. In MPR surgeons attempt to leave the presenting fetus intact, but data from the authors’ ST series suggests that this method might not be necessary. There are countries in which late termination is legal under certain circumstances. An Israeli report of 37 dichorionic twin gestations in which ST was performed between 24 and 33 weeks (mean 25.5 weeks) showed favorable outcomes with rates of prematurity less than 32 weeks, less than 34 weeks, and less than 37 weeks of 5.7%, 14.3%, and 22.9% (cumulative rates), respectively [46]. The median GA at delivery was 37 weeks, which is comparable to that of uninterrupted twin gestations. Similar to the authors’ findings, there were no differences in loss rates when the affected fetus was in the lower or higher sac. Technical aspects The following criteria are used to determine which fetus is to be selectively terminated: (1) obvious structural malformations, (2) gender differences, or (3) documented placental positions. In most cases the center and physician diagnosing the abnormality are not the same as the center and physician performing the ST. The ST might also occur several weeks after an amniocentesis or CVS, so documentation including in utero mapping of all fetuses and placentas is critical at the time of CVS [42]. If there is confusion about which fetus is which, rapid determination of karyotype by direct preparation of chorionic villi, fetal blood sampling, or fluorescence in situ hybridization on amniocytes is

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appropriate. When the affected fetus has been identified correctly, ST is performed by an ultrasound-guided intrathoracic injection of KCl (2 mEq/mL) in amounts sufficient to cause asystole. In general, 6 to 12 mEq are sufficient to achieve asystole, but in the authors’ experience more KCl is needed with an increasing GA. Before undergoing ST all patients need ultrasound confirmation of dichorionicity. This procedure should not be done in monochorionic twins because of intrafetal vascular anastomoses and the risk of injury to the remaining fetus. Potential options for ST in monochorionic twins include cord ligation, cord coagulation, or laser cord occlusion [47,48]. Controversies in selective termination An interesting ethical question is whether or not a fetus that has a lethal anomaly should be terminated. In the publication describing the authors’ first 100 cases, the authors gave the opinion that because of the potential risk of loss associated with ST it should not be performed when the fetus was likely to die in utero or shortly after birth [2]. Over time several factors have caused the authors to rethink this position. First, the authors believe that current data demonstrate with a reasonable degree of confidence that ST in the hands of experienced operators is a safe procedure that carries a relatively low pregnancy loss rate. Furthermore, ST can obviate, in part, some of the risks of prematurity associated with multifetal pregnancies, so there might be a direct benefit to the remaining fetuses by terminating a fetus that has a lethal anomaly in the same uterus. Anencepahlic fetuses in particular are known to be associated with polyhydramnios and preterm labor. Finally, the psychological and emotional impact of carrying a fetus with a lethal anomaly accompanied by concern about how the fetus or infant will die is of legitimate concern. Considering the above factors the authors now believe that patients should be extensively counseled and offered the option of ST even in the setting of a lethal anomaly.

At the crossroads of multifetal pregnancy reduction and selective termination A recent study highlights the overlap between MPR and ST. Lipitz et al compared outcomes in 46 MPRs performed at 11 to 12 weeks (early) with 49 MPRs performed at 13 to 14 weeks (late) after an early anatomic survey by ultrasound. Sonographic screening led to ST of a specific fetus because of increased nuchal translucency in nine cases, relative IUGR in three, and meningomyelocele, abdominal cysts, and cystic hygroma in one case each [49]. The rates of pregnancy loss were not different (4.3% and 4%) between the early and late MPR groups. Similarly, GA at delivery and birth weights were not different. Thus, Lipitz et al suggested that early second-trimester MPR might allow for more ST of abnormal fetuses without an adverse effect on pregnancy outcome. A larger series is needed to confirm this observation. Delaying the procedure might

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increase the psychological stress of the couple, but this stress might be mitigated by obtaining as much information as possible about the health of their fetuses before MPR. An ethical issue that might arise if MPR is delayed is the ability to do sex determination of the fetuses before MPR. This issue might be of clinical significance for families at risk for X-linked disorders.

Summary MPR and ST are important options for patients who have multifetal pregnancies. Both procedures have been shown to be technically safe and result in acceptable pregnancy loss rates and GAs at delivery. An important caveat is that these findings are observed in centers that have vast experience performing this type of procedure and should not be generalized to all centers. The authors believe that the good outcomes reported here and elsewhere are a result of having a relatively limited number of operators adhering to a strict common protocol and that they should not be generalized to all centers. Awareness of the ethical and psychological issues aids counseling of patients and their follow-up, but more information is needed in this area. Finally, it is the authors’ hope that advances in ART will decrease the need for MPR procedures in the future.

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