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Invasive Procedures in Multifetal Pregnancies
Clin Perinatol 32 (2005) 355 – 371
Invasive Procedures in Multifetal Pregnancies Meredith Rochon, MD*, Keith A. Eddleman, MD, Joanne Stone, MD Division of Maternal-Fetal Medicine, Mount Sinai Medical Center, 5 East 98th Street, Box 1171, New York, NY 10029, USA
The increased use of assisted reproductive techniques and delayed childbearing have resulted in a veritable epidemic of multiple pregnancies in the past decade, particularly those of higher order. As the number of multiple pregnancies has increased, so has the frequency with which invasive procedures are performed in these gestations. Techniques such as amniocentesis and chorionic villus sampling (CVS), first performed in singletons, are now commonly performed in multiple gestations. Multifetal pregnancy reduction and selective termination are procedures unique to multiple pregnancies and were developed to cope with their sequelae. This review discusses the various invasive techniques currently performed in multiple pregnancies.
Amniocentesis Amniocentesis is commonly performed in singleton and multiple gestations. In this invasive procedure, amniotic fluid is removed from the uterine cavity for diagnostic or therapeutic purposes. Indications for diagnostic amniocentesis include chromosomal or genetic analysis, evaluation for a neural tube or abdominal wall defect, documentation of fetal lung maturity, and testing for intrauterine infection. Each fetus of a multizygotic pregnancy is genetically unique; there-
* Corresponding author. E-mail address: [email protected] (M. Rochon). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.002 perinatology.theclinics.com
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fore, when prenatal diagnostic studies are performed, each fetus must be individually tested. Most operators also test each fetus in a monochorionic pair because, although the fetuses are usually genetically identical, rarely they can be discordant for genetic disorders owing to postzygotic mutations [1]. The relative positions of the fetal sacs should be well documented at the time of the procedure. If any of the test results are abnormal, one must be able to distinguish between fetuses.
Technique Amniocentesis is an outpatient office procedure. After the abdomen is prepared with Betadine, a 20- or 22-guage needle is inserted into the amniotic cavity under continuous ultrasound guidance. The amount of fluid removed depends on the indication; in general, it should not exceed 1 mL per week of gestation (typically, 10 to 30 mL). After extracting the necessary fluid, 1 mL of indigo carmine is injected through the same needle into the sac of the tested fetus. The needle is then withdrawn, and the procedure is repeated with the next fetus. Alternatively, a single-needle insertion technique is performed in which both fetuses are sampled with one needle by passing from one sac into the other through the dividing membrane [2]. Injection of indigo carmine ensures that each sac is tested only once. If the needle is inadvertently inserted into the same sac a second time, the fluid withdrawn will be blue, and the operator will know immediately that he or she is in the wrong sac. When high-order multiple pregnancies are sampled, each sac should be marked in succession with indigo carmine. Indigo carmine has not been associated with any fetal risk [3]. The use of methylene blue, another common dye agent, is contraindicated because of associated fetal risks, including skin staining, intestinal atresia, hemolytic anemia, and fetal death [4,5]. Whenever possible, the operator should avoid going through the placenta, because transplacental entry has been suggested in one retrospective review of multifetal amniocentesis to increase the loss rate when compared with transamniotic entry [6]. Increased numbers of needle sticks have been associated with higher loss rates in singletons [7]. Although this effect has not been evaluated in multiple gestations, it seems prudent to limit the number of attempts to two per sac. The use of antibiotic prophylaxis is not necessary. Although the risk of Rh sensitization is low, particularly without transplacental needle passage, RhoGAM should be administered for all women at risk for Rh sensitization. Genetic amniocentesis is typically performed between 15 and 22 weeks’ gestation, whereas amniocentesis for other diagnostic and therapeutic indications can be performed at any time during pregnancy. Early amniocentesis performed before 15 weeks has been described in twins [8]. When compared with amniocentesis performed after 15 weeks, early amniocentesis is associated with increased rates of fetal loss, failed procedures, multiple needle insertions, amniotic fluid leakage, failed culture, and fetal talipes equinovarus in randomized trials
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[9]. For these reasons, early amniocentesis is no longer recommended in twin or singleton pregnancies. Success and contamination Multifetal amniocentesis is feasible in nearly all pregnancies. Rarely, relative sac position or maternal characteristics such as morbid obesity or large fibroids may present a significant technical challenge to the operator. Fibroids should be avoided whenever possible because going through them is painful and renders needle manipulation difficult. When one sac completely overlies the other, the single-needle technique should be considered, although little is known regarding loss or contamination rates following this technique. The use of indigo carmine makes cross-contamination between fetuses unlikely, because it is obvious when a particular fetus is being inadvertently tested a second time. Maternal contamination can occur but is rare. Postprocedural loss rates The American College of Obstetricians and Gynecologists estimates that the loss rate after second-trimester singleton amniocentesis is 1 in 200 [10]. The limited data available on multifetal amniocentesis are for twins. Postprocedural loss rates after twin amniocentesis have been reported to range from 2.3% to 8.1% [11–16]. Given the background pregnancy loss rate for twins before 24 weeks’ gestation of approximately 6% [17], it is unclear whether the increased loss rate (above the 0.5% rate for singletons) is attributable to the twin pregnancy or the procedure. Yukobowich et al compared three retrospective cohorts: 476 twin pregnancies undergoing amniocentesis, 489 women with singletons who had amniocentesis, and 477 women with twins who presented for ultrasound studies at a similar gestational age but who did not have an invasive procedure [11]. The loss rate within 4 weeks of the procedure was significantly higher in the twin amniocentesis group (2.7%) than in the exposed singletons (0.6%) or unexposed twins (0.6%). Other studies have not confirmed a higher loss rate associated with twin amniocentesis over the background loss rate of twins [12,14]. For example, in a retrospective case-control study, Ghidini et al compared 101 twins undergoing amniocentesis with 108 twin controls and found no difference in fetal loss rates between the two groups [14]. Risk factors associated with increased loss rates after multifetal amniocentesis have not been well characterized. Data describing these risks for singleton amniocentesis have been characterized and include maternal age, vaginal bleeding in the current pregnancy, and a history of abortion [18]. Other factors associated with increased loss rates include an increased number of attempts [7], the presence of green or brown pigmented amniotic fluid [19,20], and elevated maternal serum alpha-fetoprotein (MSAFP) as the indication for amniocentesis [21]. Operator experience does not seem to affect the loss rate in singleton amniocentesis [21], although this has not been investigated in twins.
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Amniocentesis for fetal lung maturity or infection Close to term it is not necessary to test both sacs, and the fetus sampled should be the one less likely to be mature, for example, the male fetus when fetuses are discordant for gender. At earlier gestational ages, discordance in lung maturity status is more likely, particularly for twins discordant for gender [22,23]; therefore, it seems reasonable to test both fetuses in pregnancies less than 36 weeks’ gestation. When evaluating for intrauterine infection, only the lower most sac (fetus A) should be sampled, because infection generally ascends from the vagina. If clinical suspicion is high and the fluid from sac A does not show evidence of infection, amniocentesis of other fetuses can be considered.
Chorionic villus sampling Chorionic villus sampling is an invasive procedure in which placental villi are obtained for performing prenatal diagnostic studies in women at increased risk for fetal chromosomal or genetic abnormalities. It is usually performed at 10 to 12 weeks’ gestation. Technique Chorionic villus sampling can be performed using a transabdominal or transcervical approach. When testing multiple pregnancies, a combination of both routes is often used. The approach is chosen based on operator experience and the relative locations of the fetal sacs and placentas. Dichorionic fetuses are each tested separately. Monochorionic fetuses share one placenta; therefore, they must be tested together with only a single sample. Whether using a transabdominal or transcervical approach, CVS is performed under continuous ultrasound guidance using an aseptic technique. The transabdominal approach uses a 20-gauge needle that is inserted into the placenta. Chorionic villi are then aspirated as the needle is moved back and forth within the placenta under negative pressure. When testing multiple fetuses via the transabdominal approach, separate needle insertions with fresh needles are performed to avoid cross-contamination of the specimens. The transcervical approach is usually performed with an aspiration catheter. A biopsy forceps can also be used [24]. The instrument is passed through the cervix and into the placenta under ultrasound guidance, and villi are aspirated similar to the transabdominal technique. Typically, only one fetus in a multifetal pregnancy can be tested using the transcervical approach. Antibiotic prophylaxis is not necessary. RhoGAM should be administered as indicated. A detailed written description of the relative sac positions and placental locations should accompany any multifetal CVS. The relative filling of the bladder should also be noted, because it may change the appearance of the sac
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and placental locations within the uterus. The operator must be able to identify each sac correctly at a later date, particularly in the setting of an affected fetus. Success and contamination Multiple fetuses can be sampled successfully by CVS in more than 99% of cases when performed by an experienced operator [6,24–28]. Contamination of fetal samples is a real concern, although, in experienced centers, this probably occurs in less than 2% of CVS procedures [6,24–29]. Contamination is a risk because separate placentas are often fused, and, unfortunately, there is no way to mark each placenta as it is tested, as can be done with indigo carmine during multifetal amniocentesis. Several strategies are employed to minimize the risk of contamination. The operator should fully evaluate placental positions before testing. A placenta may appear anterior in some views and posterior in others, particularly if the bladder is emptied or filled. Separate needles and catheters should be used for each fetus. The tip of the aspirating device should be placed close to the umbilical cord insertion site on each placenta to minimize the risk of testing the wrong fetus. Postprocedural loss rates Few studies have investigated outcomes of CVS in multifetal pregnancies, and those that have are small and provide data primarily on twins. Brambati et al reviewed 208 multiple pregnancies undergoing CVS in the first trimester (198 sets of twins and 9 sets of triplets) and compared the pregnancy outcomes of the dichorionic/diamniotic twin cohort with that of a control population of 63 sets of twins undergoing no invasive procedure [26]. There were no total pregnancy losses in either group and no differences in fetal and perinatal losses between the study and control populations [26]. Other series also report acceptably low loss rates (0.6% to 4.2%) [6,25,28] comparable with the background loss rate of twins of approximately 6% [17]. Furthermore, more than half of the losses reported after multifetal CVS occur more than 4 weeks after the procedure at a time when it is difficult to attribute the pregnancy loss to the procedure [30]. Chorionic villus sampling versus amniocentesis Once a patient has decided to have an invasive procedure, the decision to choose one procedure over another should be based on a combination of patientspecific factors, such as the likelihood of proceeding to multifetal pregnancy reduction, the gestational age at presentation, and the experience of the operator, as well as technical factors, such as the relative position of the sacs and maternal body habitus. The indication for invasive testing is also influential. The more likely the fetus is to be affected, the stronger CVS should be considered.
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The chief advantage of CVS is that it is performed at an earlier gestational age than amniocentesis, typically between 10 and 12 weeks’ gestation versus greater than 15 weeks. If the fetus is affected, a selective termination can be performed at an earlier gestational age for a substantially lower emotional impact and perhaps a lower rate of loss after selective termination [6,29]. Conversely, if the fetus is normal, peace of mind can be achieved earlier in the pregnancy, thereby enhancing maternal-fetal bonding [31] and lowering parental stress regarding the pregnancy. Finally, the early gestational age at which CVS can be performed enables fetuses to be tested before multifetal pregnancy reduction, ensuring that the nonreduced fetuses are chromosomally normal. A potentially higher postprocedural loss rate has been widely quoted as a disadvantage of CVS when compared with amniocentesis. Nevertheless, few studies have compared these procedures in multiple gestations. Wapner et al [32] evaluated the outcome of 161 twin pregnancies undergoing CVS and 81 twin pregnancies undergoing amniocentesis and found no differences in fetal loss rates or total pregnancy loss rates. Similarly, in a more recent retrospective review, Antsaklis et al compared pregnancy outcomes of 347 twin pregnancies undergoing amniocentesis with 69 twin pregnancies undergoing CVS and found no differences in the total pregnancy loss rate before 24 weeks (4.18% versus 4.54%), the rate of preterm delivery before 32 weeks (11.8% versus 16.7%), or the total fetal loss rate (8.8% versus 10.2%) [6]. In experienced hands, CVS seems to be as safe as amniocentesis in twin pregnancies. Another disadvantage of CVS is the higher contamination rate and increased need for an additional invasive procedure, required in 5% of CVS cases compared with 0.3% of amniocentesis cases in one series [29]. Additional procedures are primarily performed for evaluation of sampling error or to confirm confined placental mosaicism [30]. Identification of confined placental mosaicism may represent an advantage of CVS, because it identifies pregnancies at increased risk of perinatal morbidity [33] that may deserve increased fetal surveillance. Chorionic villus sampling is a procedure that is not as widely available as amniocentesis, primarily because it is more difficult. Furthermore, it has been shown with singleton CVS that, unlike in amniocentesis, postprocedural loss rates decrease with operator experience [34]. Multifetal CVS represents a technically challenging procedure, and the availability of experienced operators should factor into the decision of whether to undergo amniocentesis or CVS.
Multifetal pregnancy reduction Multifetal pregnancy reduction refers to the nonselective reduction of one or more fetuses of a multifetal pregnancy. The purpose is to reduce the risk of complications associated with multifetal pregnancies and to optimize the chance of carrying and delivering one or several healthy infants. It is done by reducing the actual number of fetuses in the uterus. Multifetal pregnancy reduction should be considered by any woman with three or more fetuses.
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Chorionicity Knowledge of chorionicity is crucial before performing multifetal pregnancy reduction. The traditional technique described herein assumes multichorionic placentation in which there are none of the interfetal placental vascular anastomoses commonly found with monochorionic fetuses. If two fetuses have a shared circulation and one is injected with a toxin, there is a high likelihood that the toxin will get into the co-twin’s circulation and cause fetal death [35]. In addition, acute adverse hemodynamic changes in the survivor may occur owing to blood loss into the low-pressure vascular system of the dead fetus. For this reason, as well as the risk of pregnancy complications inherent to monochorionic twins, the monochorionic pair of a multifetal pregnancy are often preferentially reduced. Reduction of a single fetus in a monochorionic pair can be done but requires special techniques with much higher complication rates. Because of this difficulty, reduction of a single fetus in a monochorionic pair is usually only considered when one of the fetuses is anomalous (selective termination) or in the setting of twin-to-twin transfusion syndrome. Chorionicity is best established by ultrasound in the first trimester by identification of the presence or absence of the lambda sign. The lambda sign is a triangular projection of echodense tissue between two sacs representing two chorions and two amnions. Before 13 weeks, chorionicity can be correctly established by the presence or absence of the lambda sign in 100% of cases [26].
Chorionic villus sampling before multifetal pregnancy reduction One or more fetuses can be tested by CVS before multifetal pregnancy reduction. This testing is desirable for several reasons. First, patients who are considering multifetal pregnancy reduction are often at high risk for carrying a fetus with aneuploidy owing to maternal age and desire invasive testing. Second, noninvasive means for assessing aneuploidy risk have lower sensitivity and specificity for multifetal pregnancies than for singletons, and some of those that are available (second-trimester serum analyte screens or ‘‘quad’’ screens) are not reliable after multifetal pregnancy reduction owing to falsely elevated AFP [36]. CVS before multifetal pregnancy reduction provides the patient and provider with the assurance that chromosomally normal fetuses are being left intact. Several studies have shown that performing CVS before multifetal pregnancy reduction does not increase the postprocedural pregnancy loss rate above that of multifetal pregnancy reduction alone [25,37,38]. An accurate verbal description and a diagram of the relative positions of the gestational sacs and placentas must be carefully recorded so that if an abnormal karyotype is found, it can be correctly matched to the affected fetus. This description should also include the relative fullness of the bladder, because filling or emptying of the bladder can change the intrauterine appearance.
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Technique Multifetal pregnancy reduction is performed as an outpatient procedure in the office. At the authors’ center, the patient and her partner undergo significant pre-procedure counseling, usually on a day separate from the day of the procedure. Ultrasound examination is performed to confirm chorionicity. The relationship of the gestational sacs to each other is carefully noted. If CVS has been performed before multifetal pregnancy reduction, care is taken to identify correctly each fetus that has been tested. Each fetus is measured, the fluid level in each sac is assessed, and the anatomy of each fetus is examined to identify any gross abnormalities. Although multifetal pregnancy reduction is usually performed at the end of the first trimester, a time before which a comprehensive anatomic survey is likely to reveal any abnormalities, a limited assessment of the anatomy and nuchal translucency can be performed to determine the risk for aneuploidy or structural abnormality. In general, the fetuses that are reduced are selected for technical reasons and are usually those closest to the anterior uterine wall or fundus. The fetus above the cervix is avoided whenever possible because of a hypothetical increased risk of infection or uterine irritability if that fetus were reduced. Fetuses with a lagging crown-rump length, decreased fluid, increased nuchal translucency, or an obvious anomaly are preferentially reduced. If CVS has been performed before multifetal pregnancy reduction, fetuses that are known to be chromosomally normal are left intact, and abnormal or untested fetuses are preferentially reduced. After identification of the fetus to be reduced, the abdomen is prepared with Betadine. Under continuous ultrasound guidance, a 22-gauge spinal is inserted into the fetal thorax, and approximately 5 mEq of potassium chloride (2 mEq/mL) is injected. Asystole is usually seen within 1 minute of injection of potassium chloride; the needle is left in place until asystole has been observed for 2 minutes and then withdrawn. Additional fetuses can be reduced by directing the needle into a different sac or, more commonly, by using a separate needle stick. Antibiotic prophylaxis can be given and RhoGAM administered as indicated. An ultrasound 1 hour after the procedure is recommended to confirm asystole in the reduced fetuses and the presence of cardiac activity in the nonreduced fetuses. The fetuses are left in situ and, over a period of weeks to months, are resorbed. Natural history of multifetal pregnancies Multifetal pregnancy reduction was developed as a technique to optimize the pregnancy outcome of high-order multifetal pregnancies. Any discussion of whether multifetal pregnancy reduction improves these pregnancy outcomes requires an appraisal of their natural history. Multiple gestations are at higher risk for fetal, neonatal, and maternal complications when compared with singleton pregnancies. Total pregnancy loss rates (before 24 weeks) rise with an increasing number of fetuses and have been estimated to be 6% for twins [17], 11.5% for triplets [39,40], and 16.7%
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for quadruplets and quintuplets [41,42]. Similarly, mortality rates are significantly higher than for singletons and increase with the number of fetuses. As calculated from 152,233 twin, 5356 triplet, 362 quadruplet, and 36 quintuplet births in the United States from 1995 to 1997, early mortality rates (death from 20 weeks’ gestation to the first year of life) were 4.8% for twins, 8.6% for triplets, 10.8% for quadruplets, and 28.9% for quintuplets [43]. There is also a concomitant increase in associated morbidities. For example, a 47-fold increase in cerebral palsy in triplet pregnancies and an eightfold increase in twins when compared with singletons has been observed, primarily owing to high rates of prematurity [40]. In one series, 44% of 94 couples with triplets had at least one significantly impaired child [44]. Similarly increased rates are seen in other types of morbidities. The increased rate of fetal complications associated with multiple pregnancies is primarily attributable to high rates of prematurity. Furthermore, mean gestational age at delivery and birthweight decrease as the number of fetuses increases, with average gestational ages at delivery for twins, triplets, and quadruplets estimated to be 35, 33, and 31 weeks [39]. Multifetal pregnancy reduction was developed to cope with these high rates of morbidity and mortality, primarily by decreasing rates of prematurity and total pregnancy loss. Pregnancy outcomes after multifetal pregnancy reduction Observational data from the largest published single center series of 1000 cases of multifetal pregnancy reduction report an unintended pregnancy loss rate, defined as the unintended loss of the entire pregnancy before 24 weeks, of 5.4% [45], which is comparable with the loss rate of nonreduced twins and lower than the loss rate of nonreduced triplets. The largest collaborative series of more than 3500 cases from 11 centers in five countries reported an unintended loss rate of 9.6% [46]. The lower loss rate seen in the single center series is most likely explained by the inherent differences of a multicenter experience versus that of a single center with a small number of operators and a well-established protocol [30]. Furthermore, the collaborative series included some transvaginal and transcervical procedures, which have been associated with higher loss rates, whereas the single center series only used the transabdominal approach. Most of the losses in both series occurred many weeks after the procedure, making it hard to attribute these losses to multifetal pregnancy reduction. For example, Stone et al found that more than 55% of total pregnancy losses occurred more than 8 weeks after the reduction. These losses may be more reflective of the multifetal pregnancy (most reductions in this series were to twins) than of the procedure. The total pregnancy loss rate within 4 weeks of the procedure in this series was only 0.8% and accounted for 14.8% of the total losses observed [45]. Both series found that loss rates decreased with a lower starting number and finishing number of fetuses [45,46]. For example, data collected by Stone et al showed that loss rates were lowest when twins were reduced to singletons (2.5%), remained stable (approximately 5%) when the starting number was three, four, or
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five fetuses, and increased to 12.9% when the starting number was six or more [45]. There was a trend toward lower loss rates when the pregnancy was reduced to a singleton (3.5%) versus twins (5.5%), although a limited number of reductions to a singleton prevented this from being statistically significant [45]. Loss rates were significantly higher when the pregnancy was reduced to triplets (16.7%) [45]. The loss rates observed approximate those of naturally occurring twins and triplets. Loss rates in both series decreased with operator experience [45,46]. The mean gestational ages at delivery for finishing numbers of one, two, and three fetuses were 37.9, 35.3, and 33.5 weeks [45]. Multifetal pregnancy reduction improves the outcome of multifetal pregnancies above and beyond a reduction in total pregnancy loss rates. This effect is clearly illustrated in the results of a recently published meta-analysis comparing twins reduced from triplets with nonreduced triplets, which are summarized in Table 1. Multifetal pregnancy reduction significantly reduces the risk of severe prematurity and perinatal mortality while increasing the ‘‘take home baby rate.’’ The outcome of pregnancies reduced to twins seems to be comparable with that of nonreduced twins. Yaron et al compared 143 triplet pregnancies reduced to twins with 812 nonreduced twins [17]. Total pregnancy loss rates before 24 weeks were similar between reduced twins (6.2%) and nonreduced twins (5.8% to 6.3%), as was gestational age at delivery (approximately 35 weeks in both groups) and mean birthweights. Other studies have reported similar findings [30,47], although some have suggested that the mean birthweight of twins after multifetal pregnancy reduction is decreased when compared with that of nonreduced twins [48,49], particularly with increased starting numbers [45]. Psychologic impact of multifetal pregnancy reduction Despite improved pregnancy outcomes after multifetal pregnancy reduction, there is a significant psychologic impact on the parents. Most patients with highorder multiples conceive with assisted reproductive techniques, usually after many years of infertility. The decision to terminate wanted, usually normal, fetuses can be agonizing, and couples may later regret the decision to undergo the
Table 1 Meta-analysis of published studies of reduced and nonreduced triplets from 1984 to 2001 Parameter
Reduced triplets (3 to 2) (n = 2230)
Nonreduced triplets (n = 604)
Odds ratio
P
Pregnancy loss b 24 weeks Delivery b 28 weeks Delivery b 32 weeks Perinatal mortality Take home baby rate
5.1% 2.9% 10.1% 26.6/1000 93%
11.5% 8.4% 20.3% 92.2/1000 78.6%
0.45 0.35 0.5 0.3 0.3
b .001 .0001 b .0001 b .0001 .002
(0.3–0.6) (0.2–0.6) (0.37–0.66) (0.2–0.5) (0.2–0.7)
Adapted from Wimalasundera RC, Trew G, Fisk NM. Reducing the incidence of twins and triplets. Best Prac Res Clin Obstet Gynaecol 2003;17:309–29.
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procedure regardless of pregnancy outcome [50]. Patients should be counseled that parents of multiples also sustain extreme psychologic stress. Even if all of the infants are healthy, which high-order multiples usually are not, taking care of multiple infants at the same time is extremely draining physically and emotionally, not to mention economically burdensome. With the added risk of one or more infant experiencing prolonged NICU stays, the need for complex medical care, and significant deficits, the stress could be overwhelming. In a prospective study comparing patients undergoing multifetal pregnancy reduction with those who did not reduce their triplet pregnancy, mothers who underwent multifetal pregnancy reduction had less anxiety and depression and more satisfactory relationships with their children [51]. Although many women in the multifetal pregnancy reduction group expressed sadness and guilt 1 year later, the majority reported a significant reduction in emotional pain at 2 years [51].
Selective termination Selective termination is a procedure in which one anomalous fetus in a multifetal pregnancy is terminated. When one or more fetuses in a multifetal pregnancy are found to be anomalous, the patient has three choices. The first is to manage the pregnancy expectantly; the second is to terminate the entire pregnancy; and the third is to terminate selectively the affected fetus. Selective termination can be performed for a chromosomal, structural, or genetic abnormality, usually identified by ultrasound or an invasive prenatal diagnostic test such as CVS or amniocentesis. It can be performed at any time from the time of diagnosis (generally after 10 weeks) up to the legal limit of termination. The legal limit for termination in most states is 24 weeks; third-trimester selective termination can be performed legally in certain US states and in some other countries [52]. Selective termination was initially developed to prevent the survival of a severely affected infant [53]. As experience with selective termination increased with a concomitant improvement in procedural outcomes, it became increasingly offered for lethal anomalies to reduce the emotional impact of giving birth to a child who would not live [53]. It is theorized that, in some cases, termination of the anomalous twin may optimize the outcome of the normal fetus. For example, anencephaly is often complicated by polyhydramnios owing to impaired fetal swallowing, which invariably results in preterm labor. Selective termination of this fetus may decrease the rate of preterm labor and the effects of prematurity on the normal co-twin [30]. Technique As is true for multifetal pregnancy reduction, the traditional technique for selective termination can only be used if the fetuses are multichorionic. As
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discussed previously, chorionicity is usually determined by the presence or absence of the lambda sign on first-trimester ultrasound. If the pregnancy is already in the latter half of the second trimester, it may be more difficult to determine chorionicity. Fetuses discordant for gender or that appear to have separate placentas are obviously dichorionic. Specialized genetic tests such as quantitative fluorescent polymerase chain reaction assays and polymorphic small tandem repeats can be used for rapid determination of zygosity [54,55] for pregnancies with uncertain chorionicity. Another vital preprocedure consideration is correct identification of the anomalous fetus. If the fetuses are discordant for gender or a structural anomaly, the affected fetus can be determined visually at the time of the procedure by ultrasound. If the anomaly cannot be identified on ultrasound (eg, in many genetic diseases), the operator must rely on previously documented fetal and placental positions, underscoring the importance of a precise detailed description of the location of each fetus at the time of an invasive diagnostic procedure. Correct identification of the affected fetus can be challenging if several weeks have passed since the invasive diagnostic procedure, because growth of the uterus and fetuses may alter the appearance of their relative positions. Usually, the affected fetus is readily identifiable. If there is any doubt, rapid determination of karyotype by fluorescent in situ hybridization should be performed and the results obtained before selective termination [30]. Documentation of the karyotype of the terminated fetus at the time of the procedure by amniocentesis or fetal blood is recommended to confirm the correct fetus has been terminated [30]. Once the fetus to be terminated has been correctly identified, the procedure is performed in a manner similar to multifetal pregnancy reduction. Under ultrasound guidance, potassium chloride is injected into the thorax of the affected fetus via a transabdominal route and the needle left in place until asystole is observed for 2 minutes. The amount of potassium chloride required will depend on the gestational age/size of the fetus. Prophylactic antibiotics are usually given and RhoGAM administered as indicated. The fetus is left in situ while the pregnancy continues. If performed in the late first trimester or early second trimester, the fetus may be resorbed. At later gestational ages, the fetus will not be completely resorbed, but, over a period of weeks to months, the amniotic fluid around the fetus will disappear, and the fetal tissue will become significantly condensed. The reduced fetus is typically delivered with the placenta and is usually too macerated for any meaningful evaluation. Pregnancy outcome after selective termination The overall pregnancy loss rate, defined as the unintended total pregnancy loss rate before 24 weeks, was 4.0% in the largest single center series of 200 patients [56] and 7.5% in the largest collaborative experience of 402 patients [57]. The lowest loss rate (2.4%) after selective termination is observed with a starting number of two [56]. This rate increases significantly to 11.1% when starting with three or more fetuses and is highest when more than one fetus is terminated
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(42.9%) [56]. In continuing pregnancies, the outcome after selective termination is generally favorable, with low rates of prematurity and few maternal complications. For women not experiencing a pregnancy loss or electively terminating their pregnancy, the median gestational age at delivery was 37.1 weeks in one series [56]. Data from early studies suggested that rates of pregnancy loss and preterm delivery increased with increasing gestational age at the time of selective termination [57,58]. More recent data suggest that there is no advantage to performing selective termination at earlier gestational ages [56]. In fact, in one series, there was a trend toward a higher rate of pregnancy loss in patients undergoing selective termination at or before 20 weeks’ gestation when compared with selective termination after 20 weeks (5.9% versus 1.3%, P = .09) [56]. Patients and physicians should be reassured that selective termination in experienced hands is safe at any gestational age. Selective termination of a monochorionic fetus Monochorionic fetuses can occasionally be discordant for anomalies, and it may be desirable to terminate the affected co-twin. Interfetal anastomoses via the placenta prohibit the use of potassium chloride. As a result, many alternative techniques have been tried. The majority of these focus on occlusion of the cord of the affected fetus. A review of these techniques appears elsewhere in this issue.
Percutaneous umbilical blood sampling Percutaneous umbilical blood sampling (PUBS) is typically performed for special diagnostic and therapeutic indications, such as an evaluation for hydrops or infection, or to perform specialized studies that cannot be accomplished by amniocentesis or CVS. It can also be performed when an abnormality is suspected late in pregnancy for a more rapid diagnosis. PUBS is an invasive procedure in which fetal blood is sampled from the umbilical vein, usually at the placental umbilical cord insertion site. An anemic or thrombocytopenic fetus can also be transfused through the same needle if indicated. Percutaneous umbilical blood sampling is a technically challenging procedure and is considerably more invasive than other diagnostic studies, because the needle enters the fetal circulation. The procedure-related fetal loss rate following PUBS in singletons is higher than with CVS and amniocentesis and is estimated to be 1% to 2% [59]. The risk is recognized to vary with the indication, with ‘‘healthy’’ fetuses having the lowest risk (eg, those undergoing genetic studies) and ‘‘sick’’ fetuses having significantly higher risk (eg, a fetus with hydrops or severe thrombocytopenia). There is only one published study describing this technique in multiple gestations. Antsaklis et al retrospectively reviewed 89 cases of fetal blood
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sampling procedures in twin pregnancies performed from 1977 to 2000 [59]. The vast majority of these procedures were performed on unimpaired fetuses for the purpose of genetic diagnosis. The mean gestational age at the time of the procedure was 20.3 weeks. All of the fetuses (178) were successfully sampled. Seventeen pregnancies were subsequently terminated, 12 underwent selective termination, and 5 were lost to follow-up, leaving a final cohort of 55 pregnancies (110 fetuses). The overall procedure-related fetal loss rate, defined in this series as miscarriage or fetal death within 2 weeks of the procedure, was 8.2% (9/110) [59]. Because of the high loss rate and considerable technical challenge PUBS presents in multifetal pregnancies, this procedure has few true indications.
Summary Several invasive procedures are now commonly performed in multifetal pregnancies. Techniques for prenatal diagnosis performed in multifetal pregnancies, such as amniocentesis and CVS, present specific technical challenges when compared with their performance in singletons and are best performed by experienced operators to increase the success of the procedure, reduce contamination, and minimize postprocedure complications. Procedures developed to cope with the sequelae specific to multifetal pregnancies, such as multifetal pregnancy reduction and selective termination, are also commonly performed with generally good outcomes. The moral and psychologic issues associated with these procedures are extensive and complex for the patient and the physician, but it is clear that pregnancy outcomes of high-order multiples (triplets and up) are improved by multifetal pregnancy reduction. It is hope that with better regulation of assisted reproductive techniques, the need for these specialized procedures will become obsolete.
References [1] Gonsoulin W, Copeland KL, Carpenter RJ, et al. Fetal blood sampling demonstrating chimerism in monozygotic twins discordant for sex and tissue karyotype (46,XY and 45,X). Prenat Diagn 1990;10(1):25 – 8. [2] Jeanty P, Shah D, Roussis P. Single-needle insertion in twin amniocentesis. J Ultrasound Med 1990;9:511 – 7. [3] Cragan JD, Martin ML, Khoury MJ, et al. Dye use during amniocentesis and birth defects [letter]. Lancet 1993;341:1352. [4] Vincer MJ, Allen AC, Evans JR, et al. Methylene blue–induced hemolytic anemia in a neonate. CMAJ 1987;136:503 – 4. [5] Kidd SA, Lancaster PA, Anderson JC, et al. Fetal death after exposure to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenat Diagn 1996;16:39 – 47. [6] Antsaklis A, Souka AP, Daskalakis G, et al. Second-trimester amniocentesis vs chorionic villus sampling for prenatal diagnosis in multiple gestations. Ultrasound Obstet Gynecol 2002;20: 476 – 81.
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[7] Midtrimester amniocentesis for prenatal diagnosis: safety and accuracy. JAMA 1976;236: 1471 – 6. [8] Jorgensen C, Andolf E. Amniocentesis before the 15th week in single and twin gestations: complications and quality of genetic analysis. Acta Obstet Gynecol Scand 1998;77:151 – 4. [9] Johnson JM, Wilson RD, Singer J, et al. Technical factors in early amniocentesis predict adverse outcome: results of the Canadian early (EA) versus mid-trimester (MA) amniocentesis trial. Prenat Diagn 1999;19:732 – 8. [10] American College of Obstetricians and Gynecologists Committee on Practice Bulletins— Obstetrics. ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists: prenatal diagnosis of fetal chromosomal abnormalities. Obstet Gynecol 2001; 97(5 Pt 1):S1 – 12. [11] Yukobowich E, Anteby EY, Cohen SM, et al. Risk of fetal loss in twin pregnancies undergoing second trimester amniocentesis. Obstet Gynecol 2001;98:231 – 4. [12] Antsaklis A, Daskalakis G, Papantoniou N, et al. Genetic amniocentesis in multifetal pregnancies reduced to twins compared with nonreduced twin gestations. Fertil Steril 2000;74:1051 – 2. [13] Ko TM, Tseng LH, Hwa HL. Second-trimester genetic amniocentesis in twin pregnancy. Int J Gynecol Obstet 1998;61:285 – 7. [14] Ghidini A, Lynch L, Hicks C, et al. The risk of second-trimester amniocentesis in twin gestations: a case-control study. Am J Obstet Gynecol 1993;169:1013 – 6. [15] Anderson RL, Goldberg JD, Golbus MS. Prenatal diagnosis in multiple gestation: 20 years’ experience with amniocentesis. Prenat Diagn 1991;11:263 – 70. [16] Pruggmayer M, Baumann P, Schutte H, et al. Incidence of abortion after genetic amniocentesis in twin pregnancies. Prenat Diagn 1991;11:637 – 40. [17] Yaron Y, Bryant-Greenwood PK, Dave N, et al. Multifetal pregnancy reductions of triplets to twins: comparison with nonreduced triplets and twins. Am J Obstet Gynecol 1999;180:1268 – 71. [18] Papantoniou NE, Daskalakis GJ, Tziotis JG, et al. Risk factors predisposing to fetal loss following a second trimester amniocentesis. Br J Obstet Gynecol 2001;108:1053 – 6. [19] Zorn EM, Hanson FW, Greve LC, et al. Analysis of the significance of discolored amniotic fluid detected at midtrimester amniocentesis. Am J Obstet Gynecol 1986;154:1234 – 40. [20] Hess LS, Anderson RL, Golbus MS. Significance of opaque discolored amniotic fluid at secondtrimester amniocentesis. Obstet Gynecol 1986;67:44 – 6. [21] Tabor A, Philip J, Madsen M, et al. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986;1:1287 – 93. [22] Whitworth NS, Magann EF, Morrison JC. Evaluation of fetal lung maturity in diamniotic twins. Am J Obstet Gynecol 1999;180:1438 – 41. [23] Mackenzie MW. Predicting concordance of biochemical lung maturity in the preterm twin gestation. J Matern Fetal Neonatal Med 2002;12:50 – 8. [24] Casals G, Borrell A, Martinez JM, et al. Transcervical chorionic villus sampling in multiple pregnancies using a biopsy forceps. Prenat Diagn 2002;22:260 – 5. [25] Eddleman KA, Stone JL, Lynch L, et al. Chorionic villus sampling before multifetal pregnancy reduction. Am J Obstet Gynecol 2000;183:1078 – 81. [26] Brambati B, Tului L, Guercilena S, et al. Outcome of first-trimester chorionic villus sampling for genetic investigation in multiple pregnancy. Ultrasound Obstet Gynecol 2001;17:209 – 16. [27] Pergament E, Schulman JD, Copeland K, et al. The risk and efficacy of chorionic villus sampling in multiple gestations. Prenat Diagn 1992;12:377 – 84. [28] De Catte L, Liebaers I, Foulon W. Outcome of twin gestations after first trimester chorionic villus sampling. Obstet Gynecol 2000;96:714 – 20. [29] van den Berg C, Braat AP, Van Opstal D, et al. Amniocentesis or chorionic villus sampling in multiple gestations? Experience with 500 cases. Prenat Diagn 1999;19:234 – 44. [30] Rochon M, Stone J. Invasive procedures in multiple gestations. Curr Opin Obstet Gynecol 2003;15:167 – 75. [31] Caccia N, Johnson JM, Robinson GE, et al. Impact of prenatal testing on maternal-fetal bonding: chorionic villus sampling versus amniocentesis. Am J Obstet Gynecol 1991;165:1122 – 5.
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[32] Wapner RJ, Johnson A, Davis G, et al. Prenatal diagnosis in twin gestations: a comparison between second-trimester amniocentesis and first-trimester chorionic villus sampling. Obstet Gynecol 1993;82:49 – 56. [33] Stipoljev F, Latin V, Kos M, et al. Correlation of confined placental mosaicism with fetal intrauterine growth retardation: a case control study of placentas at delivery. Fetal Diagn Ther 2001;16:4 – 9. [34] Wijnberger LD, van der Schouw YT, Christiaens GC. Learning in medicine: chorionic villus sampling. Prenat Diagn 2000;20:241 – 6. [35] Benson CB, Doubilet PM, Acker D, et al. Multifetal pregnancy reduction of both fetuses of a monochorionic pair by intrathoracic potassium chloride injection of one fetus. J Ultrasound Med 1998;17:447 – 9. [36] Grau P, Robinson L, Tabsh K, et al. Elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein after multifetal pregnancy reduction. Obstet Gynecol 1990;76:1042 – 5. [37] Brambati B, Tului L, Baldi M, et al. Genetic analysis prior to selective fetal reduction in multiple pregnancy: technical aspects and clinical outcome. Hum Reprod 1995;10:818 – 25. [38] De Catte L, Camus M, Bonduelle M, et al. Prenatal diagnosis by chorionic villus sampling in multiple pregnancies prior to fetal reduction. Am J Perinatol 1998;15:339 – 43. [39] Stone J, Eddleman K. Multifetal pregnancy reduction. Curr Opin Obstet Gynecol 2000;12:491 – 6. [40] Wimalasundera RC, Trew G, Fisk NM. Reducing the incidence of twins and triplets. Best Prac Res Clin Obstet Gynaecol 2003;17:309 – 29. [41] Skrablin S, Kuvacic I, Pavicic D, et al. Maternal neonatal outcome in quadruplet and quintuplet versus triplet gestations. Eur J Obstet Gynecol Reprod Biol 2000;88:147 – 52. [42] Francois K, Alperin A, Elliott JP. Outcomes of quintuplet pregnancies. J Reprod Med 2001; 46:1047 – 51. [43] Salihu HM, Aliyu MH, Rouse DJ, et al. Potentially preventable excess mortality among higherorder multiples. Obstet Gynecol 2003;102:679 – 84. [44] Strauss A, Bettina WP, Genzel-Boroviczeny O, et al. Multifetal gestation: maternal and perinatal outcome of 112 pregnancies. Fetal Diagn Ther 2002;17:209 – 17. [45] Stone J, Eddleman K, Lynch L, et al. A single center experience with 1000 consecutive cases of multifetal pregnancy reduction. Am J Obstet Gynecol 2002;187:1163 – 7. [46] Evans MI, Berkowitz RL, Wapner RJ, et al. Improvement in outcomes of multifetal pregnancy reduction with increased experience. Am J Obstet Gynecol 2001;184:97 – 103. [47] Hwang JL, Pan HS, Huang LW, et al. Comparison of the outcomes of primary twin pregnancies and twin pregnancies following fetal reduction. Arch Gynecol Obstet 2002;267:60 – 3. [48] Alexander JM, Hammond KR, Steinkampf MP. Multifetal reduction of high-order multiple pregnancy: comparison of obstetrical outcome with nonreduced twin gestations. Fertil Steril 1995;64:1201 – 3. [49] Leondires MP, Ernst SD, Miller BT, et al. Triplets: outcomes of expectant management versus reduction for 127 pregnancies. Am J Obstet Gynecol 2000;183:454 – 9. [50] Berkowitz RL, Lynch L, Stone J, et al. The current status of multifetal pregnancy reduction. Am J Obstet Gynecol 1996;174:1265 – 72. [51] Garel M, Stark C, Blondel B, et al. Psychological reactions after multifetal pregnancy reduction: a 2-year follow-up study. Hum Reprod 1997;12:617 – 22. [52] Lipitz S, Shalev E, Meizner I, et al. Late selective termination of fetal abnormalities in twin pregnancies: a multicentre report. Br J Obstet Gynaecol 1996;103:1212 – 6. [53] Bush MC, Eddleman KE. Multifetal pregnancy reduction and selective termination. Clin Perinatol 2003;30:623 – 41. [54] Chen CP, Chern SR, Wang W. Rapid determination of zygosity and common aneuploidies from amniotic fluid cells using quantitative fluorescent polymerase chain reaction following genetic amniocentesis in multiple pregnancies. Hum Reprod 2000;15:929 – 34. [55] Cirigliano V, Canadas P, Plaja A, et al. Rapid prenatal diagnosis of aneuploidies and zygosity in multiple pregnancies by amniocentesis with single insertion of the needle and quantitative fluorescent PCR. Prenat Diagn 2003;23:629 – 33.
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[56] Eddleman KD, Stone JL, Lynch L, et al. Selective termination of anomalous fetuses in multifetal pregnancies: two hundred cases at a single center. Am J Obstet Gynecol 2002;187:1168 – 72. [57] Evans MI, Goldberg JD, Horenstein J, et al. Selective termination for structural, chromosomal, and mendelian anomalies: international experience. Am J Obstet Gynecol 1999;181:893 – 7. [58] Lynch L, Berkowitz RL, Stone J, et al. Preterm delivery after selective termination in twin pregnancies. Obstet Gynecol 1996;87:366 – 9. [59] Antsaklis A, Daskalakis G, Souka AP, et al. Fetal blood sampling in twin pregnancies. Ultrasound Obstet Gynecol 2003;22:377 – 9.
Invasive Procedures in Multifetal Pregnancies Meredith Rochon, MD*, Keith A. Eddleman, MD, Joanne Stone, MD Division of Maternal-Fetal Medicine, Mount Sinai Medical Center, 5 East 98th Street, Box 1171, New York, NY 10029, USA
The increased use of assisted reproductive techniques and delayed childbearing have resulted in a veritable epidemic of multiple pregnancies in the past decade, particularly those of higher order. As the number of multiple pregnancies has increased, so has the frequency with which invasive procedures are performed in these gestations. Techniques such as amniocentesis and chorionic villus sampling (CVS), first performed in singletons, are now commonly performed in multiple gestations. Multifetal pregnancy reduction and selective termination are procedures unique to multiple pregnancies and were developed to cope with their sequelae. This review discusses the various invasive techniques currently performed in multiple pregnancies.
Amniocentesis Amniocentesis is commonly performed in singleton and multiple gestations. In this invasive procedure, amniotic fluid is removed from the uterine cavity for diagnostic or therapeutic purposes. Indications for diagnostic amniocentesis include chromosomal or genetic analysis, evaluation for a neural tube or abdominal wall defect, documentation of fetal lung maturity, and testing for intrauterine infection. Each fetus of a multizygotic pregnancy is genetically unique; there-
* Corresponding author. E-mail address: [email protected] (M. Rochon). 0095-5108/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.02.002 perinatology.theclinics.com
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fore, when prenatal diagnostic studies are performed, each fetus must be individually tested. Most operators also test each fetus in a monochorionic pair because, although the fetuses are usually genetically identical, rarely they can be discordant for genetic disorders owing to postzygotic mutations [1]. The relative positions of the fetal sacs should be well documented at the time of the procedure. If any of the test results are abnormal, one must be able to distinguish between fetuses.
Technique Amniocentesis is an outpatient office procedure. After the abdomen is prepared with Betadine, a 20- or 22-guage needle is inserted into the amniotic cavity under continuous ultrasound guidance. The amount of fluid removed depends on the indication; in general, it should not exceed 1 mL per week of gestation (typically, 10 to 30 mL). After extracting the necessary fluid, 1 mL of indigo carmine is injected through the same needle into the sac of the tested fetus. The needle is then withdrawn, and the procedure is repeated with the next fetus. Alternatively, a single-needle insertion technique is performed in which both fetuses are sampled with one needle by passing from one sac into the other through the dividing membrane [2]. Injection of indigo carmine ensures that each sac is tested only once. If the needle is inadvertently inserted into the same sac a second time, the fluid withdrawn will be blue, and the operator will know immediately that he or she is in the wrong sac. When high-order multiple pregnancies are sampled, each sac should be marked in succession with indigo carmine. Indigo carmine has not been associated with any fetal risk [3]. The use of methylene blue, another common dye agent, is contraindicated because of associated fetal risks, including skin staining, intestinal atresia, hemolytic anemia, and fetal death [4,5]. Whenever possible, the operator should avoid going through the placenta, because transplacental entry has been suggested in one retrospective review of multifetal amniocentesis to increase the loss rate when compared with transamniotic entry [6]. Increased numbers of needle sticks have been associated with higher loss rates in singletons [7]. Although this effect has not been evaluated in multiple gestations, it seems prudent to limit the number of attempts to two per sac. The use of antibiotic prophylaxis is not necessary. Although the risk of Rh sensitization is low, particularly without transplacental needle passage, RhoGAM should be administered for all women at risk for Rh sensitization. Genetic amniocentesis is typically performed between 15 and 22 weeks’ gestation, whereas amniocentesis for other diagnostic and therapeutic indications can be performed at any time during pregnancy. Early amniocentesis performed before 15 weeks has been described in twins [8]. When compared with amniocentesis performed after 15 weeks, early amniocentesis is associated with increased rates of fetal loss, failed procedures, multiple needle insertions, amniotic fluid leakage, failed culture, and fetal talipes equinovarus in randomized trials
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[9]. For these reasons, early amniocentesis is no longer recommended in twin or singleton pregnancies. Success and contamination Multifetal amniocentesis is feasible in nearly all pregnancies. Rarely, relative sac position or maternal characteristics such as morbid obesity or large fibroids may present a significant technical challenge to the operator. Fibroids should be avoided whenever possible because going through them is painful and renders needle manipulation difficult. When one sac completely overlies the other, the single-needle technique should be considered, although little is known regarding loss or contamination rates following this technique. The use of indigo carmine makes cross-contamination between fetuses unlikely, because it is obvious when a particular fetus is being inadvertently tested a second time. Maternal contamination can occur but is rare. Postprocedural loss rates The American College of Obstetricians and Gynecologists estimates that the loss rate after second-trimester singleton amniocentesis is 1 in 200 [10]. The limited data available on multifetal amniocentesis are for twins. Postprocedural loss rates after twin amniocentesis have been reported to range from 2.3% to 8.1% [11–16]. Given the background pregnancy loss rate for twins before 24 weeks’ gestation of approximately 6% [17], it is unclear whether the increased loss rate (above the 0.5% rate for singletons) is attributable to the twin pregnancy or the procedure. Yukobowich et al compared three retrospective cohorts: 476 twin pregnancies undergoing amniocentesis, 489 women with singletons who had amniocentesis, and 477 women with twins who presented for ultrasound studies at a similar gestational age but who did not have an invasive procedure [11]. The loss rate within 4 weeks of the procedure was significantly higher in the twin amniocentesis group (2.7%) than in the exposed singletons (0.6%) or unexposed twins (0.6%). Other studies have not confirmed a higher loss rate associated with twin amniocentesis over the background loss rate of twins [12,14]. For example, in a retrospective case-control study, Ghidini et al compared 101 twins undergoing amniocentesis with 108 twin controls and found no difference in fetal loss rates between the two groups [14]. Risk factors associated with increased loss rates after multifetal amniocentesis have not been well characterized. Data describing these risks for singleton amniocentesis have been characterized and include maternal age, vaginal bleeding in the current pregnancy, and a history of abortion [18]. Other factors associated with increased loss rates include an increased number of attempts [7], the presence of green or brown pigmented amniotic fluid [19,20], and elevated maternal serum alpha-fetoprotein (MSAFP) as the indication for amniocentesis [21]. Operator experience does not seem to affect the loss rate in singleton amniocentesis [21], although this has not been investigated in twins.
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Amniocentesis for fetal lung maturity or infection Close to term it is not necessary to test both sacs, and the fetus sampled should be the one less likely to be mature, for example, the male fetus when fetuses are discordant for gender. At earlier gestational ages, discordance in lung maturity status is more likely, particularly for twins discordant for gender [22,23]; therefore, it seems reasonable to test both fetuses in pregnancies less than 36 weeks’ gestation. When evaluating for intrauterine infection, only the lower most sac (fetus A) should be sampled, because infection generally ascends from the vagina. If clinical suspicion is high and the fluid from sac A does not show evidence of infection, amniocentesis of other fetuses can be considered.
Chorionic villus sampling Chorionic villus sampling is an invasive procedure in which placental villi are obtained for performing prenatal diagnostic studies in women at increased risk for fetal chromosomal or genetic abnormalities. It is usually performed at 10 to 12 weeks’ gestation. Technique Chorionic villus sampling can be performed using a transabdominal or transcervical approach. When testing multiple pregnancies, a combination of both routes is often used. The approach is chosen based on operator experience and the relative locations of the fetal sacs and placentas. Dichorionic fetuses are each tested separately. Monochorionic fetuses share one placenta; therefore, they must be tested together with only a single sample. Whether using a transabdominal or transcervical approach, CVS is performed under continuous ultrasound guidance using an aseptic technique. The transabdominal approach uses a 20-gauge needle that is inserted into the placenta. Chorionic villi are then aspirated as the needle is moved back and forth within the placenta under negative pressure. When testing multiple fetuses via the transabdominal approach, separate needle insertions with fresh needles are performed to avoid cross-contamination of the specimens. The transcervical approach is usually performed with an aspiration catheter. A biopsy forceps can also be used [24]. The instrument is passed through the cervix and into the placenta under ultrasound guidance, and villi are aspirated similar to the transabdominal technique. Typically, only one fetus in a multifetal pregnancy can be tested using the transcervical approach. Antibiotic prophylaxis is not necessary. RhoGAM should be administered as indicated. A detailed written description of the relative sac positions and placental locations should accompany any multifetal CVS. The relative filling of the bladder should also be noted, because it may change the appearance of the sac
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and placental locations within the uterus. The operator must be able to identify each sac correctly at a later date, particularly in the setting of an affected fetus. Success and contamination Multiple fetuses can be sampled successfully by CVS in more than 99% of cases when performed by an experienced operator [6,24–28]. Contamination of fetal samples is a real concern, although, in experienced centers, this probably occurs in less than 2% of CVS procedures [6,24–29]. Contamination is a risk because separate placentas are often fused, and, unfortunately, there is no way to mark each placenta as it is tested, as can be done with indigo carmine during multifetal amniocentesis. Several strategies are employed to minimize the risk of contamination. The operator should fully evaluate placental positions before testing. A placenta may appear anterior in some views and posterior in others, particularly if the bladder is emptied or filled. Separate needles and catheters should be used for each fetus. The tip of the aspirating device should be placed close to the umbilical cord insertion site on each placenta to minimize the risk of testing the wrong fetus. Postprocedural loss rates Few studies have investigated outcomes of CVS in multifetal pregnancies, and those that have are small and provide data primarily on twins. Brambati et al reviewed 208 multiple pregnancies undergoing CVS in the first trimester (198 sets of twins and 9 sets of triplets) and compared the pregnancy outcomes of the dichorionic/diamniotic twin cohort with that of a control population of 63 sets of twins undergoing no invasive procedure [26]. There were no total pregnancy losses in either group and no differences in fetal and perinatal losses between the study and control populations [26]. Other series also report acceptably low loss rates (0.6% to 4.2%) [6,25,28] comparable with the background loss rate of twins of approximately 6% [17]. Furthermore, more than half of the losses reported after multifetal CVS occur more than 4 weeks after the procedure at a time when it is difficult to attribute the pregnancy loss to the procedure [30]. Chorionic villus sampling versus amniocentesis Once a patient has decided to have an invasive procedure, the decision to choose one procedure over another should be based on a combination of patientspecific factors, such as the likelihood of proceeding to multifetal pregnancy reduction, the gestational age at presentation, and the experience of the operator, as well as technical factors, such as the relative position of the sacs and maternal body habitus. The indication for invasive testing is also influential. The more likely the fetus is to be affected, the stronger CVS should be considered.
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The chief advantage of CVS is that it is performed at an earlier gestational age than amniocentesis, typically between 10 and 12 weeks’ gestation versus greater than 15 weeks. If the fetus is affected, a selective termination can be performed at an earlier gestational age for a substantially lower emotional impact and perhaps a lower rate of loss after selective termination [6,29]. Conversely, if the fetus is normal, peace of mind can be achieved earlier in the pregnancy, thereby enhancing maternal-fetal bonding [31] and lowering parental stress regarding the pregnancy. Finally, the early gestational age at which CVS can be performed enables fetuses to be tested before multifetal pregnancy reduction, ensuring that the nonreduced fetuses are chromosomally normal. A potentially higher postprocedural loss rate has been widely quoted as a disadvantage of CVS when compared with amniocentesis. Nevertheless, few studies have compared these procedures in multiple gestations. Wapner et al [32] evaluated the outcome of 161 twin pregnancies undergoing CVS and 81 twin pregnancies undergoing amniocentesis and found no differences in fetal loss rates or total pregnancy loss rates. Similarly, in a more recent retrospective review, Antsaklis et al compared pregnancy outcomes of 347 twin pregnancies undergoing amniocentesis with 69 twin pregnancies undergoing CVS and found no differences in the total pregnancy loss rate before 24 weeks (4.18% versus 4.54%), the rate of preterm delivery before 32 weeks (11.8% versus 16.7%), or the total fetal loss rate (8.8% versus 10.2%) [6]. In experienced hands, CVS seems to be as safe as amniocentesis in twin pregnancies. Another disadvantage of CVS is the higher contamination rate and increased need for an additional invasive procedure, required in 5% of CVS cases compared with 0.3% of amniocentesis cases in one series [29]. Additional procedures are primarily performed for evaluation of sampling error or to confirm confined placental mosaicism [30]. Identification of confined placental mosaicism may represent an advantage of CVS, because it identifies pregnancies at increased risk of perinatal morbidity [33] that may deserve increased fetal surveillance. Chorionic villus sampling is a procedure that is not as widely available as amniocentesis, primarily because it is more difficult. Furthermore, it has been shown with singleton CVS that, unlike in amniocentesis, postprocedural loss rates decrease with operator experience [34]. Multifetal CVS represents a technically challenging procedure, and the availability of experienced operators should factor into the decision of whether to undergo amniocentesis or CVS.
Multifetal pregnancy reduction Multifetal pregnancy reduction refers to the nonselective reduction of one or more fetuses of a multifetal pregnancy. The purpose is to reduce the risk of complications associated with multifetal pregnancies and to optimize the chance of carrying and delivering one or several healthy infants. It is done by reducing the actual number of fetuses in the uterus. Multifetal pregnancy reduction should be considered by any woman with three or more fetuses.
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Chorionicity Knowledge of chorionicity is crucial before performing multifetal pregnancy reduction. The traditional technique described herein assumes multichorionic placentation in which there are none of the interfetal placental vascular anastomoses commonly found with monochorionic fetuses. If two fetuses have a shared circulation and one is injected with a toxin, there is a high likelihood that the toxin will get into the co-twin’s circulation and cause fetal death [35]. In addition, acute adverse hemodynamic changes in the survivor may occur owing to blood loss into the low-pressure vascular system of the dead fetus. For this reason, as well as the risk of pregnancy complications inherent to monochorionic twins, the monochorionic pair of a multifetal pregnancy are often preferentially reduced. Reduction of a single fetus in a monochorionic pair can be done but requires special techniques with much higher complication rates. Because of this difficulty, reduction of a single fetus in a monochorionic pair is usually only considered when one of the fetuses is anomalous (selective termination) or in the setting of twin-to-twin transfusion syndrome. Chorionicity is best established by ultrasound in the first trimester by identification of the presence or absence of the lambda sign. The lambda sign is a triangular projection of echodense tissue between two sacs representing two chorions and two amnions. Before 13 weeks, chorionicity can be correctly established by the presence or absence of the lambda sign in 100% of cases [26].
Chorionic villus sampling before multifetal pregnancy reduction One or more fetuses can be tested by CVS before multifetal pregnancy reduction. This testing is desirable for several reasons. First, patients who are considering multifetal pregnancy reduction are often at high risk for carrying a fetus with aneuploidy owing to maternal age and desire invasive testing. Second, noninvasive means for assessing aneuploidy risk have lower sensitivity and specificity for multifetal pregnancies than for singletons, and some of those that are available (second-trimester serum analyte screens or ‘‘quad’’ screens) are not reliable after multifetal pregnancy reduction owing to falsely elevated AFP [36]. CVS before multifetal pregnancy reduction provides the patient and provider with the assurance that chromosomally normal fetuses are being left intact. Several studies have shown that performing CVS before multifetal pregnancy reduction does not increase the postprocedural pregnancy loss rate above that of multifetal pregnancy reduction alone [25,37,38]. An accurate verbal description and a diagram of the relative positions of the gestational sacs and placentas must be carefully recorded so that if an abnormal karyotype is found, it can be correctly matched to the affected fetus. This description should also include the relative fullness of the bladder, because filling or emptying of the bladder can change the intrauterine appearance.
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Technique Multifetal pregnancy reduction is performed as an outpatient procedure in the office. At the authors’ center, the patient and her partner undergo significant pre-procedure counseling, usually on a day separate from the day of the procedure. Ultrasound examination is performed to confirm chorionicity. The relationship of the gestational sacs to each other is carefully noted. If CVS has been performed before multifetal pregnancy reduction, care is taken to identify correctly each fetus that has been tested. Each fetus is measured, the fluid level in each sac is assessed, and the anatomy of each fetus is examined to identify any gross abnormalities. Although multifetal pregnancy reduction is usually performed at the end of the first trimester, a time before which a comprehensive anatomic survey is likely to reveal any abnormalities, a limited assessment of the anatomy and nuchal translucency can be performed to determine the risk for aneuploidy or structural abnormality. In general, the fetuses that are reduced are selected for technical reasons and are usually those closest to the anterior uterine wall or fundus. The fetus above the cervix is avoided whenever possible because of a hypothetical increased risk of infection or uterine irritability if that fetus were reduced. Fetuses with a lagging crown-rump length, decreased fluid, increased nuchal translucency, or an obvious anomaly are preferentially reduced. If CVS has been performed before multifetal pregnancy reduction, fetuses that are known to be chromosomally normal are left intact, and abnormal or untested fetuses are preferentially reduced. After identification of the fetus to be reduced, the abdomen is prepared with Betadine. Under continuous ultrasound guidance, a 22-gauge spinal is inserted into the fetal thorax, and approximately 5 mEq of potassium chloride (2 mEq/mL) is injected. Asystole is usually seen within 1 minute of injection of potassium chloride; the needle is left in place until asystole has been observed for 2 minutes and then withdrawn. Additional fetuses can be reduced by directing the needle into a different sac or, more commonly, by using a separate needle stick. Antibiotic prophylaxis can be given and RhoGAM administered as indicated. An ultrasound 1 hour after the procedure is recommended to confirm asystole in the reduced fetuses and the presence of cardiac activity in the nonreduced fetuses. The fetuses are left in situ and, over a period of weeks to months, are resorbed. Natural history of multifetal pregnancies Multifetal pregnancy reduction was developed as a technique to optimize the pregnancy outcome of high-order multifetal pregnancies. Any discussion of whether multifetal pregnancy reduction improves these pregnancy outcomes requires an appraisal of their natural history. Multiple gestations are at higher risk for fetal, neonatal, and maternal complications when compared with singleton pregnancies. Total pregnancy loss rates (before 24 weeks) rise with an increasing number of fetuses and have been estimated to be 6% for twins [17], 11.5% for triplets [39,40], and 16.7%
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for quadruplets and quintuplets [41,42]. Similarly, mortality rates are significantly higher than for singletons and increase with the number of fetuses. As calculated from 152,233 twin, 5356 triplet, 362 quadruplet, and 36 quintuplet births in the United States from 1995 to 1997, early mortality rates (death from 20 weeks’ gestation to the first year of life) were 4.8% for twins, 8.6% for triplets, 10.8% for quadruplets, and 28.9% for quintuplets [43]. There is also a concomitant increase in associated morbidities. For example, a 47-fold increase in cerebral palsy in triplet pregnancies and an eightfold increase in twins when compared with singletons has been observed, primarily owing to high rates of prematurity [40]. In one series, 44% of 94 couples with triplets had at least one significantly impaired child [44]. Similarly increased rates are seen in other types of morbidities. The increased rate of fetal complications associated with multiple pregnancies is primarily attributable to high rates of prematurity. Furthermore, mean gestational age at delivery and birthweight decrease as the number of fetuses increases, with average gestational ages at delivery for twins, triplets, and quadruplets estimated to be 35, 33, and 31 weeks [39]. Multifetal pregnancy reduction was developed to cope with these high rates of morbidity and mortality, primarily by decreasing rates of prematurity and total pregnancy loss. Pregnancy outcomes after multifetal pregnancy reduction Observational data from the largest published single center series of 1000 cases of multifetal pregnancy reduction report an unintended pregnancy loss rate, defined as the unintended loss of the entire pregnancy before 24 weeks, of 5.4% [45], which is comparable with the loss rate of nonreduced twins and lower than the loss rate of nonreduced triplets. The largest collaborative series of more than 3500 cases from 11 centers in five countries reported an unintended loss rate of 9.6% [46]. The lower loss rate seen in the single center series is most likely explained by the inherent differences of a multicenter experience versus that of a single center with a small number of operators and a well-established protocol [30]. Furthermore, the collaborative series included some transvaginal and transcervical procedures, which have been associated with higher loss rates, whereas the single center series only used the transabdominal approach. Most of the losses in both series occurred many weeks after the procedure, making it hard to attribute these losses to multifetal pregnancy reduction. For example, Stone et al found that more than 55% of total pregnancy losses occurred more than 8 weeks after the reduction. These losses may be more reflective of the multifetal pregnancy (most reductions in this series were to twins) than of the procedure. The total pregnancy loss rate within 4 weeks of the procedure in this series was only 0.8% and accounted for 14.8% of the total losses observed [45]. Both series found that loss rates decreased with a lower starting number and finishing number of fetuses [45,46]. For example, data collected by Stone et al showed that loss rates were lowest when twins were reduced to singletons (2.5%), remained stable (approximately 5%) when the starting number was three, four, or
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five fetuses, and increased to 12.9% when the starting number was six or more [45]. There was a trend toward lower loss rates when the pregnancy was reduced to a singleton (3.5%) versus twins (5.5%), although a limited number of reductions to a singleton prevented this from being statistically significant [45]. Loss rates were significantly higher when the pregnancy was reduced to triplets (16.7%) [45]. The loss rates observed approximate those of naturally occurring twins and triplets. Loss rates in both series decreased with operator experience [45,46]. The mean gestational ages at delivery for finishing numbers of one, two, and three fetuses were 37.9, 35.3, and 33.5 weeks [45]. Multifetal pregnancy reduction improves the outcome of multifetal pregnancies above and beyond a reduction in total pregnancy loss rates. This effect is clearly illustrated in the results of a recently published meta-analysis comparing twins reduced from triplets with nonreduced triplets, which are summarized in Table 1. Multifetal pregnancy reduction significantly reduces the risk of severe prematurity and perinatal mortality while increasing the ‘‘take home baby rate.’’ The outcome of pregnancies reduced to twins seems to be comparable with that of nonreduced twins. Yaron et al compared 143 triplet pregnancies reduced to twins with 812 nonreduced twins [17]. Total pregnancy loss rates before 24 weeks were similar between reduced twins (6.2%) and nonreduced twins (5.8% to 6.3%), as was gestational age at delivery (approximately 35 weeks in both groups) and mean birthweights. Other studies have reported similar findings [30,47], although some have suggested that the mean birthweight of twins after multifetal pregnancy reduction is decreased when compared with that of nonreduced twins [48,49], particularly with increased starting numbers [45]. Psychologic impact of multifetal pregnancy reduction Despite improved pregnancy outcomes after multifetal pregnancy reduction, there is a significant psychologic impact on the parents. Most patients with highorder multiples conceive with assisted reproductive techniques, usually after many years of infertility. The decision to terminate wanted, usually normal, fetuses can be agonizing, and couples may later regret the decision to undergo the
Table 1 Meta-analysis of published studies of reduced and nonreduced triplets from 1984 to 2001 Parameter
Reduced triplets (3 to 2) (n = 2230)
Nonreduced triplets (n = 604)
Odds ratio
P
Pregnancy loss b 24 weeks Delivery b 28 weeks Delivery b 32 weeks Perinatal mortality Take home baby rate
5.1% 2.9% 10.1% 26.6/1000 93%
11.5% 8.4% 20.3% 92.2/1000 78.6%
0.45 0.35 0.5 0.3 0.3
b .001 .0001 b .0001 b .0001 .002
(0.3–0.6) (0.2–0.6) (0.37–0.66) (0.2–0.5) (0.2–0.7)
Adapted from Wimalasundera RC, Trew G, Fisk NM. Reducing the incidence of twins and triplets. Best Prac Res Clin Obstet Gynaecol 2003;17:309–29.
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procedure regardless of pregnancy outcome [50]. Patients should be counseled that parents of multiples also sustain extreme psychologic stress. Even if all of the infants are healthy, which high-order multiples usually are not, taking care of multiple infants at the same time is extremely draining physically and emotionally, not to mention economically burdensome. With the added risk of one or more infant experiencing prolonged NICU stays, the need for complex medical care, and significant deficits, the stress could be overwhelming. In a prospective study comparing patients undergoing multifetal pregnancy reduction with those who did not reduce their triplet pregnancy, mothers who underwent multifetal pregnancy reduction had less anxiety and depression and more satisfactory relationships with their children [51]. Although many women in the multifetal pregnancy reduction group expressed sadness and guilt 1 year later, the majority reported a significant reduction in emotional pain at 2 years [51].
Selective termination Selective termination is a procedure in which one anomalous fetus in a multifetal pregnancy is terminated. When one or more fetuses in a multifetal pregnancy are found to be anomalous, the patient has three choices. The first is to manage the pregnancy expectantly; the second is to terminate the entire pregnancy; and the third is to terminate selectively the affected fetus. Selective termination can be performed for a chromosomal, structural, or genetic abnormality, usually identified by ultrasound or an invasive prenatal diagnostic test such as CVS or amniocentesis. It can be performed at any time from the time of diagnosis (generally after 10 weeks) up to the legal limit of termination. The legal limit for termination in most states is 24 weeks; third-trimester selective termination can be performed legally in certain US states and in some other countries [52]. Selective termination was initially developed to prevent the survival of a severely affected infant [53]. As experience with selective termination increased with a concomitant improvement in procedural outcomes, it became increasingly offered for lethal anomalies to reduce the emotional impact of giving birth to a child who would not live [53]. It is theorized that, in some cases, termination of the anomalous twin may optimize the outcome of the normal fetus. For example, anencephaly is often complicated by polyhydramnios owing to impaired fetal swallowing, which invariably results in preterm labor. Selective termination of this fetus may decrease the rate of preterm labor and the effects of prematurity on the normal co-twin [30]. Technique As is true for multifetal pregnancy reduction, the traditional technique for selective termination can only be used if the fetuses are multichorionic. As
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discussed previously, chorionicity is usually determined by the presence or absence of the lambda sign on first-trimester ultrasound. If the pregnancy is already in the latter half of the second trimester, it may be more difficult to determine chorionicity. Fetuses discordant for gender or that appear to have separate placentas are obviously dichorionic. Specialized genetic tests such as quantitative fluorescent polymerase chain reaction assays and polymorphic small tandem repeats can be used for rapid determination of zygosity [54,55] for pregnancies with uncertain chorionicity. Another vital preprocedure consideration is correct identification of the anomalous fetus. If the fetuses are discordant for gender or a structural anomaly, the affected fetus can be determined visually at the time of the procedure by ultrasound. If the anomaly cannot be identified on ultrasound (eg, in many genetic diseases), the operator must rely on previously documented fetal and placental positions, underscoring the importance of a precise detailed description of the location of each fetus at the time of an invasive diagnostic procedure. Correct identification of the affected fetus can be challenging if several weeks have passed since the invasive diagnostic procedure, because growth of the uterus and fetuses may alter the appearance of their relative positions. Usually, the affected fetus is readily identifiable. If there is any doubt, rapid determination of karyotype by fluorescent in situ hybridization should be performed and the results obtained before selective termination [30]. Documentation of the karyotype of the terminated fetus at the time of the procedure by amniocentesis or fetal blood is recommended to confirm the correct fetus has been terminated [30]. Once the fetus to be terminated has been correctly identified, the procedure is performed in a manner similar to multifetal pregnancy reduction. Under ultrasound guidance, potassium chloride is injected into the thorax of the affected fetus via a transabdominal route and the needle left in place until asystole is observed for 2 minutes. The amount of potassium chloride required will depend on the gestational age/size of the fetus. Prophylactic antibiotics are usually given and RhoGAM administered as indicated. The fetus is left in situ while the pregnancy continues. If performed in the late first trimester or early second trimester, the fetus may be resorbed. At later gestational ages, the fetus will not be completely resorbed, but, over a period of weeks to months, the amniotic fluid around the fetus will disappear, and the fetal tissue will become significantly condensed. The reduced fetus is typically delivered with the placenta and is usually too macerated for any meaningful evaluation. Pregnancy outcome after selective termination The overall pregnancy loss rate, defined as the unintended total pregnancy loss rate before 24 weeks, was 4.0% in the largest single center series of 200 patients [56] and 7.5% in the largest collaborative experience of 402 patients [57]. The lowest loss rate (2.4%) after selective termination is observed with a starting number of two [56]. This rate increases significantly to 11.1% when starting with three or more fetuses and is highest when more than one fetus is terminated
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(42.9%) [56]. In continuing pregnancies, the outcome after selective termination is generally favorable, with low rates of prematurity and few maternal complications. For women not experiencing a pregnancy loss or electively terminating their pregnancy, the median gestational age at delivery was 37.1 weeks in one series [56]. Data from early studies suggested that rates of pregnancy loss and preterm delivery increased with increasing gestational age at the time of selective termination [57,58]. More recent data suggest that there is no advantage to performing selective termination at earlier gestational ages [56]. In fact, in one series, there was a trend toward a higher rate of pregnancy loss in patients undergoing selective termination at or before 20 weeks’ gestation when compared with selective termination after 20 weeks (5.9% versus 1.3%, P = .09) [56]. Patients and physicians should be reassured that selective termination in experienced hands is safe at any gestational age. Selective termination of a monochorionic fetus Monochorionic fetuses can occasionally be discordant for anomalies, and it may be desirable to terminate the affected co-twin. Interfetal anastomoses via the placenta prohibit the use of potassium chloride. As a result, many alternative techniques have been tried. The majority of these focus on occlusion of the cord of the affected fetus. A review of these techniques appears elsewhere in this issue.
Percutaneous umbilical blood sampling Percutaneous umbilical blood sampling (PUBS) is typically performed for special diagnostic and therapeutic indications, such as an evaluation for hydrops or infection, or to perform specialized studies that cannot be accomplished by amniocentesis or CVS. It can also be performed when an abnormality is suspected late in pregnancy for a more rapid diagnosis. PUBS is an invasive procedure in which fetal blood is sampled from the umbilical vein, usually at the placental umbilical cord insertion site. An anemic or thrombocytopenic fetus can also be transfused through the same needle if indicated. Percutaneous umbilical blood sampling is a technically challenging procedure and is considerably more invasive than other diagnostic studies, because the needle enters the fetal circulation. The procedure-related fetal loss rate following PUBS in singletons is higher than with CVS and amniocentesis and is estimated to be 1% to 2% [59]. The risk is recognized to vary with the indication, with ‘‘healthy’’ fetuses having the lowest risk (eg, those undergoing genetic studies) and ‘‘sick’’ fetuses having significantly higher risk (eg, a fetus with hydrops or severe thrombocytopenia). There is only one published study describing this technique in multiple gestations. Antsaklis et al retrospectively reviewed 89 cases of fetal blood
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sampling procedures in twin pregnancies performed from 1977 to 2000 [59]. The vast majority of these procedures were performed on unimpaired fetuses for the purpose of genetic diagnosis. The mean gestational age at the time of the procedure was 20.3 weeks. All of the fetuses (178) were successfully sampled. Seventeen pregnancies were subsequently terminated, 12 underwent selective termination, and 5 were lost to follow-up, leaving a final cohort of 55 pregnancies (110 fetuses). The overall procedure-related fetal loss rate, defined in this series as miscarriage or fetal death within 2 weeks of the procedure, was 8.2% (9/110) [59]. Because of the high loss rate and considerable technical challenge PUBS presents in multifetal pregnancies, this procedure has few true indications.
Summary Several invasive procedures are now commonly performed in multifetal pregnancies. Techniques for prenatal diagnosis performed in multifetal pregnancies, such as amniocentesis and CVS, present specific technical challenges when compared with their performance in singletons and are best performed by experienced operators to increase the success of the procedure, reduce contamination, and minimize postprocedure complications. Procedures developed to cope with the sequelae specific to multifetal pregnancies, such as multifetal pregnancy reduction and selective termination, are also commonly performed with generally good outcomes. The moral and psychologic issues associated with these procedures are extensive and complex for the patient and the physician, but it is clear that pregnancy outcomes of high-order multiples (triplets and up) are improved by multifetal pregnancy reduction. It is hope that with better regulation of assisted reproductive techniques, the need for these specialized procedures will become obsolete.
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