1 Instituto Valenciano de Infertilidad (IVI), 2 Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Spain and 3 Hospital of the University of Pennsylvania, Department of Obstetrics and Gynecology, Pennsylvania, USA
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Abstract |
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Key words: embryo reduction/multifetal pregnancy/transvaginal ultrasound-guided technique
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Introduction |
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Multiple pregnancy has a higher likelihood of obstetric and perinatal morbidity and mortality, especially when more than two fetuses are present. The singleton abortion rate after IVF and embryo transfer in our centre is 22%, and that risk increases by 20% for each additional fetus (Simón et al., 1990). Triplets have a perinatal morbidity and mortality ranging from 5% to 25% (Newman et al., 1989
; Bollen et al., 1993
; Jan et al., 1997
; Yaron et al., 1999
). Some 15% of newborns from multiple pregnancies do not survive the infancy period, while 20% of surviving babies show long-term sequelae (Hobbins, 1988
).
Given these facts, first-trimester embryo reduction may be an effective and safe option (Fasouliotis and Schenker, 1997). However, psychological, sociological and ethical considerations should be taken into account when measuring the cost-effectiveness of this rescue technique. The individualization of each clinical condition, as well as meticulous selection of the number of transferred embryos, should be routine procedure in assisted reproduction treatment units.
This report describes the experience of our centre in 149 embryo reduction cases using a new modified transvaginal ultrasound-guided technique. Pregnancy outcome was compared with a non-reduced control group in order to establish the benefits of this new embryo reduction technique. It is acknowledged, however, that the correct design to demonstrate the advantages of our technique would be a prospective, controlled, randomized double-blind study comparing the different techniques.
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Materials and methods |
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A routine vaginal ultrasound, confirming the number of embryos with heart activity, was performed before surgery. Under general anaesthesia using propofol 10% (Propofol Abbot E.G.F; Abbot Laboratories, Madrid, Spain), surgical field cleaning was carried out with povidone iodine (Betadine dermic solution; Sarget Laboratories, Burdeos, France). The embryos were then visualized using a 7.5 MHz transvaginal ultrasound transducer (Sonoline SI-400; Siemens AG, Erlangen, Germany) in order to verify their number, position, size and heart activity. The smallest embryo and/or that located closest to the fundus of the uterus was selected for embryo reduction. This protocol reduced the technical difficulties of the procedure, and avoided the greater bleeding or infection risks resulting from the selection of a sac located near the cervix (Desai et al., 1993). The same 30 cmx1.8 mm outer diameter needle used for the ovarian follicular puncture (Oocyte Puncture Set; Euro Surgical Limited, Guildford, Surrey, UK) was inserted through a guide attached to the transvaginal ultrasound transducer. Exact alignment between the needle and the ultrasound screen guide was necessary to perform the procedure with accuracy. If the uterus was mobile, an assistant pushed with two hands on the hypogastrium, supporting the uterus region during the needle puncture. At this point, the surgeon started the embryo heart puncture until asystolia was confirmed. The use of a KCl and/or NaCl solution, or injection into the sac of other chemical substances was avoided. Without aspirating embryo tissue or amniotic fluid, it was possible to visualize adequately the embryo throughout the entire procedure. All embryo reductions were carried out by the same surgeon (J.R.).
Women were discharged from the clinic after a bed rest and an average observation period of 45 min. Thereafter, the following treatments were administered: 750 mg of prophylactic amoxycillin (Clamoxyl; SmithKline-Beecham Laboratories, Madrid, Spain) every 8 h for 5 days, an analgesic such as magnesic metamizol (Nolotil; Europharma Laboratories, Madrid, Spain) and, when indicated, Rh-negative immune globulin prophylaxis (Rhesogamma P; Centeon Laboratories, Barcelona, Spain). The first ultrasound was carried out after one week. All patients underwent subsequent prenatal routine follow-up.
The control group included 149 assisted reproduction patients with non-reduced singleton or twin pregnancies performed over the same time period as the studied embryo reduction group. A stratified random selection was carried out according to the number of sacs visualized (one or two).
Statistical evaluation
Data were expressed as mean ± SD. For statistical comparison, analysis of variance (ANOVA) was used to compare mean patient age, birth weight, and mean gestational age at delivery. Chi-square and Fisher's exact tests were used to compare the miscarriage, early postsurgical complications, malformations, and neonatal mortality rates. A P-value of 0.05 was considered to be statistically significant. The analyses were performed with the SPSS statistical package (Statistical Package for Social Sciences, Chicago, IL, USA).
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Results |
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The incidence of early postoperative complications, defined as observed complications between 24 h and 14 days after the embryo reduction, are shown in Table I. Patients who showed chorioamnionitis were given a dilatation and curettage (D & C), preceded by intra-operative prophylaxis with antibiotics (intravenous third-generation cephalosporin or metronidazole). After surgery, each patient took oral antibiotics for 7 days, commencing on the day of surgery (clindamycin 500 mg every 8 h, plus ciprofloxacin 500 mg every 12 h). No maternal morbidity was registered in the subsequent follow-up.
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The incidence of early complications and neonatal outcomes in reduced pregnancies was similar to that of the control group (Table IV). However, the birth weight of reduced singleton pregnancies was lower than that of their non-reduced counterparts (P < 0.02).
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Discussion |
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The transvaginal technique is performed between the seventh and 11th weeks, by injecting NaCl (Yovel et al., 1992) or KCl (Mansour et al., 1999
) solution into the fetal thorax. The injection of such substances into the embryo or fetal thorax is not a risk-free procedure however, and cases of anencephaly (Boulot et al., 1992
) or limb amputation (Roze et al., 1989
) have been described. If the KCl solution accidentally reaches the amniotic fluid of the remaining embryos, this could result in a total pregnancy loss (Tabsh, 1990
).
More recently, the transvaginal technique has been performed with total or partial embryo aspiration. Single embryo tissue aspiration was compared with KCl solution injection (Mansour et al., 1999), and showed a lower miscarriage rate (8.8% and 30% respectively). Two different groups, using transvaginal embryo puncture aspiration without injecting substances, reported a low incidence of miscarriage (05.3%) (Itskovitz-Eldor et al., 1992
; Vauthier-Brouzes and Lefebvre, 1992
). However, these series included few cases (22 and 19 patients respectively), and such low rates have not been confirmed in studies with higher numbers of patients (Evans et al., 1994
; Dechaud et al., 1998
). Another study (Coffler et al., 1999
) reported a 6.7% miscarriage rate, but 8% of these procedures failed at the first attempt, compared with only 0.7% in the present study. A summary of published reports on different embryo reduction methods and their subsequent miscarriage rates is listed in Table V
.
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Ideally, embryo reduction should be used only when there is no chance of spontaneous embryo reabsorption, which occurs in 16% to 43% of all multiple pregnancy cases (Seoud et al., 1992; Bollen et al., 1993
). However, there is controversy over when spontaneous reabsorption may occur. While some reports point to weeks 9 through 12 (Blumenfeld et al., 1992
; Bollen et al., 1993
), other studies (Manzur et al., 1995
) report that 90% of the vanishing cases occur up to the seventh week, and never after week 13. In this regard, a retrospective study of our oocyte donation programme shows that 80% of the spontaneous reabsorptions in multiple pregnancy occurred before the ninth week (unpublished data). In the present study, embryo vanishing occurred in four patients (3%) among those reduced to twins, three of them before the ninth week, and the other one during the 11th week. All of these patients continued their pregnancies with the remaining embryo.
The observed low incidence of embryo vanishing after reduction might be explained by the fact that the embryo with the smallest or weakest heart activity is the one reduced. According to others (Stern and Coulam, 1992), 79% of compromised cardiac activity and low development among 6-week-old embryos end in spontaneous reabsorption; in contrast, only 8% of those with an adequate size for their gestational age resulted in a vanishing embryo. Because the spontaneous reabsorption risk rate after transvaginal ultrasound visualization of cardiac embryo activity is only 56% (Kol et al., 1993
), it would be appropriate to schedule embryo reduction once the fetal heart is visualized.
In accordance with this, Table I shows that most of our procedures were performed between the seventh and ninth weeks. After grouping our cases according to the gestational age at procedure (<8 versus
8 weeks), we found no significant differences regarding post-surgical complications or neonatal outcomes. However, we observed that during the eighth to ninth weeks of pregnancy is the optimal period to perform embryo reduction, as later gestational ages result in greater technical difficulties, more time-consuming surgeries, and a lower probability of spontaneous embryo reabsorption.
Embryo reduction is generally an accepted alternative for quadruplets or higher-order pregnancies. However, controversy remains in cases of triplet pregnancies, even though perinatal mortality rates of 5% to 20% have been reported (Newman et al., 1989; Bollen et al., 1993
; Jan et al., 1997
). In comparing twin-reduced pregnancies with non-reduced higher-order pregnancies, reports have indicated a lower incidence of prematurity, lower birth weight, and neonatal morbidity and mortality for the reduced embryos (Macones et al., 1993
; Lipitz et al., 1994a
). It is also significant that the reduction of triplet pregnancies to twins has secondary benefits, such as lower medical costs and reduced maternal hospitalization, which consequently also reduces maternalnewborn morbidity (Souter and Murphy, 1998
). In this respect, when studying the outcome of IVF multiple pregnancy, it has been reported (Seoud et al., 1992
) that 50% of triplet pregnancies and 75% of quadruplet pregnancies required prenatal hospitalizations of long duration (up to 77 days).
We recommend embryo reduction for twin pregnancies because the obstetric risks are acceptable, and an adequate rate of at least one baby at home is almost guaranteed. In our centre, 85.1% (n = 114) of the couples who underwent a reduction to twins took both children home, and the other six couples had at least one surviving baby. Embryo reduction to singleton was considered in two patients carrying two sacs (one contained monozygotic twins and was reduced), two cases of uterine malformation, five cases with serious maternal medical risk, and six cases due to parental discretion. We did not find any significant differences between the two types of reduction with respect to early post-surgical complications, baby take-home rate or neonatal outcomes (Table III). Moreover, birth weight and gestational age at delivery, of both twins and singletons, are no different from those reported in IVF pregnancies or the general population (Seoud et al., 1992
; Lipitz et al., 1994b
; Antsaklis et al., 1999
; Kuno et al., 1999
; Yaron et al., 1999
). The fetal discordance rate in twins was 9%, significantly lower than previously described rates (Seoud et al., 1992
; Silver et al., 1997
). The malformation (2%) and perinatal mortality (4.4%) rates were in concordance with the rates usually recorded for twin pregnancies: 0.3% to 4% and 3.8% to 4.93% respectively (Little and Bryan, 1986
; Dommergues et al., 1991
; Seoud et al., 1992
; D'Souza et al., 1997
; Antsaklis et al., 1999
).
When we compared reduced pregnancies with their respective control group (Table IV), only the birth weight among those reduced to singletons was significantly lower. However, this did not represent intrauterine growth restriction, and pre-term delivery did not occur in any of these cases.
In conclusion, the transvaginal ultrasound-guided technique is a feasible option for the management and prevention of the medical and obstetric risks associated with high-order multiple pregnancy resulting from assisted reproduction treatment. Embryo reduction should be carried out between the eighth and ninth weeks of pregnancy, using the technique described in this study. Ideally, one should attempt to reduce multiple pregnancy to twins. However, if reduction to singletons is necessary (strictly selected cases), one should expect the same results in respect of post-surgical complications, expected pregnancy and neonatal outcomes.
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Notes |
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References |
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Submitted on April 14, 2000; accepted on June 30, 2000.