Embryo reduction of multifetal pregnancies following assisted reproduction treatment: a modification of the transvaginal ultrasound-guided technique

G. Ibérico1, J. Navarro1, L. Blasco1,3, C. Simón1,2, A. Pellicer1,2 and J. Remohí1,2,4

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
First-trimester transvaginal embryo reduction is an effective alternative for the management of multifetal pregnancy in assisted reproduction. We have modified the transvaginal technique by performing an intracardiac embryo puncture until asystolia is verified, without the injection of any substances. Any aspiration of embryo tissues or amniotic fluid was avoided. A total of 149 multifetal pregnancies was reduced to twins (n = 134) or singletons (n = 15) at early gestational age (7.8 ± 0.8 weeks). Eleven cases (7.3%) of miscarriage, two cases (1.3%) of chorioamnionitis, and 17 cases (11.4%) of transient spotting were recorded as postoperative complications. Vanishing of one embryo occurred in four cases (3.0%) of those reduced to twins. The baby take-home rate was 89.5% for twins and 80.0% for singletons. Pregnancy outcome was analysed and compared with a control group of women with non-reduced multiple pregnancies. The birth weight of singleton pregnancies after reduction was lower (2929 ± 160 versus 3291 ± 422 g; P < 0.02). These studies show that early transvaginal intracardiac embryo puncture is an effective and safe technique.

Key words: embryo reduction/multifetal pregnancy/transvaginal ultrasound-guided technique


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Multiple pregnancy constitutes a common iatrogenic outcome of ovarian stimulation with fertility drugs and assisted reproductive technology (Seoud et al., 1992Go). The prevalence of multiple pregnancy in these situations has shown an exponential increase during the past two decades (Botting et al., 1987Go; Mansour et al., 1999Go). Moreover, the incidence of multiple pregnancy following assisted reproduction treatment is also directly related to the number of transferred embryos (Fujii et al., 1998Go).

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., 1990Go). Triplets have a perinatal morbidity and mortality ranging from 5% to 25% (Newman et al., 1989Go; Bollen et al., 1993Go; Jan et al., 1997Go; Yaron et al., 1999Go). Some 15% of newborns from multiple pregnancies do not survive the infancy period, while 20% of surviving babies show long-term sequelae (Hobbins, 1988Go).

Given these facts, first-trimester embryo reduction may be an effective and safe option (Fasouliotis and Schenker, 1997Go). 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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Between January 1996 and December 1999, 149 procedures and their outcomes were recorded in women with multiple pregnancy (111 triplets, 32 quadruplets, six quintuplets). These pregnancies resulted from 139 IVF embryo transfers, seven intrauterine inseminations (IUI) with homologous spermatozoa, two IUI with donor spermatozoa, and one zygote intra-Fallopian tube transfer (ZIFT). Each patient was informed about the potential risks of the technique, and written consent was obtained before the surgical procedure was carried out.

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., 1993Go). 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).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The average patient was aged 33 ± 4.5 years. Of the 149 embryo reduction procedures, 128 (86%) were performed between the seventh and ninth weeks of gestation (mean 7.8 ± 0.8 weeks); 134 women (90%) underwent reduction to twins, and 15 (10%) to one embryo. The average time required for the embryo reduction was 2.1 ± 0.5 min per sac in early gestation (sixth to ninth weeks), increasing to 5.5 ± 2.4 min per sac for later procedures, due to technical difficulties brought about by increased embryo size. Nearly all embryo reduction procedures were successfully performed in a single session, and only one case had to be repeated a week later. No complications occurred due to the surgery or the use of general anaesthesia.

The incidence of early postoperative complications, defined as observed complications between 24 h and 14 days after the embryo reduction, are shown in Table IGo. 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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Table I. Type of embryo reduction and early postoperative complications
 
Complications and neonatal outcome according to the week in which the embryo reduction was performed are presented in Table IIGo. In establishing a break point at 8 weeks, no significant differences were found between the two subgroups.


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Table II. Complications and neonatal outcome according to the week in which the reduction was performed (n = 149)
 
Overall, pregnancy outcome was similar between patients in whom embryos were reduced to twins and to singletons (Table IIIGo). The non-significance of differences found might have been due to the limited number of cases included, and consequent lack of statistical power. Only transient spotting (defined as spotting of <48 h duration) showed a significant difference between the groups (P < 0.04).


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Table III. Pregnancy outcome in relation to the final number of fetuses
 
The observed fetal discordance rate in twins (defined as a birth weight difference >25%) was 9%. The pre-term delivery rate (defined as fetuses delivered before 37 weeks) in twin pregnancies was 48.5% (n = 65), with a severe pre-term rate (defined as fetuses delivered before 32 weeks) of 11.2% (n = 15). Two cases (1.3%) of stillbirth occurred. The perinatal mortality rate was 4.4% (n = 9 newborns, and a 30-week stillbirth), mainly due to severe pre-term labour. The latter group included five registered cases (2%) of newborns with congenital malformations (one each with craniosynostosis, hydrocephalus, spina bifida, pyloric stenosis and urinary tract malformations). A total of 120 patients (89.5%) with twin pregnancies took home at least one baby, while 114 (95%) of these took both babies home.

The incidence of early complications and neonatal outcomes in reduced pregnancies was similar to that of the control group (Table IVGo). However, the birth weight of reduced singleton pregnancies was lower than that of their non-reduced counterparts (P < 0.02).


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Table IV. Comparison of reduced twin and singleton pregnancies with their respective control group
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Three embryo reduction techniques have been described: transabdominal, transcervical and transvaginal. The transabdominal technique, which is performed between the ninth and 14th weeks of pregnancy, involves injection of NaCl or KCl solution near to or inside the fetal heart (Lynch et al., 1990Go; Yovel et al., 1992Go), and/or amniotic fluid aspiration. The method entails a greater technical difficulty, with miscarriage rates ranging from 10.6% to 40% (Shalev et al., 1989Go; Maymon et al., 1995Go; Antsaklis et al., 1999Go), and pre-term labour ranging from 20% to 64% of the cases (Shalev et al., 1989Go; Tabsh et al., 1990; Sebire et al., 1997Go). The transcervical technique consists of a mechanical cervical dilatation performed between the eighth and ninth weeks, followed by an embryo aspiration through the cervix using a Karman or a number 8 metallic cannula (Berkowitz et al., 1988Go; Salat-Baroux et al., 1988Go). This technique is no longer used on a practical basis due to the high complication rates, including chorioamnionitis (10%; Salat-Baroux et al., 1988Go), bleeding (33%; Berkowitz et al., 1988Go) and miscarriage (12–24.8%; Salat-Baroux et al., 1988Go; Evans et al., 1994Go; Dechaud et al., 1998Go).

The transvaginal technique is performed between the seventh and 11th weeks, by injecting NaCl (Yovel et al., 1992Go) or KCl (Mansour et al., 1999Go) 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., 1992Go) or limb amputation (Roze et al., 1989Go) 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, 1990Go).

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., 1999Go), 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 (0–5.3%) (Itskovitz-Eldor et al., 1992Go; Vauthier-Brouzes and Lefebvre, 1992Go). 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., 1994Go; Dechaud et al., 1998Go). Another study (Coffler et al., 1999Go) 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 VGo.


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Table V. Gestational age at procedure and miscarriage rate of the different techniques. A literature review
 
The partial or total embryo tissue involvement, and/or amniotic fluid aspiration add technical difficulties by prolonging surgery. Furthermore, these factors might make it difficult to visualize embryonic heart activity throughout the entire procedure. Also, it is possible that amniotic fluid aspiration may favour trophoblastic detachment (Vauthier-Brouzes and Lefebvre, 1992Go). Single puncture of the intrathoracic embryo region until asystolia is verified decreases surgery time and the risks of excessive manipulation (bleeding, infection, contractions of the uterus). This is shown by our low rates of infection (1.34%), miscarriage (7.4%) and spotting (11.4%). All cases of spotting were self-constrained in the following week with rest, without affecting the outcome of the pregnancy. Moreover, it was suggested that the necrotic tissue be left in place when using the simple puncture technique, resulting in an inflammatory reaction with prostaglandin and cytokine secretion (Sebire et al., 1997Go), thereby increasing the severe pre-term labour rate and risk of maternal coagulopathy. Fortunately, these concerns did not materialize in our patients. Our incidence of pre-term delivery with the transvaginal technique was similar (48.5%) to that reported by others (ranging from 20% to 57.8%; Shalev et al., 1989Go; Itskovitz-Eldor et al., 1992Go; Timor-Tritsch et al., 1993Go).

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., 1992Go; Bollen et al., 1993Go). However, there is controversy over when spontaneous reabsorption may occur. While some reports point to weeks 9 through 12 (Blumenfeld et al., 1992Go; Bollen et al., 1993Go), other studies (Manzur et al., 1995Go) 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, 1992Go), 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 5–6% (Kol et al., 1993Go), it would be appropriate to schedule embryo reduction once the fetal heart is visualized.

In accordance with this, Table IGo 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., 1989Go; Bollen et al., 1993Go; Jan et al., 1997Go). 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., 1993Go; Lipitz et al., 1994aGo). 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 maternal–newborn morbidity (Souter and Murphy, 1998Go). In this respect, when studying the outcome of IVF multiple pregnancy, it has been reported (Seoud et al., 1992Go) 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 IIIGo). 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., 1992Go; Lipitz et al., 1994bGo; Antsaklis et al., 1999Go; Kuno et al., 1999Go; Yaron et al., 1999Go). The fetal discordance rate in twins was 9%, significantly lower than previously described rates (Seoud et al., 1992Go; Silver et al., 1997Go). 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, 1986Go; Dommergues et al., 1991Go; Seoud et al., 1992Go; D'Souza et al., 1997Go; Antsaklis et al., 1999Go).

When we compared reduced pregnancies with their respective control group (Table IVGo), 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.


    Notes
 
4 To whom correspondence should be addressed at: Instituto Valenciano de Infertilidad, Guardia Civil 23, 46020-Valencia, Spain. E-mail: jmnavarrop{at}yahoo.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on April 14, 2000; accepted on June 30, 2000.





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