Human Reproduction vol.7 suppl.l pp.67-72, 1992
Is there an indication for embryo reduction?
J. Salat-Baroux*, J. Aknin*, J.M. Antoine*, S. Alvarez*, D. Cornet*, M. Plachof, J. Mandelbaum0 •Department of Obstetrics and Gynaecology, Hopital TENON, 4 Rue de la Chine, 75020 Paris, Universite Paris VI France 'Hdpital Necker, Unite INSERM 173
Key Words: in vitro fertilization, ovulation induction, embryo reduction, multiple pregnancies
Introduction
The incidence of multiple pregnancies after ovarian stimulation for superovulation or in vitro fertilization (IVF) has reached such a high rate that specific management is now required. Two options are available to clinicians for avoiding maternal and/or fetal complications, namely embryo reduction (Hobbins, 1988) or preventative therapy. We have published the results of a multicentre study (Salat-Baroux et al., 1988) of 42 embryo reduction procedures by transcervical aspiration. We recorded 5 complete abortions and 19% premature deliveries before 32 weeks gestational age. The issue is whether technical improvements have now made this method acceptable in specific indications. However, to minimize the use of embryo reduction, advances which have been or could be achieved in preventing multiple pregnancy should be analysed. We shall discuss the technical problems in the first part and the preventative approach in the second part of this article. It is important to evaluate the incidence of multiple pregnancies because after simple ovarian stimulation it is difficult to appreciate. Reported figures range from 11% to 44% (Gemzell and Ross, 1966; Schenker et al., 1981) and Lunenfeld et al. © Oxford University Press
67
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
The selective reduction of embryos in multiple pregnancies poses numerous medical, technical, ethical and psycho-social problems. In a retrospective study, we analysed nine hundred and twenty-two pregnancies obtained using medically assisted procreation between May 1982 and May 1990. Among 922 successful pregnancies, 372 were singleton, 102 were twin and 13 were triplet Data from this analysis and from a French multicentre study of 262 embryo reduction procedures demonstrated the value of an embryo quality score for minimizing the risk of multiple pregnancy and the existence of extremely infrequent, ethically acceptable indications for embryo reduction. These indications included ultrasound-proven malformations of one fetus, multiple pregnancies in patients with extensive uterine scarring, and multiple pregnancy despite the appropriate use of preventative measures which can be expected to make this technique unnecessary in the future.
found that multiple pregnancy occurred in 26% of 3646 cycles in a 1969 study. More accurate data can be obtained by analysing results of reproductive technologies reported in the United States IVF-ET Register for 1989, (Medical Research International Society for Assisted Reproductive Technology and the American Fertility Society, 1991), the French FIVNAT study (Arnal & Cohen, 1989) and our own study from 1982 to 1990. The United States IVF-ET Register for 1989 is a record of results obtained by 160 groups in 18211 stimulated cycles and 15392 oocyte retrieval procedures; clinical pregnancy occurred after 18% of embryo retrievals and 24% of the pregnancies were multiple (among the 2811 pregnancies, 2104 were successful, with 550 twins, 107 triplets and 10 quadruplets). The FIVNAT French Register 1986 to 1988 (Arnal and Cohen, 1989) included 50976 oocyte recovery procedures. The rate of multiple pregnancies remained stable, with twins in 20% of cases and triplets in 3%. Multiple pregnancy was positively correlated with a younger maternal age, higher numbers of transferred embryos and higher rates of fertilization per recovered oocyte and was negatively correlated with maternal age above 40. Our experience between May 1982 and May 1990 concerned 922 pregnancies of which 658 were ongoing. As shown in Table I, the multiple pregnancy rate remained stable throughout the study period with approximately 20% twin pregnancies and 3% triplet pregnancies. Triplet pregnancies were more common after oocyte donation (6%) and transfer of frozen-thawed embryos (5%). The very high rates of multiple pregnancies have led to the use of embryo reduction. There are three main technical aspects of this method. At what gestational age should reduction be conducted? What surgical approach should be chosen? What other procedures should be associated? The gestational age for selective interruption of pregnancy varies from 7 to 14 weeks and depends on the surgical approach used; 7 to 12 weeks for the transcervical approach in our series of 42 cases (SalatBaroux et al, 1988) or 8 to 12 weeks (mean ± sem: 9.4 ± 0.26) in the series of 23 cases by Dommergue et al. (1991b). Using the transabdominal route, the gestational age can be higher, up to 20 weeks in the study by Kerenyl and Chitkara (1981), and a mean of 10.7 ± 0.21 weeks of amenorrhoea in the series of 35 cases by Dommergue et al. (1991b). Although in most cases it is preferable to conduct the aspiration as early as possible (9 weeks of amenorrhoea), it should be remembered that a certain number of embryos stop growing spontaneously (Janiaux et al., 1988; Goldman et al, 1989) (approximately 18% of multiple pregnancies in our series) between the 5th and the 10th weeks of amenorrhoea. Regarding the surgical route and the associated procedures, a consensus is forming in favour of the transabdominal route under echographic control and local anaesthesia, using an 18-21
J-Salat-Baroux at at Table I. Analysis of pregnancies at Tenon Hospital between 1982 and 1990 (n - 922) 1984
1985
1986
1987
1988
1989
1990 to May
Total
Clinical pregnancies Multiple initial pregnancy Vanishing embryos
44 4 1
74 16 4
123 21 4
182 38 2
178 37 8
203 42 10
105 23 3
922 181 33
Medical reduction
_
—
_
-
1
1
2
1982
1983
(18%)
4 (2%)
Final evolution Singleton Twin
6b
23 1
41 9
2
3
68 17
90 32
108 27
117 29
n57 14
4
2
2
5
511 129 (20%)
-
18 (3%)
a b
" : The differences in each column are due to abortions or ectopics Percentages are given in parentheses
gauge needle introduced into or alongside the fetal heart. Through this, a hypertonic solution of 1.34 mM of potassium chloride is injected or, more rarely, air. No antibiotic or antispasmodic treatment is necessary, nor is cervical cerclage necessary, as it is in the transcervical route. In this latter approach, associated procedures are also necessary to avoid early or delayed abortions, which are frequently seen. More recently, selective embryo reduction under transuterine endovaginal echoscopy has been successfully used (Shalev et al, 1989; Itskovitz et al., 1989; Gonen et al., 1990, De la Fontaine et al, 1991). This method seems to combine several advantages, although to date no large randomized series has been published. Early diagnosis of multiple pregnancy and therefore early intervention is possible. The technique is easier and more reproducible compared to the transcervical approach requiring dilatation, or the transabdominal route. Finally, the risk of infection is low in all cases, on condition that the trophoblast is left in place and the aspiration is not repeated several times, if the first attempt fails. The results of selective embryo reduction can only be positive as compared to the spontaneous evolution of these multiple pregnancies (Epelboin et al, 1990). Although no systematic studies have been conducted on the outcome of triplet (Porreco et al., 1991), quadruplet or larger order multiple pregnancies, it is possible to estimate that the incidence of prematurity (Arnal and Cohen, 1989) increases from 10% in singleton pregnancies to 38% in twin pregnancies, and more than 75% in triplet or quadruplet pregnancies. A recent study in Great Britain showed that perinatal mortality was 41.6% in sextuplets, 22% in quintuplets, 20% in quadruplets and 17% in triplets. A retrospective study conducted by Pons et al. (1990) shows that in 24 triplet pregnancies, the rate of premature threatened labour was 100%. The spontaneous obstetric outcome of multiple pregnancies reported in a large 1990 Franco-American series, came to the same conclusion, and indisputably confirmed the benefit of selective embryo reduction. 68
Even so, this procedure is not without risk; in particular, the rate of abortions, especially delayed abortions, varies from 4% to 33% depending on the series (Dumez et al., 1986; SalatBaroux et al., 1988; Dommergue et al., 1991a; Boulot et al, 1989; 1990). Naturally, the rate of abortion depends on the original number of embryos and the number of embryos aspirated, but also often on the date of aspiration. Even more important for some authors is the technique of aspiration employed. Dommergue et al. (1991a), found that the abortion rate was increased by transcervical aspiration. It is certainly the case that repeated attempts, and attempts to aspirate the greatest possible amount of trophoblastic tissue, definitely increased the risk. Overall, a 30% rate of abortion with a free interval between reduction and abortion of 9 to 10 weeks was fairly frequently seen. In contrast, there is no consensus regarding the risk of prematurity. In our series of 42 cases and 32 deliveries, 19% were premature (of which 2 cases were before 32 weeks and 5 between 32 and 36 weeks). In all cases, there was premature rupture of the membranes, without any correlation with the initial number of embryos, or with the number of embryos aspirated, but this complication seemed to occur more frequently when the aspiration was conducted after the 11th week of amenorrhoea. In contrast, in the series by Dommergue et al. (1991b), 24% of deliveries occurred before 33 weeks, 22% before 36 weeks, and there was a negative correlation between gestational age and the number of embryos left in place: when 2 or 3 embryos were maintained, the gestational age was 34.9 and 34.3 weeks respectively, and 33% of these patients delivered before 33 weeks. Boulot et al., 1990 showed in their series of 34 cases that the gain over the risk of prematurity in embryo reduction is at most 2 weeks. Placental insufficiency and perinatal mortality are not negligible, and these complications are seen in all the series (Boulot et al., 1990; Newman et al., 1989; Pons et al., 1989). In the series by Dommergue et al. (1991b), four children out of a series
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
Triplet
Embryo reduction
hyperstimulation syndrome. Among 33 cases, only one case of moderate hyperstimulation occurred, but the multiple pregnancy rate (Table III) was very high after embryo transfers during spontaneous, stimulated or artificial cycles. The result indicates a need for taking other factors into account in order to avoid multiple pregnancy. Retrospective studies of reproductive technologies and particularly of IVF, including ours and investigations by El Khazn et al. (1986) and Puissant et al. (1987), have identified a number of predictive factors: Amal and Cohen (1989) emphasized the role of maternal age, whereas the studies by Puissant et al. (1987) underscored the influence of high oestradiol levels and ovarian stimulation obtained with only a low dose of HMG, and also pointed out the value of embryo scores. The embryonic score, based on uniformity or lack of uniformity of blastomere size, size of fragments and speed of embryo cleavage, can range from 1 to 6 and should be multiplied by the number of embryos transferred. The total score can vary from 1 for one embryo to 24 for four optimal embryos. Puissant et al. (1987) advocated limiting the number of goodquality embryos transferred to two in fairly young women with highly responsive ovaries. Our group carried out a similar retrospective study in 1990. We use a scoring system (Table IV) that differs slightly from that developed by the Belgian group, and takes into account the number of blastomeres, their size and fragmentation (% of the embryonic volume). Among 622 fresh embryo transfers performed in 1990 (Table V), the overall pregnancy rate was 24%, including 13 twins and 7 triplets. Analysis of the number of embryos transferred and the total embryo scoring shows that the maximum of twins and triplets for a transfer of 3 and 4 embryos is found when the embryo scoring was respectively 24-30 (11.9% twins and 4.8% of triplets) and
Table II. Factors influencing the incidence of multiple pregnancies Triplet n - 13
(a)
Twin n - 102 (b)
2.1+1.3 32.9+-3.8 34% 36% 11% 6% 7.0+3.7
2.4+1.7 32.5+4.0 40% 34% 7% 7% 6.2+2.8
1.9+1.7 31.7+4.2 43% 14% 14% 5.7+2.6
83% 7% 10% 28.1+14.2 10.6+1.9
89% 5% 6% 32.2+14.4 11.0+2.4
100% 33.7+13.7 10.3+1.6
1149+525 7.8+4.4 63% 4.4+2.5 34% 2.9+0.9
1159+457 7.9+4.1 67% 4.9+2.5 33% 3.2+0.7
1027+438 6.4+2.3 73% 4.6+2.6 29% 3.1+0.3
Singleton n-372
Number of attempts Age Absolute tubal infertility relative Idiopathic Male infertility Duration of infertility Protocol of ovulation induction GnRH analogue long protocol GnRH analogue short protocol Other Number of ampoules of HMG Duration of stimulation Oestradiol level before HCG injection Number of oocytes recovered Rate of fertilization Number of embryos Proportion of embryos frozen Mean number of embryos replaced
(c) NS NS
a > b p < 0.05
NS a < b p > 0.01 NS NS NS NS NS a < b p < 0.01
69
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
of 75 died in the neonatal period. These deaths were due to extreme prematurity. Other risks are more exceptional. There can be maternal risks such as infection, or even septicaemia or uncontrollable haemorrhage (Berkowitz et al., 1988) or fetal risks, but most cases of fetal malformation (malformation of the limbs, cleft palate, spina bifida) cannot be related to the reduction procedure, except perhaps gastroschisis after transabdominal puncture at 11 weeks (Dommergue, et al., 1991b). In summary, whatever the technique used, but perhaps more frequently with transabdominal aspiration, the rate of abortions secondary to embryo reduction remains very high, as does the number of premature deliveries, even though the figure is lower than that seen in the spontaneous outcome of multiple pregnancies. The major complications and the ethical considerations arising from the embryo reduction procedures justify a need for prevention of high multiple pregnancies. We performed a retrospective study (Table II) to identify the risk factors for multiple pregnancy. Between 1987 and 1990, we compared 372 singleton pregnancies, 102 twin pregnancies and 13 triplet pregnancies. None of the factors studied discriminated between these groups except for the dose of human menopausal gonadotrophin (HMG) used and the number of transferred embryos (significantly greater in twin and triplet pregnancies). A second, prospective approach was undertaken by our group (Salat-Baroux et al., 1990). We focused on cases where biological evidence of hyperstimulation (i.e., oestradiol levels above 2500 pg/ml on the day of ovulation induction by human chorionic gonadotrophin (HCG)) prompted us to freeze the embryos for subsequent embryo transfer, in order to avoid clinical
JJSalat-Baroax at al Table III. Pregnancy rates after deferred embryo transfers in cases of biological hyperstimulation Number of embryos transferred
Pregnancies
3 2 2
Twin Miscarriage Singleton
Stimulated (FSH) n - 18
3 2 3
Singleton Twin Twin
Artificial n = 10
3 2
Singleton Singleton
Cycles
Spontaneous n- 7
Table IV. Embryo scoring at Tenon Hospital (Plachot et al, 1991) Scoring (Plachot et al., 1991)
Embryo morphology (BLEFCO-FIVNAT) Number of blastomeres
4
0 pts 2 pts
Size of the blastomeres
Typical Atypical
4 pts 2 pts
Fragments (% of the embryo volume)
50%
4 pts 2 pts 0 pts 2 to 10
Total
Number of embryos
Score
1
2
3
4
Number of transfers
Twins
Triplets
0 5 (13.2%)
10
17 38 47 22
4-8 10-14 16-20
4 64 50
2 7 (10.9%) 12 (24%)
1 (8.3%)
6-14 16-22 24-30
5 119 134
1 (20%) 36 (30.2%) 42 (31.3%)
2 (5.6%) 5(11.9%)
2 (4.8%)
8-18 20-28 30-40
1 37 72
0 6 (16%) 33 (45.8%)
1 (16.7%) 4(12.1%)
5(15%)
30-40 (12% of twins and 15% of triplets). The optimal situation is the transfer of two embryos with a total score or 16 or of three embryos scoring 16 to 22. Thus, there is a need for a prospective study with the objective of decreasing the rate of multiple pregnancies after IVF and consequently of embryo reduction procedures. Dubuisson et al. (1990) investigated the feasibility of IVF during spontaneous cycles, with promising results of a 20.8% pregnancy rate in 120 cases. However, the cancellation rate was high (10 to 20%) and this method is applicable only in women with consistently normal ovulation (25% of cases). Simple ovulation induction, which is the reproductive technique responsible for most embryo reduction procedures, raises different problems. When increased androgen production is found over the baseline evaluation, caution is required and, rather than the use of gonadotrophin releasing hormone (GnRH) analogues (Charbonnel et al., 1987), gradual induction with purified follicle stimulating hormone (FSH) should be used (Seibel et al, 1984); follicle aspiration after parenteral HCG, 70
Total number of pregnancies
4 (8.5%) 2(9%)
suggested by Hazout et al. (1984), is promising but does not eliminate the risk of hyperstimulation. Induction of ovulation using lower doses of HCG (1500 to 2550 IU instead of 10,000) or a GnRH analogue, as proposed by Emperaire (1990), has not yet been proved satisfactory in a large sample. Ultrasound evaluation seems to be a promising means of solving this problem. Blankstein et al. (1987) and Navot et al. (1988) underscored the predictive value for hyperstimulation, and consequently multiple pregnancy, of the number of follicles measuring 25OO pg/ml on the day of the HCG injection) occurred in 75% and 43% of cases, respectively, in patients with more than ten 8-10 mm follicles in each ovary. For this parameter, the positive predictive value
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
Table V. Number of multiple pregnancies according to the embryonic score (TENON Hospital 1990)
Embryo reduction
Conclusions In conclusion, despite improvements in embryo reduction techniques, which have eliminated some complications (infections, immediate abortion), the indications are still controversial, both from an ethical viewpoint and from a medical viewpoint.
The decision may be difficult when a more or less significant fetal malformation is found. The risk of obstetrical complications is far from negligible (10% delayed abortions, 40% to 50% premature deliveries), and embryo reduction in triplet pregnancies remain controversial and should be discussed on a case by case basis. Prevention of multiple pregnancies, which is currently undergoing significant advances, should be our main goal in an effort to avoid having to make such decisions. References Aberg, A., Mitolman, F., Cantz, J. (1978) Cardiac puncture of foetus with Hurler's disease avoiding abortion of unaffected co-twin, Lancet ii, 990-991. Arnal F., Cohen J. (1989) Characte'ristiques des grossesses en fonction du nombre d'embryons transfers in F1VNAT. J. Testart et J. De Mouzon Edit, p. 93-51. Blankstein, J., Shalevs, J., Saadou, T., Kulzia, E.E., Rabinovici, J., Ariente, C, Lunenfeld, B., Serr, D.M., Mashiach, S. (1987) Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597-602. Berkowitz, R.L., Lynch, I., Chitkara, U., Wilins, J.A., Mehaleb, ICE. and Alvarez, E. (1988) Selective reduction of multifetal pregnancies in the first trimester. N. Engl. J. Med., 318, 1043-1047. Boulot, P., Deschamps, F., Galand, B., Sarda, P., Hedon, B., Laffargue, F. and Viala, J.L. (1989) Terminaison selective des grossesses g6m611aires bi-amniotiques a 20 semaines d'amdnorrhee pour malformation foetale: a propos de 2 cas realises avec succes. Press Med., 18, 494-495. Boulot, P., Hedon, B., Pelliccia, G., Deschamps, F., Denis, P., Audibert, F., Amal, F., Humeau, C, Mares, P., Laffargue, F., Viala, J.L. (1990) Obstetrical results after embryonic reductions performed on 34 multiple pregnancies. Human Reprod., 5, 1000-1013. Charbonnel, B., Krempf, M., Blanchard, P., Dano, F, Delage, C. (1987) Induction of ovulation in polycystic ovary syndrome with a combination of a luteinizing releasing hormone analog and exogenous gonadotropins. Fertil, Steril., 47, 920-924. De la fontaine, D., Mugniot-Bellamy, S., Simeon, S. and Menard, M.N. (1991) Reduction selective embryonnaire ou foetale sous echoscopie endovaginale interventionnelle. Contracept. Fertil, Sexual., 19, 473481. Dommergue, M., Nisand, I., Mandelbrot, L.,Isfer, E., Radunovic, N. and Dumez, Y. (1991a) Embryo reduction in multifetal pregnancies after infertility therapy: obstetrical risk and perinatal benefits are related to operative strategy. Fertil. Steril.. 55, 805-811. Dommergue, M., Dumez, Y., Evans, M. (1991b) Appreciation du risque obstetrical dans les grossesses multiples avec ou sans reduction embryonnaire. Rev. Fr. Gynecol. Obstet. 86.2, 105-107. Dubuisson, J.B.,. Foulot, H., Ranoux, C, Rambaud, D., Aubriot, F.X. (1990) La fecondation in vitro en cycle spontand. In Steiilitd fdminine et Procreations m£dicalement assistees. Hedon B, Frydman R, Plachot M. Doin Edit. Paris, p. 49-53. El Khazn, N., Puissant, F., Camus, M., Lejeune, B. and Leroy, F. (1986) A comparison between multiple and single pregnancies obtained by in vitro fertilization. Hum Reprod, 1, 251-254. Emperaire, J.C. (1990) Le declenchement de l'ovulation par les analogues de la LHRH: vers une reduction du risque d'hyperstimulation ovarienne? Presse, 19, 473-474. Epclboin, S., Castaing, O., Quantin, P. and Baron, J.M. (1990) Les uns sans les autres: £tude comparative des naissances multiples appes ou
71
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
was 43% and the negative predictive value (no polyfollicular response or biological hyperstimulation) was 93%. However, despite these efforts, embryo reduction remains necessary in some instances. The rate of use of this technique cannot be determined accurately. In a study aimed at collating cases worldwide, Mintz et al. (1989) showed that series are heterogeneous, with many publications referring to single cases (5 of 8) and success rates ranging from 0 to 100%. In most cases, the procedure was performed at 9-10 weeks gestational age, but the report fails to specify the indications or gestational age at delivery. In addition to these data, we published a multicentre Parisian study of 42 cases in 1988. The main indications included multiple pregnancy after simple ovulation induction and a very small number of twin pregnancies in women with severe uterine scarring. In France, a multicentre, questionnaire-based study identified 262 cases. Two salient facts emerged: most embryo reduction procedures were carried out in pregnancies with three fetuses (107 cases: 41%) or with four or more fetuses (138 cases: 52%); and 64% of embryo reduction procedures were performed after simple ovulation induction (58% after HMG/HCG and 6% after clomiphene citrate), whereas a smaller proportion of procedures were performed after IVF or gamete intraFallopian transfer (GIFT) (26%, including 39 triplet pregnancies and 30 quadruplet pregnancies). These different reports shed some light on the problems raised by embryo reduction. Although most investigators prefer transabdominal aspiration at 9-10 weeks gestational age (except for the removal of malformed fetuses when thoracic injection can be performed at 20 weeks), ethical problems are far from resolved (Zaner et al., 1990) although there is general agreement as to the need for informing couples and complying with their decisions. The social, family and especially psychological problems posed by multiple births (Garel and Blondel, 1991) and in particular the use of embryo reduction (Fauvin-Santiago et al., 1991) are sources of complications which should be taken into account. For this reason, the indications are still controversial. Chromosomal abnormalities in one of a pair of twins or presence of fetal malformations may be an indication for embryo reduction, which was first used in this situation (Kerenyl and Chitkari, 1981; Rodneck et al., 1982; Aberge/ al., 1987;Boulot el al., 1989). However, in some instances, the decision is difficult as in a case managed by our team in 1990 where selective removal of a fetus with no forearm was discussed. Other similar indications (identified as a result of advances in ultrasound evaluation) can and should be discussed in detail and the advice of an ethics committee should be sought. Furthermore, the concept that embryo reduction protects the mother and reduces the risk of obstetrical complications related to multiple pregnancy should be critically examined in triplet pregnancies (Porreco et al., 1991), if not in pregnancies with four fetuses or more.
J-Salat-B«roux at al.
Jauniaux, E., Elkazen, N. and Leroy, F. (1988) Clinical and morphologic aspects of the vanishing twin phenomenon. Obstet. Gynecol., 72, 577-581. Kerenyi, T.D., and Chitkara, U. (1981) Selective birth in twin pregnancy with discordancy for Down's syndrome. N Engl. J. Med., 304, 1525-1527. Lunenfeld, B., Insler, V., Rabau, E. (1969) Induction de l'ovulation par les gonadotropines. In Morfiacard R, Ferni J, Edit, L'ovulation, Paris, Masson 291-321. Medical Research International Society for Assisted Reproductive Technology and The American Fertility Society (1991) In vitro fertilization embryo transfer (IVFET) in the United States: 1989 results from the IVF-ET Registry. Fertil. Sterii, 55, 14-23. Mintz, Ph., Cohen, J., Loffredo, V. (1989) Reductions embryonnaires. Revue de la Literature. Contracept. Fertil. Sexual., 17, 833-836. Navot, D., Rolou, A., Birkenfeld, A., Rabinowitz, R., Brsesinski, A., Margaloth, E.J. (1988) Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol., 159, 210-215. Porreco, P.R., Burke, S., Hendrick, M.L. (1991) Multifetal reduction of triplets and pregnancy outcome. Obstet Gynecol., 78, 335-338. Rodeck, C.H., Mibashan, R.S., Abramowicz, J. and Campbell, S. (1982) Selective feticide of the affected twin by fetoscopic air embolism. Prenat Diagn., 2, 189-194. Pons, J.C, Fernandez, H., Diochin, P., Maycnga, J.M., Plu, G., Frydman, R. and Papiernick, E. (1989) Prise en charge des grossesses triples. J. Gynecol. Obstet. Biol. Reprod.. 18, 72-78. Puissant, F., Van Rysselberger M., Barlow, P., Deweze, J. and Leroy, F. (1987) Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod, 2, 705-708. Salat-Baroux, J., Alvarez, S., Antoine, J.M., Tibi, Ch., Plachot, M. and Mandelbaum, J. (1990) Treatment of hyperstimulation during in
72
vitro fertilization. Hum Reprod, 5, 36-41. Salat-Baroux, J., Tibi, Ch., Alvarez, S., Cornet, D. Antoine, J.M., Gomez, A. (1989) Prediction of hyperstimulation before ovulation induction, by ultra-sound. Abstract at the Vlth World Congress of in vitro fertilization. Jerusalem, 1-7 April. Salat-Baroux, J., Aknin, A.J., Antoine, J.M. and Alamowitch, R. (1988) The management of multiple pregnancies after induction for superovulation, Human Reprod 3, 399-405. Schenker, J.G., Yarkoui, S. and Granat, M. (1981) Multiple pregnancies following induction of ovulation. Fertil, Sterii., 35, 105-123. Seibel, M.M., Kamrova, M.M., McArde, C, Taynor, M.L. (1984) Treatment of polycystic ovary disease with chronic low dose follicle stimulating hormone. Biochemical charge and ultrasound correlation. Int. J. Fertil., 29, 39-43.
Shalev, J., Frenkel, Y., Goldenberg, M., Shalev, E., Lipitz, S., Barkai, G., Nebel, L. and Mashiach, S. (1989) Selective reduction in multiple gestations: pregnancy after transvaginal and transabdominal needle guided procedures. Fertil, Sterii., 52, 416-420. Zaner, R.M., Boehm, F.H. and Hill, G.A. (1990) Selective termination in multiple pregnancies: ethical considerations. Fertil, Stenl., 54, 203-205.
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
sans interruption selective dc grossess. Contracept. Fertil. Sexual, 18, 659. Fauvin-Santiago, M., Lefebvre, G. and Vauthier-Brouzcs, D. (1991) Psychological aspects of embryo reductions. P 158, 7th World Congress of IVF and Assisted Procreation. Paris 30 June - 3 July, Abstract in Human Reprod. p. 221. Garel, M., Blondel, M. (1991) Psychological consequences of triplets births P 160, 7th World Congress on IVF and Assisted Procreation. Paris 30 June - 3 July, Abstract in Human Reprod. p. 222. Gemzell, G. and Roos, P. (1966) Pregnancies following treatment with human gonadotropins with special reference to the problem of multiple births. A.J. Obstet Gynecol., 94, 940-945. Goldman, G.A., Dicker, D., Ferldberg, D., Ashkenazi, J., Yeshaya, A. and Goldman, J.A. (1989) The vanishing fetus: report of 17 cases of triplets and quadruplets. J. Perinat. Med., 17, 157-162. Gonen, Y., Blankier, J. and Casper, R.F. (1990) Transvaginal ultrasound in selective embryo reduction for multiple pregnancy. Obtet. Gynecol., 75, 720-722. Hazout, A., Porcher, J. and Frydman, R. (1984) Une alternative de riduction embryonnaire: la reduction folliculaire. Gynicologie 35, 119-121. Hobbins, J.C. (1988) Selective reduction: a perinatal necessity. N. Engl. J. Med.. 318, 1062-1063. Itskovitz, J., Boldes, R,. ThaJer, I., Bronstein, M., Erlik, Y. and Brandes, J. (1989) TransvaginaJ ultrasonography - guided aspiration of gestational sacs for selective abortion in multiple pregnancy. Am. J. Obstet. Gynecol. 160, 215-217.
Is there an indication for embryo reduction?
J. Salat-Baroux*, J. Aknin*, J.M. Antoine*, S. Alvarez*, D. Cornet*, M. Plachof, J. Mandelbaum0 •Department of Obstetrics and Gynaecology, Hopital TENON, 4 Rue de la Chine, 75020 Paris, Universite Paris VI France 'Hdpital Necker, Unite INSERM 173
Key Words: in vitro fertilization, ovulation induction, embryo reduction, multiple pregnancies
Introduction
The incidence of multiple pregnancies after ovarian stimulation for superovulation or in vitro fertilization (IVF) has reached such a high rate that specific management is now required. Two options are available to clinicians for avoiding maternal and/or fetal complications, namely embryo reduction (Hobbins, 1988) or preventative therapy. We have published the results of a multicentre study (Salat-Baroux et al., 1988) of 42 embryo reduction procedures by transcervical aspiration. We recorded 5 complete abortions and 19% premature deliveries before 32 weeks gestational age. The issue is whether technical improvements have now made this method acceptable in specific indications. However, to minimize the use of embryo reduction, advances which have been or could be achieved in preventing multiple pregnancy should be analysed. We shall discuss the technical problems in the first part and the preventative approach in the second part of this article. It is important to evaluate the incidence of multiple pregnancies because after simple ovarian stimulation it is difficult to appreciate. Reported figures range from 11% to 44% (Gemzell and Ross, 1966; Schenker et al., 1981) and Lunenfeld et al. © Oxford University Press
67
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
The selective reduction of embryos in multiple pregnancies poses numerous medical, technical, ethical and psycho-social problems. In a retrospective study, we analysed nine hundred and twenty-two pregnancies obtained using medically assisted procreation between May 1982 and May 1990. Among 922 successful pregnancies, 372 were singleton, 102 were twin and 13 were triplet Data from this analysis and from a French multicentre study of 262 embryo reduction procedures demonstrated the value of an embryo quality score for minimizing the risk of multiple pregnancy and the existence of extremely infrequent, ethically acceptable indications for embryo reduction. These indications included ultrasound-proven malformations of one fetus, multiple pregnancies in patients with extensive uterine scarring, and multiple pregnancy despite the appropriate use of preventative measures which can be expected to make this technique unnecessary in the future.
found that multiple pregnancy occurred in 26% of 3646 cycles in a 1969 study. More accurate data can be obtained by analysing results of reproductive technologies reported in the United States IVF-ET Register for 1989, (Medical Research International Society for Assisted Reproductive Technology and the American Fertility Society, 1991), the French FIVNAT study (Arnal & Cohen, 1989) and our own study from 1982 to 1990. The United States IVF-ET Register for 1989 is a record of results obtained by 160 groups in 18211 stimulated cycles and 15392 oocyte retrieval procedures; clinical pregnancy occurred after 18% of embryo retrievals and 24% of the pregnancies were multiple (among the 2811 pregnancies, 2104 were successful, with 550 twins, 107 triplets and 10 quadruplets). The FIVNAT French Register 1986 to 1988 (Arnal and Cohen, 1989) included 50976 oocyte recovery procedures. The rate of multiple pregnancies remained stable, with twins in 20% of cases and triplets in 3%. Multiple pregnancy was positively correlated with a younger maternal age, higher numbers of transferred embryos and higher rates of fertilization per recovered oocyte and was negatively correlated with maternal age above 40. Our experience between May 1982 and May 1990 concerned 922 pregnancies of which 658 were ongoing. As shown in Table I, the multiple pregnancy rate remained stable throughout the study period with approximately 20% twin pregnancies and 3% triplet pregnancies. Triplet pregnancies were more common after oocyte donation (6%) and transfer of frozen-thawed embryos (5%). The very high rates of multiple pregnancies have led to the use of embryo reduction. There are three main technical aspects of this method. At what gestational age should reduction be conducted? What surgical approach should be chosen? What other procedures should be associated? The gestational age for selective interruption of pregnancy varies from 7 to 14 weeks and depends on the surgical approach used; 7 to 12 weeks for the transcervical approach in our series of 42 cases (SalatBaroux et al, 1988) or 8 to 12 weeks (mean ± sem: 9.4 ± 0.26) in the series of 23 cases by Dommergue et al. (1991b). Using the transabdominal route, the gestational age can be higher, up to 20 weeks in the study by Kerenyl and Chitkara (1981), and a mean of 10.7 ± 0.21 weeks of amenorrhoea in the series of 35 cases by Dommergue et al. (1991b). Although in most cases it is preferable to conduct the aspiration as early as possible (9 weeks of amenorrhoea), it should be remembered that a certain number of embryos stop growing spontaneously (Janiaux et al., 1988; Goldman et al, 1989) (approximately 18% of multiple pregnancies in our series) between the 5th and the 10th weeks of amenorrhoea. Regarding the surgical route and the associated procedures, a consensus is forming in favour of the transabdominal route under echographic control and local anaesthesia, using an 18-21
J-Salat-Baroux at at Table I. Analysis of pregnancies at Tenon Hospital between 1982 and 1990 (n - 922) 1984
1985
1986
1987
1988
1989
1990 to May
Total
Clinical pregnancies Multiple initial pregnancy Vanishing embryos
44 4 1
74 16 4
123 21 4
182 38 2
178 37 8
203 42 10
105 23 3
922 181 33
Medical reduction
_
—
_
-
1
1
2
1982
1983
(18%)
4 (2%)
Final evolution Singleton Twin
6b
23 1
41 9
2
3
68 17
90 32
108 27
117 29
n57 14
4
2
2
5
511 129 (20%)
-
18 (3%)
a b
" : The differences in each column are due to abortions or ectopics Percentages are given in parentheses
gauge needle introduced into or alongside the fetal heart. Through this, a hypertonic solution of 1.34 mM of potassium chloride is injected or, more rarely, air. No antibiotic or antispasmodic treatment is necessary, nor is cervical cerclage necessary, as it is in the transcervical route. In this latter approach, associated procedures are also necessary to avoid early or delayed abortions, which are frequently seen. More recently, selective embryo reduction under transuterine endovaginal echoscopy has been successfully used (Shalev et al, 1989; Itskovitz et al., 1989; Gonen et al., 1990, De la Fontaine et al, 1991). This method seems to combine several advantages, although to date no large randomized series has been published. Early diagnosis of multiple pregnancy and therefore early intervention is possible. The technique is easier and more reproducible compared to the transcervical approach requiring dilatation, or the transabdominal route. Finally, the risk of infection is low in all cases, on condition that the trophoblast is left in place and the aspiration is not repeated several times, if the first attempt fails. The results of selective embryo reduction can only be positive as compared to the spontaneous evolution of these multiple pregnancies (Epelboin et al, 1990). Although no systematic studies have been conducted on the outcome of triplet (Porreco et al., 1991), quadruplet or larger order multiple pregnancies, it is possible to estimate that the incidence of prematurity (Arnal and Cohen, 1989) increases from 10% in singleton pregnancies to 38% in twin pregnancies, and more than 75% in triplet or quadruplet pregnancies. A recent study in Great Britain showed that perinatal mortality was 41.6% in sextuplets, 22% in quintuplets, 20% in quadruplets and 17% in triplets. A retrospective study conducted by Pons et al. (1990) shows that in 24 triplet pregnancies, the rate of premature threatened labour was 100%. The spontaneous obstetric outcome of multiple pregnancies reported in a large 1990 Franco-American series, came to the same conclusion, and indisputably confirmed the benefit of selective embryo reduction. 68
Even so, this procedure is not without risk; in particular, the rate of abortions, especially delayed abortions, varies from 4% to 33% depending on the series (Dumez et al., 1986; SalatBaroux et al., 1988; Dommergue et al., 1991a; Boulot et al, 1989; 1990). Naturally, the rate of abortion depends on the original number of embryos and the number of embryos aspirated, but also often on the date of aspiration. Even more important for some authors is the technique of aspiration employed. Dommergue et al. (1991a), found that the abortion rate was increased by transcervical aspiration. It is certainly the case that repeated attempts, and attempts to aspirate the greatest possible amount of trophoblastic tissue, definitely increased the risk. Overall, a 30% rate of abortion with a free interval between reduction and abortion of 9 to 10 weeks was fairly frequently seen. In contrast, there is no consensus regarding the risk of prematurity. In our series of 42 cases and 32 deliveries, 19% were premature (of which 2 cases were before 32 weeks and 5 between 32 and 36 weeks). In all cases, there was premature rupture of the membranes, without any correlation with the initial number of embryos, or with the number of embryos aspirated, but this complication seemed to occur more frequently when the aspiration was conducted after the 11th week of amenorrhoea. In contrast, in the series by Dommergue et al. (1991b), 24% of deliveries occurred before 33 weeks, 22% before 36 weeks, and there was a negative correlation between gestational age and the number of embryos left in place: when 2 or 3 embryos were maintained, the gestational age was 34.9 and 34.3 weeks respectively, and 33% of these patients delivered before 33 weeks. Boulot et al., 1990 showed in their series of 34 cases that the gain over the risk of prematurity in embryo reduction is at most 2 weeks. Placental insufficiency and perinatal mortality are not negligible, and these complications are seen in all the series (Boulot et al., 1990; Newman et al., 1989; Pons et al., 1989). In the series by Dommergue et al. (1991b), four children out of a series
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
Triplet
Embryo reduction
hyperstimulation syndrome. Among 33 cases, only one case of moderate hyperstimulation occurred, but the multiple pregnancy rate (Table III) was very high after embryo transfers during spontaneous, stimulated or artificial cycles. The result indicates a need for taking other factors into account in order to avoid multiple pregnancy. Retrospective studies of reproductive technologies and particularly of IVF, including ours and investigations by El Khazn et al. (1986) and Puissant et al. (1987), have identified a number of predictive factors: Amal and Cohen (1989) emphasized the role of maternal age, whereas the studies by Puissant et al. (1987) underscored the influence of high oestradiol levels and ovarian stimulation obtained with only a low dose of HMG, and also pointed out the value of embryo scores. The embryonic score, based on uniformity or lack of uniformity of blastomere size, size of fragments and speed of embryo cleavage, can range from 1 to 6 and should be multiplied by the number of embryos transferred. The total score can vary from 1 for one embryo to 24 for four optimal embryos. Puissant et al. (1987) advocated limiting the number of goodquality embryos transferred to two in fairly young women with highly responsive ovaries. Our group carried out a similar retrospective study in 1990. We use a scoring system (Table IV) that differs slightly from that developed by the Belgian group, and takes into account the number of blastomeres, their size and fragmentation (% of the embryonic volume). Among 622 fresh embryo transfers performed in 1990 (Table V), the overall pregnancy rate was 24%, including 13 twins and 7 triplets. Analysis of the number of embryos transferred and the total embryo scoring shows that the maximum of twins and triplets for a transfer of 3 and 4 embryos is found when the embryo scoring was respectively 24-30 (11.9% twins and 4.8% of triplets) and
Table II. Factors influencing the incidence of multiple pregnancies Triplet n - 13
(a)
Twin n - 102 (b)
2.1+1.3 32.9+-3.8 34% 36% 11% 6% 7.0+3.7
2.4+1.7 32.5+4.0 40% 34% 7% 7% 6.2+2.8
1.9+1.7 31.7+4.2 43% 14% 14% 5.7+2.6
83% 7% 10% 28.1+14.2 10.6+1.9
89% 5% 6% 32.2+14.4 11.0+2.4
100% 33.7+13.7 10.3+1.6
1149+525 7.8+4.4 63% 4.4+2.5 34% 2.9+0.9
1159+457 7.9+4.1 67% 4.9+2.5 33% 3.2+0.7
1027+438 6.4+2.3 73% 4.6+2.6 29% 3.1+0.3
Singleton n-372
Number of attempts Age Absolute tubal infertility relative Idiopathic Male infertility Duration of infertility Protocol of ovulation induction GnRH analogue long protocol GnRH analogue short protocol Other Number of ampoules of HMG Duration of stimulation Oestradiol level before HCG injection Number of oocytes recovered Rate of fertilization Number of embryos Proportion of embryos frozen Mean number of embryos replaced
(c) NS NS
a > b p < 0.05
NS a < b p > 0.01 NS NS NS NS NS a < b p < 0.01
69
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
of 75 died in the neonatal period. These deaths were due to extreme prematurity. Other risks are more exceptional. There can be maternal risks such as infection, or even septicaemia or uncontrollable haemorrhage (Berkowitz et al., 1988) or fetal risks, but most cases of fetal malformation (malformation of the limbs, cleft palate, spina bifida) cannot be related to the reduction procedure, except perhaps gastroschisis after transabdominal puncture at 11 weeks (Dommergue, et al., 1991b). In summary, whatever the technique used, but perhaps more frequently with transabdominal aspiration, the rate of abortions secondary to embryo reduction remains very high, as does the number of premature deliveries, even though the figure is lower than that seen in the spontaneous outcome of multiple pregnancies. The major complications and the ethical considerations arising from the embryo reduction procedures justify a need for prevention of high multiple pregnancies. We performed a retrospective study (Table II) to identify the risk factors for multiple pregnancy. Between 1987 and 1990, we compared 372 singleton pregnancies, 102 twin pregnancies and 13 triplet pregnancies. None of the factors studied discriminated between these groups except for the dose of human menopausal gonadotrophin (HMG) used and the number of transferred embryos (significantly greater in twin and triplet pregnancies). A second, prospective approach was undertaken by our group (Salat-Baroux et al., 1990). We focused on cases where biological evidence of hyperstimulation (i.e., oestradiol levels above 2500 pg/ml on the day of ovulation induction by human chorionic gonadotrophin (HCG)) prompted us to freeze the embryos for subsequent embryo transfer, in order to avoid clinical
JJSalat-Baroax at al Table III. Pregnancy rates after deferred embryo transfers in cases of biological hyperstimulation Number of embryos transferred
Pregnancies
3 2 2
Twin Miscarriage Singleton
Stimulated (FSH) n - 18
3 2 3
Singleton Twin Twin
Artificial n = 10
3 2
Singleton Singleton
Cycles
Spontaneous n- 7
Table IV. Embryo scoring at Tenon Hospital (Plachot et al, 1991) Scoring (Plachot et al., 1991)
Embryo morphology (BLEFCO-FIVNAT) Number of blastomeres
4
0 pts 2 pts
Size of the blastomeres
Typical Atypical
4 pts 2 pts
Fragments (% of the embryo volume)
50%
4 pts 2 pts 0 pts 2 to 10
Total
Number of embryos
Score
1
2
3
4
Number of transfers
Twins
Triplets
0 5 (13.2%)
10
17 38 47 22
4-8 10-14 16-20
4 64 50
2 7 (10.9%) 12 (24%)
1 (8.3%)
6-14 16-22 24-30
5 119 134
1 (20%) 36 (30.2%) 42 (31.3%)
2 (5.6%) 5(11.9%)
2 (4.8%)
8-18 20-28 30-40
1 37 72
0 6 (16%) 33 (45.8%)
1 (16.7%) 4(12.1%)
5(15%)
30-40 (12% of twins and 15% of triplets). The optimal situation is the transfer of two embryos with a total score or 16 or of three embryos scoring 16 to 22. Thus, there is a need for a prospective study with the objective of decreasing the rate of multiple pregnancies after IVF and consequently of embryo reduction procedures. Dubuisson et al. (1990) investigated the feasibility of IVF during spontaneous cycles, with promising results of a 20.8% pregnancy rate in 120 cases. However, the cancellation rate was high (10 to 20%) and this method is applicable only in women with consistently normal ovulation (25% of cases). Simple ovulation induction, which is the reproductive technique responsible for most embryo reduction procedures, raises different problems. When increased androgen production is found over the baseline evaluation, caution is required and, rather than the use of gonadotrophin releasing hormone (GnRH) analogues (Charbonnel et al., 1987), gradual induction with purified follicle stimulating hormone (FSH) should be used (Seibel et al, 1984); follicle aspiration after parenteral HCG, 70
Total number of pregnancies
4 (8.5%) 2(9%)
suggested by Hazout et al. (1984), is promising but does not eliminate the risk of hyperstimulation. Induction of ovulation using lower doses of HCG (1500 to 2550 IU instead of 10,000) or a GnRH analogue, as proposed by Emperaire (1990), has not yet been proved satisfactory in a large sample. Ultrasound evaluation seems to be a promising means of solving this problem. Blankstein et al. (1987) and Navot et al. (1988) underscored the predictive value for hyperstimulation, and consequently multiple pregnancy, of the number of follicles measuring 25OO pg/ml on the day of the HCG injection) occurred in 75% and 43% of cases, respectively, in patients with more than ten 8-10 mm follicles in each ovary. For this parameter, the positive predictive value
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
Table V. Number of multiple pregnancies according to the embryonic score (TENON Hospital 1990)
Embryo reduction
Conclusions In conclusion, despite improvements in embryo reduction techniques, which have eliminated some complications (infections, immediate abortion), the indications are still controversial, both from an ethical viewpoint and from a medical viewpoint.
The decision may be difficult when a more or less significant fetal malformation is found. The risk of obstetrical complications is far from negligible (10% delayed abortions, 40% to 50% premature deliveries), and embryo reduction in triplet pregnancies remain controversial and should be discussed on a case by case basis. Prevention of multiple pregnancies, which is currently undergoing significant advances, should be our main goal in an effort to avoid having to make such decisions. References Aberg, A., Mitolman, F., Cantz, J. (1978) Cardiac puncture of foetus with Hurler's disease avoiding abortion of unaffected co-twin, Lancet ii, 990-991. Arnal F., Cohen J. (1989) Characte'ristiques des grossesses en fonction du nombre d'embryons transfers in F1VNAT. J. Testart et J. De Mouzon Edit, p. 93-51. Blankstein, J., Shalevs, J., Saadou, T., Kulzia, E.E., Rabinovici, J., Ariente, C, Lunenfeld, B., Serr, D.M., Mashiach, S. (1987) Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597-602. Berkowitz, R.L., Lynch, I., Chitkara, U., Wilins, J.A., Mehaleb, ICE. and Alvarez, E. (1988) Selective reduction of multifetal pregnancies in the first trimester. N. Engl. J. Med., 318, 1043-1047. Boulot, P., Deschamps, F., Galand, B., Sarda, P., Hedon, B., Laffargue, F. and Viala, J.L. (1989) Terminaison selective des grossesses g6m611aires bi-amniotiques a 20 semaines d'amdnorrhee pour malformation foetale: a propos de 2 cas realises avec succes. Press Med., 18, 494-495. Boulot, P., Hedon, B., Pelliccia, G., Deschamps, F., Denis, P., Audibert, F., Amal, F., Humeau, C, Mares, P., Laffargue, F., Viala, J.L. (1990) Obstetrical results after embryonic reductions performed on 34 multiple pregnancies. Human Reprod., 5, 1000-1013. Charbonnel, B., Krempf, M., Blanchard, P., Dano, F, Delage, C. (1987) Induction of ovulation in polycystic ovary syndrome with a combination of a luteinizing releasing hormone analog and exogenous gonadotropins. Fertil, Steril., 47, 920-924. De la fontaine, D., Mugniot-Bellamy, S., Simeon, S. and Menard, M.N. (1991) Reduction selective embryonnaire ou foetale sous echoscopie endovaginale interventionnelle. Contracept. Fertil, Sexual., 19, 473481. Dommergue, M., Nisand, I., Mandelbrot, L.,Isfer, E., Radunovic, N. and Dumez, Y. (1991a) Embryo reduction in multifetal pregnancies after infertility therapy: obstetrical risk and perinatal benefits are related to operative strategy. Fertil. Steril.. 55, 805-811. Dommergue, M., Dumez, Y., Evans, M. (1991b) Appreciation du risque obstetrical dans les grossesses multiples avec ou sans reduction embryonnaire. Rev. Fr. Gynecol. Obstet. 86.2, 105-107. Dubuisson, J.B.,. Foulot, H., Ranoux, C, Rambaud, D., Aubriot, F.X. (1990) La fecondation in vitro en cycle spontand. In Steiilitd fdminine et Procreations m£dicalement assistees. Hedon B, Frydman R, Plachot M. Doin Edit. Paris, p. 49-53. El Khazn, N., Puissant, F., Camus, M., Lejeune, B. and Leroy, F. (1986) A comparison between multiple and single pregnancies obtained by in vitro fertilization. Hum Reprod, 1, 251-254. Emperaire, J.C. (1990) Le declenchement de l'ovulation par les analogues de la LHRH: vers une reduction du risque d'hyperstimulation ovarienne? Presse, 19, 473-474. Epclboin, S., Castaing, O., Quantin, P. and Baron, J.M. (1990) Les uns sans les autres: £tude comparative des naissances multiples appes ou
71
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
was 43% and the negative predictive value (no polyfollicular response or biological hyperstimulation) was 93%. However, despite these efforts, embryo reduction remains necessary in some instances. The rate of use of this technique cannot be determined accurately. In a study aimed at collating cases worldwide, Mintz et al. (1989) showed that series are heterogeneous, with many publications referring to single cases (5 of 8) and success rates ranging from 0 to 100%. In most cases, the procedure was performed at 9-10 weeks gestational age, but the report fails to specify the indications or gestational age at delivery. In addition to these data, we published a multicentre Parisian study of 42 cases in 1988. The main indications included multiple pregnancy after simple ovulation induction and a very small number of twin pregnancies in women with severe uterine scarring. In France, a multicentre, questionnaire-based study identified 262 cases. Two salient facts emerged: most embryo reduction procedures were carried out in pregnancies with three fetuses (107 cases: 41%) or with four or more fetuses (138 cases: 52%); and 64% of embryo reduction procedures were performed after simple ovulation induction (58% after HMG/HCG and 6% after clomiphene citrate), whereas a smaller proportion of procedures were performed after IVF or gamete intraFallopian transfer (GIFT) (26%, including 39 triplet pregnancies and 30 quadruplet pregnancies). These different reports shed some light on the problems raised by embryo reduction. Although most investigators prefer transabdominal aspiration at 9-10 weeks gestational age (except for the removal of malformed fetuses when thoracic injection can be performed at 20 weeks), ethical problems are far from resolved (Zaner et al., 1990) although there is general agreement as to the need for informing couples and complying with their decisions. The social, family and especially psychological problems posed by multiple births (Garel and Blondel, 1991) and in particular the use of embryo reduction (Fauvin-Santiago et al., 1991) are sources of complications which should be taken into account. For this reason, the indications are still controversial. Chromosomal abnormalities in one of a pair of twins or presence of fetal malformations may be an indication for embryo reduction, which was first used in this situation (Kerenyl and Chitkari, 1981; Rodneck et al., 1982; Aberge/ al., 1987;Boulot el al., 1989). However, in some instances, the decision is difficult as in a case managed by our team in 1990 where selective removal of a fetus with no forearm was discussed. Other similar indications (identified as a result of advances in ultrasound evaluation) can and should be discussed in detail and the advice of an ethics committee should be sought. Furthermore, the concept that embryo reduction protects the mother and reduces the risk of obstetrical complications related to multiple pregnancy should be critically examined in triplet pregnancies (Porreco et al., 1991), if not in pregnancies with four fetuses or more.
J-Salat-B«roux at al.
Jauniaux, E., Elkazen, N. and Leroy, F. (1988) Clinical and morphologic aspects of the vanishing twin phenomenon. Obstet. Gynecol., 72, 577-581. Kerenyi, T.D., and Chitkara, U. (1981) Selective birth in twin pregnancy with discordancy for Down's syndrome. N Engl. J. Med., 304, 1525-1527. Lunenfeld, B., Insler, V., Rabau, E. (1969) Induction de l'ovulation par les gonadotropines. In Morfiacard R, Ferni J, Edit, L'ovulation, Paris, Masson 291-321. Medical Research International Society for Assisted Reproductive Technology and The American Fertility Society (1991) In vitro fertilization embryo transfer (IVFET) in the United States: 1989 results from the IVF-ET Registry. Fertil. Sterii, 55, 14-23. Mintz, Ph., Cohen, J., Loffredo, V. (1989) Reductions embryonnaires. Revue de la Literature. Contracept. Fertil. Sexual., 17, 833-836. Navot, D., Rolou, A., Birkenfeld, A., Rabinowitz, R., Brsesinski, A., Margaloth, E.J. (1988) Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol., 159, 210-215. Porreco, P.R., Burke, S., Hendrick, M.L. (1991) Multifetal reduction of triplets and pregnancy outcome. Obstet Gynecol., 78, 335-338. Rodeck, C.H., Mibashan, R.S., Abramowicz, J. and Campbell, S. (1982) Selective feticide of the affected twin by fetoscopic air embolism. Prenat Diagn., 2, 189-194. Pons, J.C, Fernandez, H., Diochin, P., Maycnga, J.M., Plu, G., Frydman, R. and Papiernick, E. (1989) Prise en charge des grossesses triples. J. Gynecol. Obstet. Biol. Reprod.. 18, 72-78. Puissant, F., Van Rysselberger M., Barlow, P., Deweze, J. and Leroy, F. (1987) Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod, 2, 705-708. Salat-Baroux, J., Alvarez, S., Antoine, J.M., Tibi, Ch., Plachot, M. and Mandelbaum, J. (1990) Treatment of hyperstimulation during in
72
vitro fertilization. Hum Reprod, 5, 36-41. Salat-Baroux, J., Tibi, Ch., Alvarez, S., Cornet, D. Antoine, J.M., Gomez, A. (1989) Prediction of hyperstimulation before ovulation induction, by ultra-sound. Abstract at the Vlth World Congress of in vitro fertilization. Jerusalem, 1-7 April. Salat-Baroux, J., Aknin, A.J., Antoine, J.M. and Alamowitch, R. (1988) The management of multiple pregnancies after induction for superovulation, Human Reprod 3, 399-405. Schenker, J.G., Yarkoui, S. and Granat, M. (1981) Multiple pregnancies following induction of ovulation. Fertil, Sterii., 35, 105-123. Seibel, M.M., Kamrova, M.M., McArde, C, Taynor, M.L. (1984) Treatment of polycystic ovary disease with chronic low dose follicle stimulating hormone. Biochemical charge and ultrasound correlation. Int. J. Fertil., 29, 39-43.
Shalev, J., Frenkel, Y., Goldenberg, M., Shalev, E., Lipitz, S., Barkai, G., Nebel, L. and Mashiach, S. (1989) Selective reduction in multiple gestations: pregnancy after transvaginal and transabdominal needle guided procedures. Fertil, Sterii., 52, 416-420. Zaner, R.M., Boehm, F.H. and Hill, G.A. (1990) Selective termination in multiple pregnancies: ethical considerations. Fertil, Stenl., 54, 203-205.
Downloaded from http://humrep.oxfordjournals.org/ at Columbia University Libraries on November 13, 2014
sans interruption selective dc grossess. Contracept. Fertil. Sexual, 18, 659. Fauvin-Santiago, M., Lefebvre, G. and Vauthier-Brouzcs, D. (1991) Psychological aspects of embryo reductions. P 158, 7th World Congress of IVF and Assisted Procreation. Paris 30 June - 3 July, Abstract in Human Reprod. p. 221. Garel, M., Blondel, M. (1991) Psychological consequences of triplets births P 160, 7th World Congress on IVF and Assisted Procreation. Paris 30 June - 3 July, Abstract in Human Reprod. p. 222. Gemzell, G. and Roos, P. (1966) Pregnancies following treatment with human gonadotropins with special reference to the problem of multiple births. A.J. Obstet Gynecol., 94, 940-945. Goldman, G.A., Dicker, D., Ferldberg, D., Ashkenazi, J., Yeshaya, A. and Goldman, J.A. (1989) The vanishing fetus: report of 17 cases of triplets and quadruplets. J. Perinat. Med., 17, 157-162. Gonen, Y., Blankier, J. and Casper, R.F. (1990) Transvaginal ultrasound in selective embryo reduction for multiple pregnancy. Obtet. Gynecol., 75, 720-722. Hazout, A., Porcher, J. and Frydman, R. (1984) Une alternative de riduction embryonnaire: la reduction folliculaire. Gynicologie 35, 119-121. Hobbins, J.C. (1988) Selective reduction: a perinatal necessity. N. Engl. J. Med.. 318, 1062-1063. Itskovitz, J., Boldes, R,. ThaJer, I., Bronstein, M., Erlik, Y. and Brandes, J. (1989) TransvaginaJ ultrasonography - guided aspiration of gestational sacs for selective abortion in multiple pregnancy. Am. J. Obstet. Gynecol. 160, 215-217.
