- Email: [email protected]
Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France: 1987 to 1989)*
FERTILITY AND STERILITY Copyright
(j;l
Vol. 61, No.2, February 1994
1994 The American Fertility Society
Printed on acid-free paper in U. S. A.
Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France: 1987 to 1989)*
Pierre Rufat, M.D.t:j: Franc;ois Olivennes, M.D.§ Jacques de Mouzon, M.D.t
Michel Dehan, M.D.§ Rene Frydman, M.D.§
Institut National de la Sante et de la Recherche Medicale (INSERM), Bicetre, and H6pital Antoine-Beclere, Clamart, France
Objective: To describe the outcome of pregnancies conceived by IVF and the follow-up of the children after a minimum of 1 year of life. Design: Survey of clinical pregnancies and follow-up of the children and comparison with national statistics. Settings: All clinical pregnancies from 11 French centers between January 1987 and June 1989. Patients: A total of 1,637 pregnancies resulting in 1,263 deliveries and 1,669 live-born or stillborn children and 1,411 alive children after 1 year. Main Outcome Measures: Gestational age of birth, birth weight, mortality rates, prevalence of congenital malformation, and prevalence of disorders during the follow-up of the children. Results: The preterm birth rate was 22.7% of all deliveries and 12.2% of single deliveries compared with 5.6% in France, and 34.7% of babies weighed <2,500 g compared with 5.2% in France. The rate of perinatal, neonatal, and infant mortality were higher than the national average. The rate of malformation (2.86%) was comparable with national survey (2.08%). The health of children diseased during the whole follow-up was approximately 2%. Conclusion: The health of children after 1 year of live is close normal. Fertil Steril 1994;61:324-30 Key Words: IVF perinatal outcome, obstetrical data, pediatric data, malformation
Since the birth of Louise Brown in 1978 (1), the first child produced by IVF, several thousand births Received February 1, 1993; revised and accepted October 6, 1993. * Task force group: Jean-Marie Antoine, M.D., (Hopital Tenon, Paris, France); Paul Barriere, M.D., (Centre hospitalier universitaire, Nantes, France); Sylvie Bulwa, M.D., (Hopital Saint-Vincent-de-Paul, Paris, France); Isabelle Cedrin-Durnerin, M.D., (Hopital Jean-Verdier, Bondy, France); Anne de Crepi, M.D., (Hopital Bichat, Paris, France); Jean-Bernard Dubuisson, M.D., (Hopital Port-Royal, Paris, France); Sylvie Epelboin, M.D., (Hopital Saint-Vincent-de-Paul, Paris, France); Herve Foulot, M.D., (Hopital Port-Royal, Paris, France); Christine Francoual, M.D., (Hopital Saint-Vincent-de-Paul, Paris, France); Arlette Guichard, M.D., (Hopital Baudelocque, Paris, France); Jean-Noel Hugues, M.D., (Hopital Jean-Verdier, Bondy, France); Dominique Le Lanou, M.D., (Centre hospitalier universitaire, Rennes, France); Gilles Lefebvre, M.D., (Hopital La Pitie-Salpetriere, Paris, France); Fran<;oise Merlet, 324
Rufat et al.
Outcome of IVF
after assisted reproductive technology (ART) have taken place throughout the world (2-5). Studies performed on these pregnancies and their progress have revealed differences from those conceived by natural methods: multiple pregnancies account for one quarter of the pregnancies, and the prematurity rate and rates of perinatal and neonatal mortality
M.D., (Hopital de Poissy, Poissy, France); Jacques Salat-Baroux, M.D., (Hopital Tenon, Paris, France); Isabelle Trocellier, M.D., (Centre hospitalier universitaire, Nantes, France); Daniele Vautier-Brouzes, M.D., (Hopital La Pitie-Salpetriere, Paris, France). t INSERM U292, Hopital Bicetre. :j: Reprint requests: Pierre Rufat, M.D., INSERM U292, Hopital de Bicetre, Les Cabanons, 78 rue du g€meral Leclerc, 94275 Le Kremlin-Bicetre Cedex, France. § Hopital Antoine-Beclere.
Fertility and Sterility
are higher (2-6). These rates are also higher for monofetal pregnancies (3). Similarly, some malformations, particularly neurological malformations, might be more frequent (7). However, no survey has yet concerned itself with both the outcome ofpregnancies and the subsequent condition of the children after their first year of life. To assess the outcomes of both pregnancies and children after IVF -ET, we carried out a multicenter survey studying the progress of all pregnancies conceived using this technique between the months of January 1987 and June 1989, together with pediatric follow-up of the children after 1 year. MATERIALS AND METHODS
Eleven ART centers volunteered to take part in this study, including 9 in the Paris area and 2 provincial centers. The ART centers took part in this study on a voluntary basis, with a view to producing a homogeneous register of information and achieving exhaustivity for each center. All except one were university hospitals. One of the centers contributed more than a quarter of the study's data (28%), whereas 4 other centers accounted for 13% together. All clinical pregnancies recorded by the centers and resulting from IVF-ET, GIFT, zygote intrafallop ian transfer or frozen ETs, performed between January 1,1987 and June 30,1989, were included in the study. Purely chemical pregnancies with an hCG level < 1,000 mID /mL were excluded. Obstetrical data were collected through doctors consulting the medical file of patients in each ART center, or by contacting the team that took care of delivery. The obstetrical form included data on the infertility diagnosis and the technique involved, the progress and outcome of the pregnancy, and information on the child at birth. A questionnaire was used to monitor the children, filled in from the pediatric file if the child was monitored in the center and by mail to all parents or by telephone if the parents did not reply. This provided us with medical follow-up data on each child covering any possible hospital visits, malformations, and diseases. The survey's analysis included a description of the IVF indications, the characteristics of the pregnancies and the children at birth, and the condition of the children during follow-up. We also selected four major indicators (prematurity, low birth rate, the presence of a malformation, and infant mortality) to determine which factors could playa role in the occurrence of complications. Vol. 61, No.2, February 1994
The pregnancy term was calculated in theoretical weeks of amenorrhea, with 14 days added to the difference between the date of oocyte retrieval and the date of delivery. This calculation enabled us to align our data close to the usual measure for gestation, which is from the 1st day of the last menstrual period (LMP). Only children whose term was 25 weeks of amenorrhea or more were included in the study; deliveries performed before 25 weeks of amenorrhea were considered as miscarriages. The maternal arterial hypertension was defined by a diastolic blood pressure> 100 mm Hg during pregnancy. To assess the influence of a variation of a few days on calculating prematurity, we carried out a simulation on different calculations of the pregnancy term. The pregnancy term was calculated with 16 days added to the difference between the date of oocyte retrieval and the date of delivery. Low birth rate was defined if birth weight was below the 10th percentile of curves established in a national survey (8), according to the child's sex and the delivery term, from 34 weeks of amenorrhea upward. The proportion of children weighing <1,500 or 2,500 g at birth was also used as an indicator of low birth rate. All the files of children presenting a pediatric disorder (that is, any abnormality as cystitis, myopia, asthma) were reviewed by a college of three pediatricians, who defined the malformations involved and specified the condition during follow-up (Tables 1 and 2). Their decisions were made unanimously. During the period of inclusion, 1,686 clinical pregnancies were recorded in the 11 centers, but it was not possible to fill in the obstetrical form for 49 patients of these, and they were not taken into account in the rest of the analysis. In all, information on the progress and outcome of the clinical pregnancies was collected for 1,637 pregnancies (97%) and 1,669 children, 1,637 of whom were live-born. During their 1st year of life, 34 children died; another child died at 2 years of age from a cardiovascu1ar malformation. Of the 1,602 children alive at the time of the survey after a minimum of 1 year of life, 191 children (12%) had been lost to follow-up, and the outcome after 1 year oflife was known for 1,411 children. The data were analyzed using the SAS software (Statistical Analysis Software; SAS Institute Inc., Cary, NC). The analysis included a description of different variables (percentages for quantitative variables, mean and standard deviation for qualitative variables). The tests used were Pearson's x2 Rufat et al.
Outcome of IVF
325
r Table 1 Malformations at Birth and During Follow-up in 48 Children Malformation
No.
Chromosomal defects Down's syndrome (trisomy 21)* Otherst Cardiovascular malformations Interventricular communication Transposition of great vessels Coarctation of the aorta Pulmonary stenosis Unspecifiedt Neurologic malformations Anencephalus:j: Cerebral malformation Parietal cyst Spina bifida:j: Meningocele Urogenital malformations Kidney agenesis Pyeloureteral stenosist Complex vesico-uterine malformation Other renal abnormalities Other urogenital disorderst Polymalformative syndromet Other malformations Clubfoot Atresia of the esophagus Laparoschisis Scoliosis with vertebral malformationt Trigeminal angioma Pulmonary hypoplasia Cleft lip
11 8 3 8
3 1 1 1 2 6 1 2 1 1 1 7 1 1 1 2 2
5 11 3 3 1 1 1 1 1
* Including five TAs (1 for twins).
t If one diagnosed during the follow-up. :j:TA.
test and multiple regression. Risk factors were analyzed using logistic regression, and odds ratios (OR) were computed with their 95% confidence intervals (CI).
cies resulted in delivery after 25 weeks of amenorrhea, representing 77% of clinical pregnancies. More than a quarter of these (347) were multiple pregnancies (23% twin, 4% triplet or higher order), including two quadruple pregnancies and one quintuple pregnancy. A cesarean section was performed in 36% (455) of deliveries, more than a quarter of the single pregnancies (28%) and especially for multiple pregnancies where it became virtually the rule. The overall rate of prematurity was very high (23%) but was largely linked to multiple pregnancies (Table 3). The rate of preterm births from monofetal pregnancies was still high at 12% (112). A modification of only 2 days on calculating prematurity induced a 3% reduction in the rate ofprematurity for single pregnancies, moving from 12.2% to 9.4%. Mortality varied considerably according to the type of pregnancy (Table 3); it was four times greater for children from a triplet or higher order pregnancy than for those born in a single pregnancy. The different measurements of low birth rate also increased with more multiple pregnancies (Table 3). They were still high for single pregnancies, as 15% (124) of the children had a birth weight lower than the 10th percentile of the reference curves. The sex ratio showed a slight preponderance of the male sex and varied little between the types of pregnancy. The rate of malformations was not statistically different, averaging 2.40% for all births (40 babies out of 1,669 children) and 2.86% including the therapeutic abortions (Table 1). Six malformations were diagnosed after the 1st week of life during the follow-up. Our analysis of risk factors was confined to monofetal pregnancies (Table 4). In our study maternal,
RESULTS The main indication for ART was tubal infertility, either alone (59%) or in combination with other causes of infertility (9%). Unexplained infertility accounted for 13% ofthe couples, and a male cause alone was present in 7% of cases. The technique most often used (86%) was IVF-ET, with GIFT representing 12% of successful attempts. Nearly 23% (375) ofthe pregnancies were spontaneously terminated, after either a miscarriage (19%) or an ectopic pregnancy (4%). Moreover, 7 therapeutic abortions (T A) were carried out for fetal malformations (Table 1), and of the 21 embryo reductions performed, 1 resulted in the complete termination of pregnancy. A total of 1,263 pregnan326
Rufat et al.
Outcome of IVF
Table 2
Disorders Considered in Follow-up in 25 Children Disorder
No.
Due to congenital abnormalities Secondary to malformation Chromosomic disorders Enzymopathy Secondary to intrauterine growth retardation Due to perinatal events Secondary to preterm birth Asphyxia Infection Acquired Psychological problems Acute leukemia Renal lithiasis
13 7 3 2 1 8 5 2 1 4 2 1 1
Fertility and Sterility
Table 3
General Data Concerning the Children Type of pregnancy
Prematurity' (term in weeks of amenorrhea) 25 to 27 28 to 31 32 to 33 34 to 35 36 25 to 36 Mortality (per 1,000 babies) Perinatal* Neonatalt Infantt Mean weight (g):j: Low birth rate (%) Weight <1,500 gt Weight <2,500 gt Weight <10th percentile:j: Malformation' (per 1,000) Excluding T As Including T As§ Sex ratio (M:F)
Singleton
Twin
Triplet or higher order
Total
%
%
%
%
Degree of significance
0.3 1.8 0.8 3.6 5.7 12.2
2.8 2.8 8.3 13.8 16.2 43.8
1.8 16.1 25.0 17.9 23.2 83.9
1.0 2.6 3.6 6.6 8.9 22.7
18.6 9.9 14.3 3,095 ± 561
34.4 14.1 19.4 2,363 ± 532
81.9 36.8 61.3 1,927 ± 524
30.6 14.1 20.8 2,719 ± 697
1.6 12.3 15.0
5.9 55.4 49.6
18.8 84.4 62.4
4.9 34.7 29.8
P < 10-6 P < 10-6 P < 10-6
18.6 24.9 1.20
30.9 34.2 0.96
29.2 29.2 1.29
24.0 28.6 1.12
NSl! NS NS
P < 10-6
P P P P
< < < <
0.001 0.05 0.001 10-6
* Of all births taken together (n = 1,669: singletons = 916; twins = 582; triplets = 171). t Of all live births (n = 1,637: singletons = 906; twins = 568; triplets = 163).
:j: Measured for live children born after 34 weeks of ameorrhea (n = 1,384: singletons = 827; twins = 464; triplets = 93). § Including the 7 T As (one of which was performed on a twin pregnancy). l! NS, not significant.
only the arterial hypertension during pregnancy appeared to be significantly related to low birth rate (OR = 3.4; CI = [1.9 to 6.1]). This relationship between hypertension and low birth rate remained significant after adjusting for maternal age and the term at of birth (OR = 2.8; CI = [1.5 to 5.3]). However, arterial hypertension was not related to other major indicators when the mother's age, which was higher than that indicated by the annual reports of the French registry FIVNAT (2), was taken into account. This analysis found no significant difference between other risk factors and complications; it should be noted, however, that complications were more frequent when the maternal age exceeded 40 years, but this was not significant. The child's condition was known for 1,411 ofthe children after 1 year of life (88%). The proportion of children recorded as diseased during the whole follow-up period remained close to 2% (30).
cies and children after IVF-ET (3,9). Moreover, it takes into account the T As and the follow-up for the rate of malformations and has a small rate of loss to follow-up of children. With regard to the progress of pregnancy and the child's condition at birth, the low proportion of cases for which no information could be collected (3%) confirms that the results were valid; exhaustivity was almost reached by each participating center. Though the results of this study are a good reflection of the activities of the centers involved, they cannot be considered as representative and cannot be directly extrapolated to all pregnancies after IVF -ET in France for this period. This is because first, the centers were not chosen at random but participated voluntarily, and second, the survey included only one fifth of pregnancies resulting from IVF-ET in France between January 1987 and June 1989 (approximately 9,000 pregnancies, according to the national survey (10». The causes of infertility are close to those indicated by the annual reports of the French registry FIVNAT (2), for both average age and the main indications for IVF -ET. An etiology of tubal origin was found in 68% of the women in this survey
DISCUSSION
The survey presented here represents one of the largest series in literature on follow-up ofpregnanVol. 61, No.2, February 1994
Rufat et al.
Outcome of IVF
327
Table 4
Complications and Risk Factors Single pregnancies Prematurity after 25 weeks of amenorrhea
Malformation except TAs
Low birth rate 10th percentile
Infant mortality
%
%
%
%
Overall rate Infertility population* Female (n = 634) Male (n = 68) Mixed (n = 74) Unexplained (n = 117) Unspecified (n = 23) Technique IVF (n = 804) GIFT (n = 86) No. of embryos or oocytes transferred* 1 (n = 143) 2 (n = 142) 3 (n = 296) 4 (n = 175) 5 or more (n = 112) Maternal age* <30 years (n = 153) 30 to 34 years (n = 390) 35 to 39 years (n = 302) ;>:40 years (n = 43) Unknown (n = 28) Hypertension (during pregnancy) No (n = 854) Yes (n = 62) Odds ratio [CI95%]
12.2
1.86
15.0
1.43
1204 8.8 6.8 14.0 8.7
2.05 2.94 0 1.71 0
15.7 4.8 4.5 15.8 26.3
1.59 1.47 0 0.87 4.3
11.8 9.5
2.11 0
14.9 1504
1.63 0
10.5 12.1 10.7 12.8 11.1
lAO 2.11 1.69 2.86 1.79
10.8 18.1 15.8 11.9 18.6
2.84 1.03 2.30 0
10.7 11.3 11.7 20.9 10.7
1.96 1.54 1.32 2.33 10.71
14.6 15.9 13.0 17.9 25.0
1.32 0.78 1.66 4.65 3.57
11.1 18.6 2.0t [1.1 to 3.9]
1.76 3.23 1.9 [004 to 8.3]
13.1 34.6 3At [1.9 to 6.1]
1.55 5.00 4.3t [1.1 to 16.0]
* Difference not significant for each risk factor.
(compared with 62% to 69% during this period in France). The total rate single pregnancies found in this survey (73%) was similar to that found in France (2) (72%) and in other countries such as Britain (3) (77%) and the United States (5,6) (75%). Equally, 77% (1,263) of the clinical pregnancies assisted by ART and recorded in this survey resulted in a delivery; the same happened for the United States (5) (75% ). These data showed that the selection biais was low and the results could be considered representative for ART activity in France. Information on the follow-up of the children is relatively complete: only almost 12% (191) of all the children (1,602) were lost to follow-up during monitoring after 1 year. Other studies analyzing the child's condition after the perinatal period had an equivalent rate ofloss to follow-up but for a shorter follow-up period (14% at 1 year in Britain [3]) or a smaller number of children (Vos MTJA, Alberda ATh, abstract). The overall rate of prematurity (Table 3) was 328
Rufat et al.
Outcome of IVF
lAO
t Degree of significance P < 0.05.
very high, with 22.7% of children born before 37 weeks of amenorrhea. This rate was due mainly to the high proportion of multiple pregnancies. Although the legal limit for prematurity in France is 28 weeks of amenorrhea, several children were liveborn before this term and benefited from neonatal resuscitation techniques; it seemed preferable to lower the limit to 25 weeks of amenorrhea. It is difficult to compare prematurity rates with other studies because the prematurity thresholds are different, ranging from 20 weeks of amenorrhea in Australia (4) and the United States (5, 6) to 28 weeks of amenorrhea in Britain (3). However, the prematurity rates for single (12.2%), double (43.8%), and triplet pregnancies (83.9%) remained slightly lower than those in the English study (respectively, 13%,57%, and 95%), where the prematurity threshold was the highest (thus underestimating the number of preterm births by our criteria). If we had taken a limit of 28 weeks of amenorrhea in our study, as in Britain, the prematurity rates would be cut slightly to 11.9%, 41.0%, Fertility and Sterility
and 82.1 %. The prematurity rate for single pregnancies was significantly higher in Australia (17%) (Lancaster P, abstract), whereas for multiple pregnancies after ART an Israeli study found similar rates (40% for twin pregnancies and 80% for triplet pregnancies [11]). Nevertheless, the high prematurity rate for single pregnancies was the result of the births after 32 weeks of amenorrhea, and the babies born before 32 weeks of amenorrhea represented 3.6%. In the absence of a reference population to compare the prematurity rate in naturally conceived triplets, the rates observed in twins (43.8%) and single children (12.2%) were higher than those found in national surveys in both France (8) (35.5% and 5.6%, respectively) and Britain (3). The higher prematurity for twins is more difficult to determine because the total population of twins in national surveys (8) is not high enough to obtain an accurate measurement and make a comparison, even though there seems to be higher prematurity among children conceived by IVF-ET. It is difficult, however, to make an unbiased comparison between preterm births in pregnancies resulting from ART and those observed in natural pregnancies. During an ART attempt, the day of oocyte retrieval and the day of delivery are known exactly. Although we have systematically added 14 days between these two dates to get close to a term of gestation measured from the theoretical date of the LMP, this kind of accuracy is not found in studies of natural pregnancies. The day of ovulation is itself uncertain, and the mean length of the first phase of the ovulatory cycle might be> 14 days (12). A modification of only 2 days on calculating prematurity induced a 3% reduction in the rate ofprematurity for single pregnancies. Yet, the rate of low birth rate rises when the rate of prematurity decreases. There is no question here of explaining away the rise in prematurity simply by a discrepancy in accurate measurement ofthe term; the point is simply to show that this notion needs to be introduced into comparisons between a sample and the general population, especially because a high rate of prematurity has been noted in a Swedish national study of women presenting difficulties in conceiving (13). The women with infertility problems were shown to have an increased age and more spontaneous abortions and stillbirths. The high rate of previous extrauterine pregnancies also indicated the inclusion of a group of women with tubal problems as women who underwent ART techniques. These two hypothVol. 61, No.2, February 1994
eses, inaccurate determination of the term and subfecundity, could explain the absence of any significant link between the prematurity rate among single pregnancies and the risk factors we recorded (Table 4). The high overall level of low birth rate (34.7%) can largely be attributed to multiple births (Table 4). However, low birth rate was also high in single pregnancies: 12.3% (111) of these children had a birth weight lower than 2,500 g, whereas the correspondingproportion in national surveys (8) is 5.2%. These results were also mentioned in the English study (3). Nonetheless, the high level of prematurity interferes with any accurate determination of low birth rate, and we therefore preferred a definition of low birth rate measured against the 10th percentile of national reference curves. This definition provides a low birth rate measurement that is partly independent of the child's term at birth, which is not possible with a definition fixed on a limit weight (1,500 or 2,500 g). We could therefore look separately at low birth rate and prematurity for children whose term was at least 34 weeks of amenorrhea: the level oflow birth rate was still high for single children because at the 10th percentile 15% (124) of children were found to have a low birth weight instead of the theoretical 10% (x 2 = 20.3, df = 1, P < 0.001). Of the risk factors taken into account in looking for links with low birth rate, only a history of maternal arterial hypertension during pregnancy appeared to be significant after adjusting for the mother's age and the term (OR = 2.8, CI = [1.5 to 5.3]). This relationship was also mentioned by the English team (9). The variations in low birth rate levels observed for the different IVF -ET indications (Table 4) were not significant, just as for parity; in spite of everything, it would seem that the level oflow birth rate for couples with a male component to their sterility was lower. Infant mortality acted as the main indicator in follow-up of children up to 1 year. The above average infant mortality found in this survey reflects the joint roles played by a high rate of prematurity, widespread low birth rate, and the large number of multiple pregnancies. Even if the analysis is restricted to single births, this increase in average mortality persists partly because of prematurity, but it is not statistically significant (1.43% in our study compared with 0.97% on a national level (7), x2 = 2.0, df = 1). If a standard rate of infant mortality is calculated taking prematurity into account (with prematurity rates taken from national surveys Rufat et al.
Outcome of IVF
329
r [
I
I!
[8]), the adjusted rate of infant mortality falls slightly to 1.14%. Prematurity does not appear to be the sole explanation for infant mortality, but none of the risk factors selected (Table 4) seems to be linked to infant mortality. The proportion of serious malformations encountered in this survey, even when TAs and malformations diagnosed during the follow-up are included (2.86%), was close to that recorded in other studies (3, 6,9) on children born after ART and to the proportion recorded in France (8) without IVF-ET (2.08%) (X 2 = 4.8, df = 1). Given the small size of the sample, none of the risk factors sought seemed to be linked to the malformations, including maternal age, which may seem surprising, but reflects probably this study's lack of power because it covers only 48 malformations. More detailed analysis could be made only on a much wider population or an international survey. Only one death was recorded in children during follow-up after the 1st year. The proportion of living children with a medical disorder remained constant at approximately 2% throughout the 3 years. These were either children retaining complications to their congenital malformation and perinatal events or children who had contracted a disease (Table 2). This proportion of abnormal children is well below that found in a Dutch study (Vos MTJA, Alberda ATh, abstract) that monitored 173 children between 1 and 3 years and recorded nine serious abnormalities in living children; however, the criteria were not exactly the same as those adopted for this study, and monitoring focused on only 80% of the children born after an IVF -ET -assisted pregnancy. In any event, as with malformations, the absence of a control group and the small number of diseased children prevent any firm conclusions in this area. This survey on the progress of pregnancies and the outcomes of children after IVF -ET on a wide population confirms an increase in prematurity, low birth rate and infant mortality for all the pregnancies. It also shows that these risks are also high for pregnancies leading to the birth of a single child, when compared with spontaneous pregnancies in national statistics. On the other hand, it reveals a rate of malformation, even when T As are included, and a proportion of diseased children largely similar to those found in the population as a whole. Some errors in determining the term, selection of couples asking for IVF-ET (these couples are at least subfertile) and controlled ovarian hyperstimulation
330
Rufat et al.
Outcome of IVF
(Olivennes F, personal communication) could be related to these higher risks of prematurity, low birth rate, or infant mortality, as has been suggested by a Swedish national survey (13) and another American study (14). To measure the influence of these factors and the rate of malformations more accurately, a wider reaching and more prospective survey would be needed, with the presence of a control group of natural pregnancies and another control group of pregnancies after ovulatory stimulation.
REFERENCES 1. Steptoe PC, Edwards RG. Birth after reimplantation of a human embryo [letter]. Lancet 1978;2:366. 2. FIVNAT, de Mouzon J, Bachelot A, Logerot H. IVF in France: FIVNAT data 1986-1990. Contracept Fertil Sex (Paris) 1991;19:554-7. 3. Report of the Working Party on Children Conceived by In Vitro Fertilisation. Births in Great Britain resulting from assisted conception, 1978-87. Br Med J 1990;300:1229-33. 4. Australian In Vitro Fertilization Group. High incidence of preterms births and early losses in pregnancy after in vitro fertilization. Br Med J 1985;291:1160-3. 5. Medical Research International and the Society of Assisted Reproduction Technology, The American Fertility Society. In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1987 results from the national IVF-ET registry. Fertil Steril 1989;51:13-9. 6. Medical Research International and the Society of Assisted Reproduction Technology, The American Fertility Society. In vitro fertilization/embryo transfer in the United States: 1989 results from the national IVF /ET registry. Fertil Steril 1991;55:14-23. 7. Lancaster P. Congenital malformations after in vitro fertilisation. Lancet 1987;2:1392. 8. Rumeau-Rouquette C, du Mazaubrun C, Rabarizon Y. Naitre en France-l0 ans d'evolution. Paris: Doin EditeursEditions INSERM, 1984. 9. Doyle P, Beral V, Maconochie N. Preterm deliveries, low birth weight andsmall-for-gestational-age in liveborn singleton babies resulting from IVF. Hum Reprod 1992;7:425-8. 10. Antoine JM, Hedon B. Review of medically assisted procreation in France in 1990. Main results of the 1991 GEFF study. Contracept Fertil Sex (Paris) 1991;19:550-3. 11. Friedler S, Mashiach S, Laufer N. Births in Israel resulting from in-vitro fertilization/embryo transfer, 1982-1989: National Registry of the Israeli Association for Fertility Research. Hum Reprod 1992;7:1159-63. 12. Spira A, Spira N, Papiernik-Berkauer E, Schwartz D. Pattern of menstrual cycles and incidence of congenital malformation. Early Hum Dev 1985;11:317-24. 13. Ghazi HA, Spielberger C, Kallen B. Delivery outcome after infertility-a registry study. Fertil Steril 1991;55:726-32. 14. Williams MA, Goldman MB, Mittendorf R, Monson RR. Subfertility and the risk of low birth weight. Fertil Steril 1991;56:668-71.
Fertility and Sterility
(j;l
Vol. 61, No.2, February 1994
1994 The American Fertility Society
Printed on acid-free paper in U. S. A.
Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France: 1987 to 1989)*
Pierre Rufat, M.D.t:j: Franc;ois Olivennes, M.D.§ Jacques de Mouzon, M.D.t
Michel Dehan, M.D.§ Rene Frydman, M.D.§
Institut National de la Sante et de la Recherche Medicale (INSERM), Bicetre, and H6pital Antoine-Beclere, Clamart, France
Objective: To describe the outcome of pregnancies conceived by IVF and the follow-up of the children after a minimum of 1 year of life. Design: Survey of clinical pregnancies and follow-up of the children and comparison with national statistics. Settings: All clinical pregnancies from 11 French centers between January 1987 and June 1989. Patients: A total of 1,637 pregnancies resulting in 1,263 deliveries and 1,669 live-born or stillborn children and 1,411 alive children after 1 year. Main Outcome Measures: Gestational age of birth, birth weight, mortality rates, prevalence of congenital malformation, and prevalence of disorders during the follow-up of the children. Results: The preterm birth rate was 22.7% of all deliveries and 12.2% of single deliveries compared with 5.6% in France, and 34.7% of babies weighed <2,500 g compared with 5.2% in France. The rate of perinatal, neonatal, and infant mortality were higher than the national average. The rate of malformation (2.86%) was comparable with national survey (2.08%). The health of children diseased during the whole follow-up was approximately 2%. Conclusion: The health of children after 1 year of live is close normal. Fertil Steril 1994;61:324-30 Key Words: IVF perinatal outcome, obstetrical data, pediatric data, malformation
Since the birth of Louise Brown in 1978 (1), the first child produced by IVF, several thousand births Received February 1, 1993; revised and accepted October 6, 1993. * Task force group: Jean-Marie Antoine, M.D., (Hopital Tenon, Paris, France); Paul Barriere, M.D., (Centre hospitalier universitaire, Nantes, France); Sylvie Bulwa, M.D., (Hopital Saint-Vincent-de-Paul, Paris, France); Isabelle Cedrin-Durnerin, M.D., (Hopital Jean-Verdier, Bondy, France); Anne de Crepi, M.D., (Hopital Bichat, Paris, France); Jean-Bernard Dubuisson, M.D., (Hopital Port-Royal, Paris, France); Sylvie Epelboin, M.D., (Hopital Saint-Vincent-de-Paul, Paris, France); Herve Foulot, M.D., (Hopital Port-Royal, Paris, France); Christine Francoual, M.D., (Hopital Saint-Vincent-de-Paul, Paris, France); Arlette Guichard, M.D., (Hopital Baudelocque, Paris, France); Jean-Noel Hugues, M.D., (Hopital Jean-Verdier, Bondy, France); Dominique Le Lanou, M.D., (Centre hospitalier universitaire, Rennes, France); Gilles Lefebvre, M.D., (Hopital La Pitie-Salpetriere, Paris, France); Fran<;oise Merlet, 324
Rufat et al.
Outcome of IVF
after assisted reproductive technology (ART) have taken place throughout the world (2-5). Studies performed on these pregnancies and their progress have revealed differences from those conceived by natural methods: multiple pregnancies account for one quarter of the pregnancies, and the prematurity rate and rates of perinatal and neonatal mortality
M.D., (Hopital de Poissy, Poissy, France); Jacques Salat-Baroux, M.D., (Hopital Tenon, Paris, France); Isabelle Trocellier, M.D., (Centre hospitalier universitaire, Nantes, France); Daniele Vautier-Brouzes, M.D., (Hopital La Pitie-Salpetriere, Paris, France). t INSERM U292, Hopital Bicetre. :j: Reprint requests: Pierre Rufat, M.D., INSERM U292, Hopital de Bicetre, Les Cabanons, 78 rue du g€meral Leclerc, 94275 Le Kremlin-Bicetre Cedex, France. § Hopital Antoine-Beclere.
Fertility and Sterility
are higher (2-6). These rates are also higher for monofetal pregnancies (3). Similarly, some malformations, particularly neurological malformations, might be more frequent (7). However, no survey has yet concerned itself with both the outcome ofpregnancies and the subsequent condition of the children after their first year of life. To assess the outcomes of both pregnancies and children after IVF -ET, we carried out a multicenter survey studying the progress of all pregnancies conceived using this technique between the months of January 1987 and June 1989, together with pediatric follow-up of the children after 1 year. MATERIALS AND METHODS
Eleven ART centers volunteered to take part in this study, including 9 in the Paris area and 2 provincial centers. The ART centers took part in this study on a voluntary basis, with a view to producing a homogeneous register of information and achieving exhaustivity for each center. All except one were university hospitals. One of the centers contributed more than a quarter of the study's data (28%), whereas 4 other centers accounted for 13% together. All clinical pregnancies recorded by the centers and resulting from IVF-ET, GIFT, zygote intrafallop ian transfer or frozen ETs, performed between January 1,1987 and June 30,1989, were included in the study. Purely chemical pregnancies with an hCG level < 1,000 mID /mL were excluded. Obstetrical data were collected through doctors consulting the medical file of patients in each ART center, or by contacting the team that took care of delivery. The obstetrical form included data on the infertility diagnosis and the technique involved, the progress and outcome of the pregnancy, and information on the child at birth. A questionnaire was used to monitor the children, filled in from the pediatric file if the child was monitored in the center and by mail to all parents or by telephone if the parents did not reply. This provided us with medical follow-up data on each child covering any possible hospital visits, malformations, and diseases. The survey's analysis included a description of the IVF indications, the characteristics of the pregnancies and the children at birth, and the condition of the children during follow-up. We also selected four major indicators (prematurity, low birth rate, the presence of a malformation, and infant mortality) to determine which factors could playa role in the occurrence of complications. Vol. 61, No.2, February 1994
The pregnancy term was calculated in theoretical weeks of amenorrhea, with 14 days added to the difference between the date of oocyte retrieval and the date of delivery. This calculation enabled us to align our data close to the usual measure for gestation, which is from the 1st day of the last menstrual period (LMP). Only children whose term was 25 weeks of amenorrhea or more were included in the study; deliveries performed before 25 weeks of amenorrhea were considered as miscarriages. The maternal arterial hypertension was defined by a diastolic blood pressure> 100 mm Hg during pregnancy. To assess the influence of a variation of a few days on calculating prematurity, we carried out a simulation on different calculations of the pregnancy term. The pregnancy term was calculated with 16 days added to the difference between the date of oocyte retrieval and the date of delivery. Low birth rate was defined if birth weight was below the 10th percentile of curves established in a national survey (8), according to the child's sex and the delivery term, from 34 weeks of amenorrhea upward. The proportion of children weighing <1,500 or 2,500 g at birth was also used as an indicator of low birth rate. All the files of children presenting a pediatric disorder (that is, any abnormality as cystitis, myopia, asthma) were reviewed by a college of three pediatricians, who defined the malformations involved and specified the condition during follow-up (Tables 1 and 2). Their decisions were made unanimously. During the period of inclusion, 1,686 clinical pregnancies were recorded in the 11 centers, but it was not possible to fill in the obstetrical form for 49 patients of these, and they were not taken into account in the rest of the analysis. In all, information on the progress and outcome of the clinical pregnancies was collected for 1,637 pregnancies (97%) and 1,669 children, 1,637 of whom were live-born. During their 1st year of life, 34 children died; another child died at 2 years of age from a cardiovascu1ar malformation. Of the 1,602 children alive at the time of the survey after a minimum of 1 year of life, 191 children (12%) had been lost to follow-up, and the outcome after 1 year oflife was known for 1,411 children. The data were analyzed using the SAS software (Statistical Analysis Software; SAS Institute Inc., Cary, NC). The analysis included a description of different variables (percentages for quantitative variables, mean and standard deviation for qualitative variables). The tests used were Pearson's x2 Rufat et al.
Outcome of IVF
325
r Table 1 Malformations at Birth and During Follow-up in 48 Children Malformation
No.
Chromosomal defects Down's syndrome (trisomy 21)* Otherst Cardiovascular malformations Interventricular communication Transposition of great vessels Coarctation of the aorta Pulmonary stenosis Unspecifiedt Neurologic malformations Anencephalus:j: Cerebral malformation Parietal cyst Spina bifida:j: Meningocele Urogenital malformations Kidney agenesis Pyeloureteral stenosist Complex vesico-uterine malformation Other renal abnormalities Other urogenital disorderst Polymalformative syndromet Other malformations Clubfoot Atresia of the esophagus Laparoschisis Scoliosis with vertebral malformationt Trigeminal angioma Pulmonary hypoplasia Cleft lip
11 8 3 8
3 1 1 1 2 6 1 2 1 1 1 7 1 1 1 2 2
5 11 3 3 1 1 1 1 1
* Including five TAs (1 for twins).
t If one diagnosed during the follow-up. :j:TA.
test and multiple regression. Risk factors were analyzed using logistic regression, and odds ratios (OR) were computed with their 95% confidence intervals (CI).
cies resulted in delivery after 25 weeks of amenorrhea, representing 77% of clinical pregnancies. More than a quarter of these (347) were multiple pregnancies (23% twin, 4% triplet or higher order), including two quadruple pregnancies and one quintuple pregnancy. A cesarean section was performed in 36% (455) of deliveries, more than a quarter of the single pregnancies (28%) and especially for multiple pregnancies where it became virtually the rule. The overall rate of prematurity was very high (23%) but was largely linked to multiple pregnancies (Table 3). The rate of preterm births from monofetal pregnancies was still high at 12% (112). A modification of only 2 days on calculating prematurity induced a 3% reduction in the rate ofprematurity for single pregnancies, moving from 12.2% to 9.4%. Mortality varied considerably according to the type of pregnancy (Table 3); it was four times greater for children from a triplet or higher order pregnancy than for those born in a single pregnancy. The different measurements of low birth rate also increased with more multiple pregnancies (Table 3). They were still high for single pregnancies, as 15% (124) of the children had a birth weight lower than the 10th percentile of the reference curves. The sex ratio showed a slight preponderance of the male sex and varied little between the types of pregnancy. The rate of malformations was not statistically different, averaging 2.40% for all births (40 babies out of 1,669 children) and 2.86% including the therapeutic abortions (Table 1). Six malformations were diagnosed after the 1st week of life during the follow-up. Our analysis of risk factors was confined to monofetal pregnancies (Table 4). In our study maternal,
RESULTS The main indication for ART was tubal infertility, either alone (59%) or in combination with other causes of infertility (9%). Unexplained infertility accounted for 13% ofthe couples, and a male cause alone was present in 7% of cases. The technique most often used (86%) was IVF-ET, with GIFT representing 12% of successful attempts. Nearly 23% (375) ofthe pregnancies were spontaneously terminated, after either a miscarriage (19%) or an ectopic pregnancy (4%). Moreover, 7 therapeutic abortions (T A) were carried out for fetal malformations (Table 1), and of the 21 embryo reductions performed, 1 resulted in the complete termination of pregnancy. A total of 1,263 pregnan326
Rufat et al.
Outcome of IVF
Table 2
Disorders Considered in Follow-up in 25 Children Disorder
No.
Due to congenital abnormalities Secondary to malformation Chromosomic disorders Enzymopathy Secondary to intrauterine growth retardation Due to perinatal events Secondary to preterm birth Asphyxia Infection Acquired Psychological problems Acute leukemia Renal lithiasis
13 7 3 2 1 8 5 2 1 4 2 1 1
Fertility and Sterility
Table 3
General Data Concerning the Children Type of pregnancy
Prematurity' (term in weeks of amenorrhea) 25 to 27 28 to 31 32 to 33 34 to 35 36 25 to 36 Mortality (per 1,000 babies) Perinatal* Neonatalt Infantt Mean weight (g):j: Low birth rate (%) Weight <1,500 gt Weight <2,500 gt Weight <10th percentile:j: Malformation' (per 1,000) Excluding T As Including T As§ Sex ratio (M:F)
Singleton
Twin
Triplet or higher order
Total
%
%
%
%
Degree of significance
0.3 1.8 0.8 3.6 5.7 12.2
2.8 2.8 8.3 13.8 16.2 43.8
1.8 16.1 25.0 17.9 23.2 83.9
1.0 2.6 3.6 6.6 8.9 22.7
18.6 9.9 14.3 3,095 ± 561
34.4 14.1 19.4 2,363 ± 532
81.9 36.8 61.3 1,927 ± 524
30.6 14.1 20.8 2,719 ± 697
1.6 12.3 15.0
5.9 55.4 49.6
18.8 84.4 62.4
4.9 34.7 29.8
P < 10-6 P < 10-6 P < 10-6
18.6 24.9 1.20
30.9 34.2 0.96
29.2 29.2 1.29
24.0 28.6 1.12
NSl! NS NS
P < 10-6
P P P P
< < < <
0.001 0.05 0.001 10-6
* Of all births taken together (n = 1,669: singletons = 916; twins = 582; triplets = 171). t Of all live births (n = 1,637: singletons = 906; twins = 568; triplets = 163).
:j: Measured for live children born after 34 weeks of ameorrhea (n = 1,384: singletons = 827; twins = 464; triplets = 93). § Including the 7 T As (one of which was performed on a twin pregnancy). l! NS, not significant.
only the arterial hypertension during pregnancy appeared to be significantly related to low birth rate (OR = 3.4; CI = [1.9 to 6.1]). This relationship between hypertension and low birth rate remained significant after adjusting for maternal age and the term at of birth (OR = 2.8; CI = [1.5 to 5.3]). However, arterial hypertension was not related to other major indicators when the mother's age, which was higher than that indicated by the annual reports of the French registry FIVNAT (2), was taken into account. This analysis found no significant difference between other risk factors and complications; it should be noted, however, that complications were more frequent when the maternal age exceeded 40 years, but this was not significant. The child's condition was known for 1,411 ofthe children after 1 year of life (88%). The proportion of children recorded as diseased during the whole follow-up period remained close to 2% (30).
cies and children after IVF-ET (3,9). Moreover, it takes into account the T As and the follow-up for the rate of malformations and has a small rate of loss to follow-up of children. With regard to the progress of pregnancy and the child's condition at birth, the low proportion of cases for which no information could be collected (3%) confirms that the results were valid; exhaustivity was almost reached by each participating center. Though the results of this study are a good reflection of the activities of the centers involved, they cannot be considered as representative and cannot be directly extrapolated to all pregnancies after IVF -ET in France for this period. This is because first, the centers were not chosen at random but participated voluntarily, and second, the survey included only one fifth of pregnancies resulting from IVF-ET in France between January 1987 and June 1989 (approximately 9,000 pregnancies, according to the national survey (10». The causes of infertility are close to those indicated by the annual reports of the French registry FIVNAT (2), for both average age and the main indications for IVF -ET. An etiology of tubal origin was found in 68% of the women in this survey
DISCUSSION
The survey presented here represents one of the largest series in literature on follow-up ofpregnanVol. 61, No.2, February 1994
Rufat et al.
Outcome of IVF
327
Table 4
Complications and Risk Factors Single pregnancies Prematurity after 25 weeks of amenorrhea
Malformation except TAs
Low birth rate 10th percentile
Infant mortality
%
%
%
%
Overall rate Infertility population* Female (n = 634) Male (n = 68) Mixed (n = 74) Unexplained (n = 117) Unspecified (n = 23) Technique IVF (n = 804) GIFT (n = 86) No. of embryos or oocytes transferred* 1 (n = 143) 2 (n = 142) 3 (n = 296) 4 (n = 175) 5 or more (n = 112) Maternal age* <30 years (n = 153) 30 to 34 years (n = 390) 35 to 39 years (n = 302) ;>:40 years (n = 43) Unknown (n = 28) Hypertension (during pregnancy) No (n = 854) Yes (n = 62) Odds ratio [CI95%]
12.2
1.86
15.0
1.43
1204 8.8 6.8 14.0 8.7
2.05 2.94 0 1.71 0
15.7 4.8 4.5 15.8 26.3
1.59 1.47 0 0.87 4.3
11.8 9.5
2.11 0
14.9 1504
1.63 0
10.5 12.1 10.7 12.8 11.1
lAO 2.11 1.69 2.86 1.79
10.8 18.1 15.8 11.9 18.6
2.84 1.03 2.30 0
10.7 11.3 11.7 20.9 10.7
1.96 1.54 1.32 2.33 10.71
14.6 15.9 13.0 17.9 25.0
1.32 0.78 1.66 4.65 3.57
11.1 18.6 2.0t [1.1 to 3.9]
1.76 3.23 1.9 [004 to 8.3]
13.1 34.6 3At [1.9 to 6.1]
1.55 5.00 4.3t [1.1 to 16.0]
* Difference not significant for each risk factor.
(compared with 62% to 69% during this period in France). The total rate single pregnancies found in this survey (73%) was similar to that found in France (2) (72%) and in other countries such as Britain (3) (77%) and the United States (5,6) (75%). Equally, 77% (1,263) of the clinical pregnancies assisted by ART and recorded in this survey resulted in a delivery; the same happened for the United States (5) (75% ). These data showed that the selection biais was low and the results could be considered representative for ART activity in France. Information on the follow-up of the children is relatively complete: only almost 12% (191) of all the children (1,602) were lost to follow-up during monitoring after 1 year. Other studies analyzing the child's condition after the perinatal period had an equivalent rate ofloss to follow-up but for a shorter follow-up period (14% at 1 year in Britain [3]) or a smaller number of children (Vos MTJA, Alberda ATh, abstract). The overall rate of prematurity (Table 3) was 328
Rufat et al.
Outcome of IVF
lAO
t Degree of significance P < 0.05.
very high, with 22.7% of children born before 37 weeks of amenorrhea. This rate was due mainly to the high proportion of multiple pregnancies. Although the legal limit for prematurity in France is 28 weeks of amenorrhea, several children were liveborn before this term and benefited from neonatal resuscitation techniques; it seemed preferable to lower the limit to 25 weeks of amenorrhea. It is difficult to compare prematurity rates with other studies because the prematurity thresholds are different, ranging from 20 weeks of amenorrhea in Australia (4) and the United States (5, 6) to 28 weeks of amenorrhea in Britain (3). However, the prematurity rates for single (12.2%), double (43.8%), and triplet pregnancies (83.9%) remained slightly lower than those in the English study (respectively, 13%,57%, and 95%), where the prematurity threshold was the highest (thus underestimating the number of preterm births by our criteria). If we had taken a limit of 28 weeks of amenorrhea in our study, as in Britain, the prematurity rates would be cut slightly to 11.9%, 41.0%, Fertility and Sterility
and 82.1 %. The prematurity rate for single pregnancies was significantly higher in Australia (17%) (Lancaster P, abstract), whereas for multiple pregnancies after ART an Israeli study found similar rates (40% for twin pregnancies and 80% for triplet pregnancies [11]). Nevertheless, the high prematurity rate for single pregnancies was the result of the births after 32 weeks of amenorrhea, and the babies born before 32 weeks of amenorrhea represented 3.6%. In the absence of a reference population to compare the prematurity rate in naturally conceived triplets, the rates observed in twins (43.8%) and single children (12.2%) were higher than those found in national surveys in both France (8) (35.5% and 5.6%, respectively) and Britain (3). The higher prematurity for twins is more difficult to determine because the total population of twins in national surveys (8) is not high enough to obtain an accurate measurement and make a comparison, even though there seems to be higher prematurity among children conceived by IVF-ET. It is difficult, however, to make an unbiased comparison between preterm births in pregnancies resulting from ART and those observed in natural pregnancies. During an ART attempt, the day of oocyte retrieval and the day of delivery are known exactly. Although we have systematically added 14 days between these two dates to get close to a term of gestation measured from the theoretical date of the LMP, this kind of accuracy is not found in studies of natural pregnancies. The day of ovulation is itself uncertain, and the mean length of the first phase of the ovulatory cycle might be> 14 days (12). A modification of only 2 days on calculating prematurity induced a 3% reduction in the rate ofprematurity for single pregnancies. Yet, the rate of low birth rate rises when the rate of prematurity decreases. There is no question here of explaining away the rise in prematurity simply by a discrepancy in accurate measurement ofthe term; the point is simply to show that this notion needs to be introduced into comparisons between a sample and the general population, especially because a high rate of prematurity has been noted in a Swedish national study of women presenting difficulties in conceiving (13). The women with infertility problems were shown to have an increased age and more spontaneous abortions and stillbirths. The high rate of previous extrauterine pregnancies also indicated the inclusion of a group of women with tubal problems as women who underwent ART techniques. These two hypothVol. 61, No.2, February 1994
eses, inaccurate determination of the term and subfecundity, could explain the absence of any significant link between the prematurity rate among single pregnancies and the risk factors we recorded (Table 4). The high overall level of low birth rate (34.7%) can largely be attributed to multiple births (Table 4). However, low birth rate was also high in single pregnancies: 12.3% (111) of these children had a birth weight lower than 2,500 g, whereas the correspondingproportion in national surveys (8) is 5.2%. These results were also mentioned in the English study (3). Nonetheless, the high level of prematurity interferes with any accurate determination of low birth rate, and we therefore preferred a definition of low birth rate measured against the 10th percentile of national reference curves. This definition provides a low birth rate measurement that is partly independent of the child's term at birth, which is not possible with a definition fixed on a limit weight (1,500 or 2,500 g). We could therefore look separately at low birth rate and prematurity for children whose term was at least 34 weeks of amenorrhea: the level oflow birth rate was still high for single children because at the 10th percentile 15% (124) of children were found to have a low birth weight instead of the theoretical 10% (x 2 = 20.3, df = 1, P < 0.001). Of the risk factors taken into account in looking for links with low birth rate, only a history of maternal arterial hypertension during pregnancy appeared to be significant after adjusting for the mother's age and the term (OR = 2.8, CI = [1.5 to 5.3]). This relationship was also mentioned by the English team (9). The variations in low birth rate levels observed for the different IVF -ET indications (Table 4) were not significant, just as for parity; in spite of everything, it would seem that the level oflow birth rate for couples with a male component to their sterility was lower. Infant mortality acted as the main indicator in follow-up of children up to 1 year. The above average infant mortality found in this survey reflects the joint roles played by a high rate of prematurity, widespread low birth rate, and the large number of multiple pregnancies. Even if the analysis is restricted to single births, this increase in average mortality persists partly because of prematurity, but it is not statistically significant (1.43% in our study compared with 0.97% on a national level (7), x2 = 2.0, df = 1). If a standard rate of infant mortality is calculated taking prematurity into account (with prematurity rates taken from national surveys Rufat et al.
Outcome of IVF
329
r [
I
I!
[8]), the adjusted rate of infant mortality falls slightly to 1.14%. Prematurity does not appear to be the sole explanation for infant mortality, but none of the risk factors selected (Table 4) seems to be linked to infant mortality. The proportion of serious malformations encountered in this survey, even when TAs and malformations diagnosed during the follow-up are included (2.86%), was close to that recorded in other studies (3, 6,9) on children born after ART and to the proportion recorded in France (8) without IVF-ET (2.08%) (X 2 = 4.8, df = 1). Given the small size of the sample, none of the risk factors sought seemed to be linked to the malformations, including maternal age, which may seem surprising, but reflects probably this study's lack of power because it covers only 48 malformations. More detailed analysis could be made only on a much wider population or an international survey. Only one death was recorded in children during follow-up after the 1st year. The proportion of living children with a medical disorder remained constant at approximately 2% throughout the 3 years. These were either children retaining complications to their congenital malformation and perinatal events or children who had contracted a disease (Table 2). This proportion of abnormal children is well below that found in a Dutch study (Vos MTJA, Alberda ATh, abstract) that monitored 173 children between 1 and 3 years and recorded nine serious abnormalities in living children; however, the criteria were not exactly the same as those adopted for this study, and monitoring focused on only 80% of the children born after an IVF -ET -assisted pregnancy. In any event, as with malformations, the absence of a control group and the small number of diseased children prevent any firm conclusions in this area. This survey on the progress of pregnancies and the outcomes of children after IVF -ET on a wide population confirms an increase in prematurity, low birth rate and infant mortality for all the pregnancies. It also shows that these risks are also high for pregnancies leading to the birth of a single child, when compared with spontaneous pregnancies in national statistics. On the other hand, it reveals a rate of malformation, even when T As are included, and a proportion of diseased children largely similar to those found in the population as a whole. Some errors in determining the term, selection of couples asking for IVF-ET (these couples are at least subfertile) and controlled ovarian hyperstimulation
330
Rufat et al.
Outcome of IVF
(Olivennes F, personal communication) could be related to these higher risks of prematurity, low birth rate, or infant mortality, as has been suggested by a Swedish national survey (13) and another American study (14). To measure the influence of these factors and the rate of malformations more accurately, a wider reaching and more prospective survey would be needed, with the presence of a control group of natural pregnancies and another control group of pregnancies after ovulatory stimulation.
REFERENCES 1. Steptoe PC, Edwards RG. Birth after reimplantation of a human embryo [letter]. Lancet 1978;2:366. 2. FIVNAT, de Mouzon J, Bachelot A, Logerot H. IVF in France: FIVNAT data 1986-1990. Contracept Fertil Sex (Paris) 1991;19:554-7. 3. Report of the Working Party on Children Conceived by In Vitro Fertilisation. Births in Great Britain resulting from assisted conception, 1978-87. Br Med J 1990;300:1229-33. 4. Australian In Vitro Fertilization Group. High incidence of preterms births and early losses in pregnancy after in vitro fertilization. Br Med J 1985;291:1160-3. 5. Medical Research International and the Society of Assisted Reproduction Technology, The American Fertility Society. In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1987 results from the national IVF-ET registry. Fertil Steril 1989;51:13-9. 6. Medical Research International and the Society of Assisted Reproduction Technology, The American Fertility Society. In vitro fertilization/embryo transfer in the United States: 1989 results from the national IVF /ET registry. Fertil Steril 1991;55:14-23. 7. Lancaster P. Congenital malformations after in vitro fertilisation. Lancet 1987;2:1392. 8. Rumeau-Rouquette C, du Mazaubrun C, Rabarizon Y. Naitre en France-l0 ans d'evolution. Paris: Doin EditeursEditions INSERM, 1984. 9. Doyle P, Beral V, Maconochie N. Preterm deliveries, low birth weight andsmall-for-gestational-age in liveborn singleton babies resulting from IVF. Hum Reprod 1992;7:425-8. 10. Antoine JM, Hedon B. Review of medically assisted procreation in France in 1990. Main results of the 1991 GEFF study. Contracept Fertil Sex (Paris) 1991;19:550-3. 11. Friedler S, Mashiach S, Laufer N. Births in Israel resulting from in-vitro fertilization/embryo transfer, 1982-1989: National Registry of the Israeli Association for Fertility Research. Hum Reprod 1992;7:1159-63. 12. Spira A, Spira N, Papiernik-Berkauer E, Schwartz D. Pattern of menstrual cycles and incidence of congenital malformation. Early Hum Dev 1985;11:317-24. 13. Ghazi HA, Spielberger C, Kallen B. Delivery outcome after infertility-a registry study. Fertil Steril 1991;55:726-32. 14. Williams MA, Goldman MB, Mittendorf R, Monson RR. Subfertility and the risk of low birth weight. Fertil Steril 1991;56:668-71.
Fertility and Sterility