Neonatologists are at the bottom of the cascade of events triggered by AC. Their main concerns deal with the total number of infants born after AC, the percentages of premature and/or growth-retarded neonates with their specific morbidity, and the malformation rate.
The global impact in terms of number of neonates is based on estimates since most registers refer to IVF only and they do not report exhaustive data. In France epidemiological studies have estimated the annual number of births "after treatment" at 12,000, for a total number of births around 711,000 [2]. In 1996 the total number of registered IVF in France was about 204,000 for a total number of pregnancies of about 20,000. Still official registrations came to 17,500 live neonates.
The number of infants born after insemination with partner’s sperm and/or ovarian stimulation remains highly speculative, most of this medical assistance taking place in private practice.
A better-known feature is the "epidemic of multiple iatrogenic pregnancies". Either expressed in percentages of multiple pregnancies after AC, 22% to 27% [3-4], or increases in overall rates of multiple pregnancies [5] in parallel with the use of AC, or contribution of AC to multiple births, all reports agree on the striking increase of twins, triplets, and higher order pregnancies, and put the bulk of the blame on AC, even if some part may be due to "delayed" spontaneous pregnancies in women over 30 years. The resulting increase in prematurity and/or very low birth weight, mortality and morbidity, has practical implications for neonatal services.
1. Malformation rates
No special interest has been given to neonates born neither after plain ovarian stimulation nor after artificial insemination with partner’s sperm, for the same reason as to their number. The French CECOS registers of artificial insemination with frozen donor sperm have offered a large screening cohort, including abortions for prenatally diagnosed malformations and/or chromosomal anomalies. The global frequency of malformations was 1.7%, "similar to that recorded in natural procreation" [1], in spite of a light increase in trisomy 21 related to maternal age and independently to donor age. Neonates born after IVF have been particularly scrutinized for malformations. Reliable studies have reported rates of major malformations of 1% to 2.5%, of minor malformations of 1.4% to 3.6% and global rates of 2.8% to 3.4% (cryopreserved embryos) [1]. These rates were within the expected range for spontaneous pregnancies, at most at the upper limit. However, they might be underestimated because of incomplete notification of minor birth defects and unwillingness to ascertain all birth defects. No special types of malformations have been noted. Malformations in multiple pregnancies have received opposite evaluations.
Reassuring accounts including large numbers of children born after ICSI [6-7] have however reported rates of major malformations of 2.6-3.3%, with a slight increase of de novo and transmitted (from the father) chromosomal aberrations [7]. In a prenatal cytogenetic analysis after ICSI, chromosome aberrations were found in 12.7% of cases, 6 out of 8 being of paternal origin [8]. The recent reports of a fetal trisomy resulting from balanced paternal translocation and of microdeletions of the Y chromosome in severe unexplained oligozoospermia open scary prospects, both in terms of severe congenital anomalies and of later hereditary male infertility.
2. Neonatal outcome in singletons
After IVF/GIFT [3], singletons represented 73-78% of neonates and included stillbirths in 5.3 to 6.4 per thousand births. A high proportion was born by cesarean section, 26% in France, of which 16-18% were performed on principle, up to 43% "mostly elective" in London. The mean birth-weight was about 300g below the respective national average [3]. The neonatal outcome of full-term singletons was mostly as good as in spontaneous pregnancies.
However, prematurity and intra-uterine growth retardation (IGUR) did not spare singletons. The prematurity rate was significantly higher after IVF in French surveys, 7.7 to 9.1% [3], while the national rate for singletons in 1995 was 4.5%. Other series reported rates up to 13% and even 15% [1].
The neonatal mortality rate was 6 per thousand births and the resulting perinatal death rate was around 11-12 per thousand births, instead of the usual 8 per thousand in Western Europe [1].
3. Neonatal outcome in twins
There has been a general outcry about the soaring rate of multiple pregnancies in parallel with the development of AC, well above 20% and up to 34% after IVF [9] but mainly after plain, ovarian stimulation. However, a cohort study in a limited area showed that 20% of twins in Flanders were born after ovarian stimulation in 1987-91 [1].
After IVF, the rate of twin pregnancies in the French surveys was 22-25% [3], producing 35% of IVF births. Stillbirths occurred in 14 to 19 per thousand births [3]. The rate of delivery by cesarean section was much higher than in singletons, 55-64% [3]. The neonatal outcome is dominated by prematurity and growth retardation. Premature birth was reported in 39-42% of twin pregnancy [3], close to the rate for twins in the national 1995 survey, 39%. IUGR was present in 47-53% [3]. Twin neonates were transferred in 37% of cases to neonatal units of various levels. The neonatal mortality rate was 18 per thousand births or noted to be seven times higher in twins. The resulting perinatal mortality rate was 31-40 per thousand-birth [3].
The Port-Royal NICU experience described the problems of the transferred babies. From 1/01/87 to 31/12/92, in 70 twin IVF pregnancies (6 stillbirths, 35 cesarean section), 134 neonates were born alive, of which 118 premature (39 of them <32 weeks), 120 weighed <2500g (26 of them <1000g), 5 had congenital malformations (one died of severe congenital heart disease), 9 other babies died (5 were <1000g). The neuro-developmental status was followed for more than 4 years in all 124 survivors: 70 were normal, 38 had minor deficits (16 wore glasses), 10 (6<1000g) had moderate and 6 (4<1000g) had major neuro-developmental sequelæ (cerebral palsy and/or mental retardation and/or sensory deficits). This short series illustrated the burden of prematurity, in particular the extreme prematurity in terms of mortality and heavy sequelæ. None had psychological help.
These difficulties in twins have been shown to be comparable with the ones observed in spontaneously conceived twins. This does not mean that they are tolerable: in fact, the basic problem is that numerous twin pregnancies, whatever their mode of conception may be, are not properly managed because of an inadequate perception of their real level of risk by the mothers, who are often admitted shortly before delivery, when it is too late to delay premature birth, and in maternity sites devoid from level III perinatal care.
Therefore, should we really encourage reduction of higher order pregnancies to twins? Even without discussing the emotional effects of reductions, in a recent study of such "reduced" pregnancies, the neonatal outcome carried an increased incidence of pregnancy complications (premature labor and pregnancy induced hypertension), with lower mean gestational age at delivery and lower mean birth-weight than in spontaneous twin pregnancies [11].
4. Neonatal outcome in triplets
The natural rate of triplet pregnancies is around 1/10,000 [1] The basic rate has been multiplied by 3 to 8 times. After IVF, triplet pregnancies accounted for 3 to 8% of pregnancies but for 10 to 13% of neonates [3].
The rate of stillbirths was 30-32 per thousand births [3]. Cesarean section was performed in 89-95% of cases, 73% on principle. Prematurity rate was 85-87 %, and IUGR was observed in 72-76% of neonates [3]. Transfer to a neonatal unit was required for 89% of neonates. Neonatal mortality rate was around 25 per thousand births, or 20 times higher in triplets and higher order neonates than in singletons. The resulting perinatal mortality rates were 54-79 per thousand births [3].
However, in spite of the classical heavy toll paid to prematurity, it is possible to obtain an "acceptable" degree of prematurity. In France where almost every mother has Social Security benefits, triplet pregnancies are protected by early prolonged sick leaves, the routine hospital admission to a level III maternity site, mostly between 26 and 30 weeks of gestation until delivery. Premature delivery then takes place between 32 and 36 weeks of gestation in a majority of cases. In a recent study comparing triplets from AC and from spontaneous pregnancies [12], the worst neonatal outcomes in terms of prematurity below 32 weeks and IUGR were observed in spontaneous pregnancies. All neonatal deaths occurred in neonates weighing <1000g. At follow-up for more than 3 years and up to 10 years, moderate and major deficits were observed in 6 of 33 followed children in spontaneous triplets, 4 of 65 after ovarian stimulation, 1 of 98 after IVF and none of 11 after GIFT [12]. The three years of infant care following birth of triplets are a hardship for the parents.
The outcome of higher order pregnancies worsens in parallel with the number of fetuses, even after reduction, and it will not be discussed here.
Conclusion
To date, the neonatal outcome after AC is marred by stillbirths, IUGR, and prematurity, specially after IVF and GIFT, and even in singletons though to a minor degree. The major drawback of AC is the occurrence of multiple pregnancies. For the future, the emergent problems of ICSI are a deep concern.
Multiple pregnancies after any mode of conception are associated with increased prematurity and IUGR, which result in increased mortality and morbidity, thus in turn increasing the rate of cerebral palsy in survivors. The crude prevalence of cerebral palsy was 2.3/1000 in singletons, 12.6 in twins, 44.8 in triplets [13]. Twin pregnancies produced a child with cerebral palsy 8 times more often than singleton pregnancies did, and triplet pregnancies 47 times more often [14]. Neonatologists on the front line and pediatricians later on are busy enough with the children of unpredictable spontaneous multiple pregnancies. The "global proliferation of IVF programs" [15] and other fertility therapy has produced an overwhelming number of multiple pregnancies, which "strain neonatal intensive care facilities", and constitute a financial burden for the parents and the society. The cost of initial management, hospitalization, and later care must be considered in the overall evaluation of the AC cost, which is thereby greatly increased. On the other hand, the psychological consequences on the child are still little studied and they may be much more important than it has been stated.
The overall data suggest do reconsider the technical aspects of the various steps of IVF, and other AC. They must, above all, open a new debate about the indications of IVF or ICSI, which should be exceptional procedures, only authorized in the hands of blameless teams in terms of technical and scientific abilities, but also of moral and human qualities, thoughtful and considerate of the basically abnormal way of "conceiving in lab test tube" [16].
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