IVF BABIES: HOW THEY SIZE UP An interview with Dr. Karl G. Nygren, MD, PhD by Beverly Hanck and Véronique Robert - SUMMER 2011

IVF BABIES: HOW THEY SIZE UP
An interview with Dr. Karl G. Nygren, MD, PhD

by Beverly Hanck and Véronique Robert

The increasing use of in vitro fertilization (IVF) has fuelled concern as to its safety for the related children and their mothers. The unique data provided by health registers in Sweden allowed researchers to conduct a survey of 16,280 children born in Sweden from IVF between 1982 and 2001.1,2,3,4,5,6 They concluded at that time that the vast majority of IVF children, including those conceived through intracytoplasmic sperm injection (ICSI), were healthy and thriving (see Creating Families, 2009, Spring Issue). Any higher risks observed appeared to be related to multiple births and to maternal factors like age and infertility.

One of the researchers involved in this study is Dr. Karl G. Nygren. Dr. Nygren is Chairman of ICMART, the International Committee Monitoring ART as well as Cochairman of the Swedish National Committee for follow-up of IVF children, among other responsibilities. He and his colleagues just completed a second study covering another 15,517 IVF children up to and including 2006. We asked him to summarize the results of this new research, as well as compare outcomes and long-term follow-up based on data from both study periods with a total of 31,850 IVF children..

Why did you deem it necessary to conduct a second study?

During the past 25 years, important changes in IVF have impacted the outcome of pregnancies. Besides the introduction of ICSI in 1992, there have been new techniques in freezing of embryos and the successful transfer of thawed embryos, transfers at the blastocyst stage (when the embryo is five days old), as well as the trend toward single embryo transfer. Easier access to assisted reproduction technologies has meant that more couples with less severe fertility issues have resorted to IVF, and this has certainly had a positive effect on pregnancy outcomes.

How did you proceed?

All IVF pregnancies which resulted in a delivery were reported by all the IVF clinics in Sweden and further information was obtained by cross-referencing with national health registers. With more detailed data from the second study, we were able to follow time trends and to analyze several new features, such as the effects of blastocyst transfers and the phenomenon of “vanishing” twins. Comparing the two study periods was possible as the number of women and infants were similar.

How would you summarize the results?

ICSI procedures had increased over time and now hovered at around 50%. The use of cryopreserved embryos had also increased to about 10% and single embryo transfers reached 70%. The median age for women having their first child with IVF decreased from 34 to 32 years, while age at first birth increased from 25 to 28-29 in the general population. The period of involuntary childlessness decreased slightly and maternal smoking had also decreased markedly in both IVF mothers and women in the general population over time.

As for pregnancy complications, in our first study it was reported that they were higher after IVF when compared to the general population. An increased rate of cesarean sections was also noted. In the second study, a pattern of declining risk was noted for preeclampsia, premature rupture of membranes, cesarean section, preterm birth, low birth weight, intrauterine growth retardation, early neonatal death, and some congenital malformations. Risks were unchanged for placenta previa and some congenital malformations.

How about the rate of multiple births?

There was also a sharp decline in multiple births during the years 2002-2006; in 2002, the rate was down to 21% from a maximum of over 30% in 1991, and it continued to decline reaching 6% in 2006. During these years there were only 11 IVF-related triplet deliveries. Multiple births declined due to the increased use of single embryo transfer. Single embryo transfer represented 25% of embryo transfers in 2002, but was up to 75% in 2006-2007. In only six instances had three embryos been transferred (2002-2003). Two sacs were identified early by ultrasound in 195 pregnancies, but only one infant was born – a phenomenon called “the vanishing twin”. Vanishing twins represented 16.5% of the 1,183 pregnancies where two sacs were identified. An unpublished analysis of these cases showed no deviations from other singletons with respect to preterm birth, low birth weight, intrauterine growth retardation, or congenital malformations. An overall reduction of the number of IVF twins directly affected the rates of preterm birth, low birth weight, and intrauterine growth retardation, which all declined sharply.

How would you describe the newborn’s condition?

In the second period, the average preterm rate after IVF was 7.5%, against a population rate of 5.1%; the average low birth weight rate was 5.3% against a population rate of 3.1%; and the average intrauterine growth retardation rate was 3.3% against a population rate of 2.1%. For all outcomes, the risks were thus about 50% higher compared with the general population. It should be noted that, to a large extent, these were due to maternal characteristics such as year of birth, maternal age, parity, smoking, body mass index, and number of previous miscarriages.

For the duration of the second study, a decline was observed in the number of complications affecting babies. The rate of cerebral bleeding, convulsions, respiratory diagnoses, use of mechanical ventilation, and of sepsis/pneumonia went down. This is largely explained by the declining rate of multiple births; changes among singletons were hardly noticeable.

There was a slight decline in stillbirth rates throughout both study periods. The total risk for early neonatal death declined markedly during both periods as well, while the risk for singletons remained relatively unchanged.

A small risk increase for any congenital malformation was seen after IVF. Over the course of both periods as well, there was only a relatively weak decline in the congenital malformation rate. Some malformations showed a specifically high risk in the first period. For some of them, a risk increase of the same magnitude was carried over into the second period. This was the case for any cardiovascular defect and limb reduction defects. For others, a risk increase remained, but the risk estimate was significantly lower for the second period than for the first – this was observed for neural tube defects, cardiac septum defects, and oesophageal atresia. For a third group of malformations – orofacial clefts, small bowel atresia, anal atresia, and hypospadias – a risk was seen during the first but not during the second study period.

Did you note different outcomes depending on IVF methods employed?

Very few differences were found after using different types of IVF techniques, particularly between standard IVF and ICSI. We could not verify the difference in congenital malformation rates after ICSI using cryopreserved or fresh sperm samples, or standard IVF using cryopreserved sperm. On the other hand we found some evidence of a higher malformation rate, and possibly also a higher rate of preterm birth, after a blastocyst transfer.

You also studied the effect of drugs used for the treatment?

Indeed, it is important to monitor their effects, as some deviations may result from them. With respect to IVF, attention has been largely directed to the offspring, but maternal complications and long-term effects of the hormonal treatments usually given before IVF procedures have also caused concern. Testing must be repeated in separate studies or by continued observation for results to be significant.

What about the impact of the sharply increased proportion of SET, single embryo transfer?

There was, however, a clear-cut and easily understandable decrease in the multiple birth rate as a consequence of the reduction of the number of embryos transferred. A lower rate of multiple births could easily explain the drastic decline in many neonatal adverse outcomes. In particular, the strong decline of the twinning rate, while the neonatal outcome became markedly better, supports the opinion that single embryo transfer is beneficial.

Among singleton infants, relatively small changes occurred and these changes were more
difficult to evaluate. They could be the result of more women with less pronounced fertility problems being included in the second study than in the first. The only possible effect of a technical modification was the increased risk seen after blastocyst transfer, but these findings are preliminary and require further study. Among the neonatal diagnoses studied during the second period, only respiratory problems increased among singletons.

Our data for the entire study period and for the two periods separately, indicate no sign of an increased risk for intrauterine death in pregnancies after IVF. This contrasts with a recent study from Denmark, where a marked increase in stillbirth risk was claimed. We cannot explain the discrepancy between the two studies, but it seems unlikely that the IVF technique by itself would increase the risk for stillbirth.

What were the results for the long-term follow-up?

In a previous study we showed that IVF children used more hospital care than other children, at least up to the age of 8 years. Much of the care provided was for conditions associated with the central nervous system, damage including cerebral palsy, congenital malformations, infections, asthma, and accidents. In order to study long-term effects on some specific conditions, we conducted substudies on five different outcomes: cerebral palsy, attention deficit hyperactivity disorder, poor visual acuity, asthma, and cancer.

In the long term, an increased risk of cerebral palsy was observed but it was strongly linked to multiple births. We found some evidence that the risk for cerebral palsy declined when the rate of multiple births went down, but it is still too early to draw firm conclusions. A moderate increase in the risk of attention deficit hyperactivity disorder was noted, but this condition is difficult to study epidemiologically and is largely genetic. Twinning did not seem to increase the attention deficit disorder risk and – if the risk is at all present – it may remain basically unchanged. Poor visual acuity was also demonstrated, mainly as a result of cerebral damage. A much more common effect was that on asthma, where many perinatal factors have been shown to act as risk factors, including cesarean section. Finally, a slight increase in the cancer risk of IVF children was identified. Possible intermediary factors could be preterm birth and neonatal asphyxia. All outcomes except for asthma are of low prevalence, and a moderate risk increase still represents only a low absolute risk for a child born after IVF.

Did you look into the risk for maternal cancer due to IVF hormone treatments?

This concern has been expressed repeatedly. We found no evidence for such an effect. It is
true that the risk for ovarian cancer was higher after IVF than among the control women, but
an increased risk for ovarian cancer was seen even before IVF. This indicates an association between ovarian pathology, leading both to infertility and the need of IVF, and an increased risk of ovarian cancer. The hormonal treatments required for IVF did not seem to raise cancer risks, at least not in premenopausal women. The lower risks for breast and cervical cancers are difficult to explain but may be a result of more intensive screening and therefore identification and treatment of precancerous conditions, or to less use of oral contraceptives.

What conclusion do you draw about the safety of IVF after these two studies?

The 25-year survey of delivery outcomes after IVF in Sweden verified the presence of a
number of deviations, but it also showed, most importantly, that most of them have been declining with time, mainly as a result of the lower rate of multiple births due to the increased use of single embryo transfer. In general, it can be said that children born from IVF, as well as their mothers, are doing very well, and outcomes can be expected to continue to improve as more progress is accomplished in IVF procedures.

References

1Källén, B., Finnström, O., Nygren, K. and Olausson, P. (2005). In vitro fertilization (IVF) in Sweden: Risk for congenital malformations after different IVF methods. Birth Defects Research Part A: Clinical and Molecular Teratology 73 (3), 162-169.

2Källén, B., Finnström, O., Nygren, K.G., Otterblad Olausson, P. (2005). Temporal trends in multiple births after in vitro fertilisation in Sweden, 1982-2001: a register study. BMJ 331, 382-3.

3Källén B, Finnström O, Nygren KG, Otterblad Olausson P. (2005). In vitro fertilization (IVF) in Sweden: infant outcome after different IVF fertilization methods. Fertil Steril, 84 (3), 611-17.

4Källén B, Finnström O, Nygren KG, Otterblad Olausson P. (2005). In vitro fertilization in Sweden: child morbidity including cancer risk. Fertil Steril, 84 (3), 605-10.

5Källén B, Finnström O, Nygren KG, Otterblad Olausson P. (2005). In vitro fertilization in Sweden: maternal characteristics. Acta Obst Gynecol Scand, 84, 1185-91.

6Källén B, Finnström O, Nygren KG, Otterblad Olausson P., Wennerholm. U.-B. (2005). In vitro fertilisation in Sweden: obstetric characteristics, maternal morbidity, and mortality. BJOG, 112, 1529-35.