Human Reproduction vol.15 no.3 pp.

604607, 2000

Incidence of cancer in children born after in-vitro

fertilization

Fiona Bruinsma1,5, Alison Venn1, Paul Lancaster2,

Andrew Speirs3 and David Healy4
1Centre

for the Study of Mothers and Childrens Health,

La Trobe University, 251 Faraday Street, Carlton, 3053, Victoria,
2Australian Institute of Health and Welfare National Perinatal
Statistics Unit, University of New South Wales, Sydney, 2031,
NSW, 3Reproductive Biology Unit, Royal Womens Hospital,
Carlton, 3053, Victoria and 4Monash IVF & Department of
Obstetrics and Gynaecology, Monash University, Monash Medical
Centre, Clayton, 3168, Victoria, Australia
5To

whom correspondence should be addressed

Evaluation of the long-term health of children born using

in-vitro fertilization (IVF) provides important information
to clinicians and consumers. Until very recently, there have
been no published data on the incidence of cancer in
children conceived as a result of IVF, despite a number of
case reports of neuroblastoma in children conceived using
fertility drugs. This study used a record-linkage cohort
design to investigate the incidence of cancer in children
born after IVF. The study included all conceptions using
assisted reproductive technologies between 1979 and 1995
at two clinics in Victoria, Australia that resulted in a live
birth. Data on births were linked with a population-based
cancer registry to determine the number of cases of cancer
that occurred. The standardized incidence ratio (SIR) was
calculated by comparing the observed number of cases to
the expected number of cases. The final cohort included
5249 births. The median length of follow-up was 3 years,
9 months (range 015 years). In all, 4.33 cases of cancer
were expected and six were observed, giving a SIR of
1.39 (95% CI 0.623.09). This study found that children
conceived using IVF and related procedures did not have
a significantly increased incidence of cancer in comparison
to the general population.
Key words: cancer incidence/children/IVF/long-term follow-up

Introduction
Utilization of assisted reproductive technologies has rapidly
increased over the past decade. During 1995, 1.1% of all
births in Australia were the result of assisted reproductive
technologies (Hurst et al., 1997). The introduction of a new
procedure brings with it a responsibility to evaluate and
monitor both the short and longer term outcomes of the
intervention (Royal Commission on New Reproductive
Technologies, 1993; Buitendijk, 1999; Doyle, 1999). Shortterm outcomes of assisted reproductive technology, for example
the number of live births and neonatal deaths, the rate of
604

multiple birth, preterm deliveries and babies born at low birth

weight, have been well documented. The health of children
beyond the neonatal period has been less well evaluated. Many
of the phases of assisted reproductive technology treatment,
for instance, the use of fertility drugs to stimulate multiple
folliculogenesis, the process of oocyte retrieval and preparation of spermatozoa, the growth of embryos in culture
medium, and the freezing and thawing of embryos, have the
potential to have a harmful effect on the developing embryo
(Buitendijk, 1999).
Case-control studies have reported a significantly increased
risk of neuroblastoma with prenatal exposure to fertility drugs
(Kramer et al., 1987; Michalek et al., 1996). There have also
been case series reports of embryonal tumours in children born
to women who conceived as a result of fertility treatment
(Melamed et al., 1982; White et al., 1990; Toren et al., 1995).
Neuroblastomas are tumours of the sympathetic nervous system
that are derived from the embryonic neural crest. They are the
most common type of cancer in children 1 year of age in
Victoria, Australia (Giles et al., 1993).
While case series reports are useful for suggesting possible
adverse effects of treatment and generating hypotheses for
further investigation, studies that measure associations between
exposure and disease (such as case-control and cohort studies)
are needed to substantiate the reports. Because case-control
studies are often prone to recall bias, a well-designed cohort
study is generally believed to provide a higher level of evidence
of an association than that obtained from a case-control study
(Greenhalgh, 1997).
Until very recently there were no population-based data on
the incidence of cancer in children conceived as a result of
in-vitro fertilization (IVF). The two published studies, conducted in the UK and Sweden, of children born after IVF did
not find a significantly increased incidence of cancer (Doyle
et al., 1998; Bergh et al., 1999). The present study investigated
the incidence of cancer in 5249 children born as a result of
assisted reproductive technologies in Australia.
Materials and methods
The study included all conceptions using assisted reproductive technologies between 1979 and the end of 1995 at either the Royal Womens
Hospital, Melbourne IVF or Monash IVF, Victoria, Australia that
resulted in a live birth. It included conceptions by IVF, gamete intraFallopian transfer (GIFT) and intracytoplasmic sperm injection (ICSI)
but excluded conceptions by artificial insemination or ovulation
induction without IVF or GIFT. Pregnancies that ended in a stillbirth
were excluded, as were those where the parents resided overseas
or interstate.
Data were collected from clinics and the National Perinatal Statistics
European Society of Human Reproduction and Embryology

Incidence of cancer in children born after IVF

Table I. Pregnancy characteristics

Number

Percentage (%)

Plurality
Singleton
Twin
Triplet and higher order multiple

3528
750
79

81.0
17.2
1.8

Type of transfer
Fresh
Frozen
Unknown

3118
1194
45

71.6
27.4
1.0

Figure 1. Number of conceptions resulting in live births for each

year of study (19791995).
Table II. Drug usage

Unit (NPSU), Australian Institute of Health and Welfare to ensure

that we had the most complete coverage of births possible. Data
collected from the clinics were obtained from computerized records
(where available) or from medical records. The contribution of clinics
to the register of births held by the NPSU is not mandatory; however,
accreditation from the national accrediting body requires participation
in the registry (Lancaster et al., 1995).
Data items collected on each birth included parents names,
mothers date of birth, address, babys date of birth and sex, type of
infertility, drugs used for ovarian stimulation in the conception
cycle, drugs used in the luteal phase, obstetric complications and
pregnancy outcome.
Ascertainment of cases of invasive cancer was by record-linkage
with the population-based Victorian Cancer Registry (VCR). Cancer
notification to the VCR became a statutory requirement of all hospitals
and pathology laboratories in 1981. Ascertainment of childhood
cancer cases diagnosed before this time is thought to be practically
complete because the major treatment centre for the State had been
part of a voluntary notification scheme since 1959. Data held by the
cancer registry include full name, sex, date of birth, date of diagnosis,
histological type of tumour, date of last known contact and vital
status (Giles et al., 1993). Follow-up for each child was from the
date of birth until (i) diagnosis of cancer, or (ii) the date of death, or
(iii) the end of 1996 (if the child was 15 years old at that time) or,
(iv) the date of the childs 15th birthday.
The expected number of cases was calculated by applying the
Victorian age-specific population-based cancer incidence from the
years 19821995 to the person-years follow-up in each age group of
children. The standardized incidence ratio (SIR) was determined by
calculating the ratio of the observed number of cancer cases to the
expected number.
Prior to commencement of the study, calculations indicated that
there was 80% power ( 0.05) to detect a SIR of 6 for
neuroblastoma and a SIR of 2.8 for all childhood cancers combined.
The expected numbers of cancers were derived from the estimated
age-specific person-years and age-specific population cancer rates.

Results
Characteristics of the cohort
The data set included 5579 live births, of which 330 were
subsequently excluded because the parents resided overseas
or interstate, giving a final cohort of 5249 births. The 5249
births were from 4357 pregnancies. The annual number of
births increased substantially over the study period. Figure 1
illustrates the number of conceptions resulting in a live birth

Ovarian stimulation
Natural cycle only
Clomiphene only
Clomiphene and HMG or FSH
HMG or FSH only
GnRH agonist and HMG or FSH
GnRH agonist only
Other drugs
Unknown
Luteal support*
HCG
Progesterone pessaries
Oestrogen and progesterone
Other
No drugs administered

Number

Percentage (%)

1327
31
1029
89
1697
43
135
6

30.5
0.7
23.6
2.0
39.0
1.0
3.1
0.1

1509
473
281
22
1784

37.1
11.6
6.9
0.6
43.8

*Denominator n 4069; 288 patients missing information on luteal support

excluded.
HMG human menopausal gonadotrophin; FSH follicle stimulating
hormone; GnRH gonadotrophin-releasing hormone.

for each year of the study. Over 50% of births were conceived
in the last 4 years of the study.
Multiple pregnancy occurred in 19% of pregnancies (Table
I). Over two-thirds of pregnancies resulted from the transfer
of fresh embryos (IVF) or from the transfer of oocytes and
spermatozoa for GIFT (Table I). The use of frozen embryos
has increased during the 1990s: 60.6% of pregnancies conceived during 19931995 resulted from the transfer of frozen
embryos.
Information on the drugs used to stimulate multiple folliculogenesis was available from both the clinic and NPSU. If a
discrepancy occurred, records were checked and the appropriate
correction made. If frozen embryos were transferred, or a
woman was the recipient of donated oocytes, the stimulation
details refer to the drugs that were administered at the time of
transfer. Details are not given on drugs used at the time of
oocyte collection. Gonadotrophin-releasing hormone agonists
(GnRHa) combined with human menopausal gonadotrophin
(HMG) or follicle stimulating hormone (FSH) was the most
commonly used stimulation regime (Table II). The use of this
regime increased rapidly in the late 1980s and continued into
the 1990s. In the early to mid-1980s, clomiphene and HMG
or FSH was used more frequently. The number of natural
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F.Bruinsma et al.

Table III. Infant characteristics

Singleton births
(n 3528)

Twin births
(n 1487)

Higher order multiple births

(n 234)

Number

Percentage (%)

Number

Percentage (%)

Number

Percentage (%)

2.2
8.2
52.9
23.2
7.7
5.8

136
639
627
10
6
69

9.1
43.0
42.2
0.7
0.4
4.6

86
121
18
0
0
9

36.8
51.7
7.7
0
0
3.8

1.2
2.1
9.5
51.2
35.7
0.3

59
148
608
650
18
4

4.0
9.9
40.9
43.7
1.2
0.3

22
79
127
3
3
0

9.4
33.7
54.3
1.3
1.3
0

Birthweight group (g)

1499
79
15002499
289
25003499
1866
35003999
817
4000
272
Missing
205
Gestational age (weeks)
2027
42
2832
75
3336
337
3739
1805
4042
1258
42
11

Table IV. Characteristics of cancer cases

Cancer

Brain
Connective tissue
Leukaemia
Leukaemia
Leukaemia
(unspecified)
Salivary gland

Treatment details

Infant characteristics

Cause of infertility

Procedure Stimulation

Age at diagnosis Sex

(years, months)

Plurality

Male factor
Unexplained
Ovulation disorder
Male factor
Tubal

IVF
IVF
FET
GIFT
IVF

CC, HMG
CC, HMG

Unexplained

GIFT

GnRHa, HMG
CC, HMG

3,
6,
2,
2,
6,

5
4
7
8
9

Female
Male
Male
Male
Male

Singleton
Multiple
Singleton
Singleton
Multiple

CC, HMG, other

0, 8

Female

Singleton

GIFT gamete intra-Fallopian transfer; IVF in-vitro fertilization; FET frozen embryo transfer; CC
clomiphene citrate; GnRHa gonadotrophin-releasing hormone agonist; HCG human chorionic
gonadotrophin; HMG human menopausal gonadotrophin.

cycles reflects the increasing use of frozen embryo transfers

during the 1990s.
Human chorionic gonadotrophin (HCG) was the most commonly used preparation for luteal support, followed by progesterone pessaries and then oestrogen and progesterone (Table
II). A very small number of women received HCG and
progesterone (19) or other unspecified luteal support (three)
during their pregnancy. Prior to 1990 the majority of pregnant
women did not receive luteal support, by 19931995 this had
fallen to 29% of pregnancies.
Approximately 13% of singleton births and 60% of multiple
births occurred prior to 37 weeks gestation. Only 15 deliveries
occurred after 43 weeks. Overall, 10.4% of singleton births and
57.1% of multiple births were of low birthweight (2500 g). A
total of 12.9% of multiple births were very low birthweight
(1500 g) (Table III).
The median age at the end of follow-up was 3 years, 9
months (range 015 years). 87.4% of the cohort had at least
1 year of follow-up. Of those who had 1 year of follow-up,
8% (54/660) died in the first year of life and one had a diagnosis
of cancer. The total number of person-years contributed was
23 854.6.
606

Cancer cases
The expected number of cases of childhood cancer was
calculated as 4.33, compared with an observed of six. This
gave a SIR for all childhood cancers of 1.39 (95% CI 0.62
3.09). There were two cases of acute lymphoid leukaemia
(ICD-9 204), one case of unspecified leukaemia (ICD-9
208), one malignant neoplasm of the brain (ICD-9 191),
one malignant neoplasm of the soft tissue (ICD-9 171) and
one malignant neoplasm of the salivary gland (ICD-9 142).
No cases of neuroblastoma were observed. Age at diagnosis
ranged from 8 months to 6 years, 9 months (Table IV). One
child died 13 months after diagnosis. The remaining five
children were alive at the end of follow-up. The malignant
neoplasm of the salivary gland was one of only two cases
reported to the Victorian Cancer Registry between 1982
and 1995.
Discussion
This study was initiated to investigate findings of case-control
studies (Kramer et al., 1987; Michalek et al., 1996) and case
reports (White et al., 1990; Toren et al., 1995) that suggested

Incidence of cancer in children born after IVF

that children who had been conceived using fertility drugs

may be at an increased risk of neuroblastoma. While casereports can be useful for highlighting potential problems
and generating hypotheses, it is important that the possible
associations are substantiated with large, population-based
studies. This study found that children conceived using assisted
reproductive technologies did not have a significantly increased
incidence of cancer in comparison to the general population.
We did not observe any cases of neuroblastoma in this study
population. Our findings are consistent with those reported in
the UK and Sweden (Doyle et al., 1998; Bergh et al., 1999).
The study conducted in the UK of 2507 children expected 3.5
cases and observed two cases (Doyle et al., 1998). Although
the recently published Swedish study included a larger number
of children (5856) than our study, a smaller number of cases
(3.6) was expected (Bergh et al., 1999). This difference was
primarily due to a difference in the distribution of year of
birth and the associated person-years follow-up. When the
findings of the three studies were combined, 11.4 cases of
childhood cancer were expected compared with 12 observed,
giving a SIR of 1.05 (95% CI 0.61.8).
A limitation of our study was that the median length of
follow-up was relatively short (3 years, 9 months). However,
the study was initiated to address concerns about the incidence
of neuroblastoma in children born after IVF. Neuroblastoma
most commonly occurs in the first year of life. Secondly, the
calculation of the expected number of cases is based on the
number of person-years each child contributes and takes into
account differential lengths of follow-up. Our population-based
study contains the largest number of person-years follow-up
to date and contributes to knowledge about the health of
children born after IVF. Further large studies will be needed
to detect a small increase in the overall incidence of cancer
or an increase in the incidence of individual types of cancer
with statistical significance.

Kramer, S., Ward, E., Meadows, A. et al. (1987) Medical and drug risk factors
associated with neuroblastoma: a case-control study. J. Natl Cancer Inst.,
78, 797804.
Lancaster, P., Shafir, E. and Huang, J. (1995) Assisted Conception, Australia
and New Zealand, 1992 and 1993. AIHW National Perinatal Statistics
Unit, Sydney.
Melamed, L., Bujanover, Y., Hammer, J. et al. (1982) Hepatoblastoma in an
infant born to a mother after hormonal treatment for sterility. N. Engl. J.
Med., 307, 820.
Michalek, A., Buck, G., Nasca, P. et al. (1996) Gravid health status, medication
use and risk of neuroblastoma. Am. J. Epidemiol., 143, 9961001.
Royal Commission on New Reproductive Technologies (1993) Proceed
with care: Final report of the Royal Commission on New Reproductive
Technologies. Minister of Government Services, Canada.
Toren, A., Sharon, N., Mandel, M. et al. (1995) Two embryonal cancers after
in vitro fertilisation. Cancer, 76, 23722374.
White, L., Giri, N., Vowels, M. et al. (1990) Neuroectodermal tumour in
children born after assisted conception. Lancet, 336, 1577.
Received on August 19, 1999; accepted on November 12, 1999

Acknowledgements
We thank Professor Judith Lumley, Ms Lyndsey Watson and Dr
Graham Giles for their assistance with the study. Special thanks to
Monash IVF and the Royal Womens Hospital/Melbourne IVF,
without whose co-operation this study would not have been possible.

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