ARTICLE

Cerebral Palsy Among Children Born After in Vitro

Fertilization: The Role of Preterm Delivery—A
Population-Based, Cohort Study
Dorte Hvidtjørn, MPHa, Jakob Grove, PhDa, Diana E. Schendel, PhDb, Michael Væth, PhDc, Erik Ernst, PhDd, Lene F. Nielsen, MPHa,
Poul Thorsen, PhDa

aNorth Atlantic Neuro-Epidemiology Alliances, Department of Epidemiology, and cDepartment of Biostatistics, Institute of Public Health, University of Aarhus, Aarhus,
Denmark; bCenters for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, Georgia; dFertility Section, Department
of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. Our aim was to assess the incidence of cerebral palsy among children
conceived with in vitro fertilization and children conceived without in vitro
www.pediatrics.org/cgi/doi/10.1542/
fertilization. peds.2005-2585
METHODS. A population-based, cohort study, including all live-born singletons and doi:10.1542/peds.2005-2585
twins born in Denmark between January 1, 1995, and December 31, 2000, was The findings and conclusions in this report
are those of the authors and do not
performed. Children conceived with in vitro fertilization (9255 children) were necessarily represent the views of the
identified through the In Vitro Fertilization Register; children conceived without in Centers for Disease Control and Prevention.
vitro fertilization (394 713) were identified through the Danish Medical Birth Key Words
Register. Cerebral palsy diagnoses were obtained from the National Register of in vitro fertilization, cerebral palsy, preterm

Hospital Discharges. The main outcome measure was the incidence of cerebral Abbreviations
IVF—in vitro fertilization
palsy in the in vitro fertilization and non-in vitro fertilization groups. ICSI—intracytoplasmic sperm injection
CP— cerebral palsy
RESULTS. Children born after in vitro fertilization had an increased risk of cerebral NRHD—National Register of Hospital
palsy; these results were largely unchanged after adjustment for maternal age, Discharges
HRR— hazard rate ratio
gender, parity, small-for-gestational age status, and educational level. The inde- CI— confidence interval
pendent effect of in vitro fertilization vanished after additional adjustment for SGA—small for gestational age
multiplicity or preterm delivery. When both multiplicity and preterm delivery Accepted for publication Mar 6, 2006

were included in the multivariate models, preterm delivery remained associated Address correspondence to Dorte Hvidtjørn,
MPH, NANEA, Department of Epidemiology,
strongly with the risk of cerebral palsy. University of Aarhus, Paludan-Müllers vej 17,
8000 Aarhus C, Denmark. E-mail: dh@soci.au.
CONCLUSIONS. The large proportions of preterm deliveries with in vitro fertilization, dk
primarily for twins but also for singletons, pose an increased risk of cerebral palsy. PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2006 by the
American Academy of Pediatrics

PEDIATRICS Volume 118, Number 2, August 2006 475

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I N VITRO FERTILIZATION (IVF), including intracytoplas-
mic sperm injection (ICSI), is a common service
within the Danish health care system, with the highest
availability in Europe.1 Methodologic shortcomings in
the evaluation of risks from IVF are well known, because
the situation is complex and large sample sizes are
needed to study infrequent events. It is known that IVF
is associated with preterm delivery, an acknowledged
complication for assisted reproduction with multiple
births2,3 but also for IVF singletons.2,4,5 Uncertainty re-
mains regarding whether any risk of IVF stems from the
underlying cause of infertility or from the treatment.6
Only subfertility (defined as prolonged time to preg-
nancy or seeking fertility advice) has been explored;
subfertility itself was associated with low birth weight
and preterm delivery.7–10
Cerebral palsy (CP) represents a group of disorders
that result from damage to the immature brain, with
permanent motor disorders and frequently impaired
mental development.11 Almost one half of all children
with CP are delivered preterm,11 and twins have a four-
fold higher risk of developing CP than do singletons.12,13
The increased risk of CP among twins has been associ-
ated with features specific to twin pregnancies, such as
monochorionic pregnancies, twin-twin transfusion syn-
drome, and discordant birth weights in twin pairs,14,15
which suggests that the cause of CP for some twins may
differ from that for singletons. Finally, being small for
gestational age (SGA) is also associated with IVF2 and is
a risk factor for CP, especially among children born at
term or near term.16 The associations among IVF, mul-
tiple births, preterm delivery, and SGA status suggest
that IVF may result in an increased risk of CP.
There are only a few population-based, cohort studies
addressing the question of long-term neurologic se-
quelae, such as CP, among children born after IVF.17–19 A
population-based, Swedish study by Stromberg et al17
found an increased risk of CP among 5680 children born
after IVF between 1982 and 1995. In a population-
based, Danish study, Pinborg et al18 found no difference
in risk of CP among IVF twins, compared with non-IVF
twins, with adjustment for gender, year of birth, mater-
nal age, and gestational age. Lidegaard et al19 found a
statistically significantly increased risk of CP among IVF
singletons, of all Danish singletons born between 1995
and 2001, although no statistical adjustment was made
for gestational age.
The aim of this population-based, cohort study was to
assess the overall risk of CP among IVF children, com-
pared with non-IVF children, including all live-born sin-
gletons and twins born in Denmark between 1995 and
2000. Unlike other Danish studies,18,19 we considered the
risk of CP both for singletons and twins combined and
for singletons and twins separately. A key goal was to
clarify the effects of preterm delivery, multiple births,
and SGA status on the risk of CP after IVF. To add new
476 HVIDTJØRN et al
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information and to address the shortcomings of some
previous studies, we also estimated associations between
the risk of CP, the underlying cause of infertility, and the
treatment method for all children born after IVF in this
6-year period.
METHODS
This cohort study was based on data from Danish na-
tional registers, and linkage between the registers was
achieved with the civil registration number, which is a
unique number given to all citizens in Denmark. Our
study included all singletons and twins born alive be-
tween January 1, 1995, and December 31, 2000, as
identified through the Danish Medical Birth Register,
which contains information on all births in Denmark.20
Data on IVF exposure for study infants were obtained
through the IVF Register.21 The IVF Register contains
information on underlying causes of infertility and types
of fertility treatment, namely, conventional IVF or ICSI,
egg donation, number of embryos transferred, and
whether the embryos transferred were fresh or frozen
and thawed (frozen embryo replacement). Since 1994, it
has been mandatory for fertility clinics (public and pri-
vate) to report each treatment cycle to the register. The
register does not record intrauterine insemination or
induction of ovulation without IVF. Permission to con-
duct this study was obtained from the Danish Data Pro-
tection Agency.
Children diagnosed as having CP were identified
through the National Register of Hospital Discharges
(NRHD), on the basis of hospital inpatient discharge
codes and outpatient diagnoses.22 CP was defined with
an International Classification of Diseases, 10th Revision, code
of G80.0 to G83.9 in the NRHD. Follow-up monitoring
of the cohort for a CP diagnosis was through December
31, 2001, corresponding to a range of 1 to 7 years of age.
Additional covariate information was obtained from
the Medical Birth Register, NRHD, and Statistics Den-
mark, including gestational age, multiplicity, infant gen-
der, maternal age and educational level, birth weight,
and parity. Maternal age was categorized as ⬍30 years
(reference category), 30 through 34 years, or ⱖ35 years.
Gestational age was treated as a continuous variable
(with weeks as the analytic unit); preterm delivery was
defined as delivery before 37 completed weeks of gesta-
tion. Educational level was categorized as basic school
(9 –10 years of education), vocational training or inter-
mediate-length education (11–16 years of education;
reference category), or university education (ⱖ17 years
of education). Parity was dichotomized as primiparous
or multiparous (reference category). Multiplicity was
categorized as singletons (reference category) or twins,
excluding triplets or higher multiple births because they
occur for only 2% of IVF children (191 children). The
IVF legislation in Denmark was changed in 1997 to
recommend that only 2 fresh or 3 frozen and thawed
embryos be transferred per cycle, as a rule23; conse-
quently, the number of multiple births higher than twins
actually decreased throughout the study period. SGA
was defined as birth weight ⬍2 SDs from the expected
birth weight at the specific gestational age, with the
method described by Marsal et al.24
We attempted to assess selected risk factors for CP
specific to twin pregnancies. We estimated discordant
birth weights in twin pairs, defined as birth weight vari-
ation between twins of ⱖ20% (relative to the heavier
twin).14 Monochorionicity is associated with CP, and
monochorionicity is more frequent among non-IVF
twins. We had no information on chorionicity; there-
fore, we calculated the risk of CP for twins of opposite
gender only (thereby removing the effect of a monocho-
rionic placenta). We had no information on twin-twin
transfusion syndrome.
The risk of receiving a CP diagnosis was measured as
the incidence rate, with the child as the unit of analysis.
The incidence rate was defined as the number of chil-
dren who received a CP diagnosis in a given time frame
(1995–2001) divided by the total number of person-
years the children in the cohort were at risk for the
diagnosis during that time. The follow-up period varied
from 1 to 7 years of age; therefore, some children with
CP might not have been diagnosed before the end of the
follow-up period. Also, because the number of IVF treat-
ments increased during the study period, a dispropor-
tionate number of IVF children had shorter follow-up
times, compared with non-IVF children. To deal with
these aspects of the data, we used Cox regression models
in the statistical analysis and the incidence rate ratio was
estimated as the hazard rate ratio (HRR), with 95%
confidence intervals (CIs). It was verified graphically
that the proportional-hazards assumption was met.
To account for correlations between twins in the co-
hort, robust variance estimates were calculated with the
method described by Lin and Wei.25 Robust variance
estimates were not applied to subsequent siblings be-
cause, although subsequent siblings would share the
same mother, they would not share several of the crucial
confounders included in the analyses, such as maternal
age, parity, gender, and perhaps even maternal educa-
tional level. To gauge the extent to which the correlation
between siblings might cause variance to be underesti-
mated, we fit a model in which the robust variance
estimates were calculated by taking into account the
siblings; the results were no different from those with
the model taking into account only the twin correlation.
Finally, we also estimated CP risk in a stratified analysis
that included only 1 pregnancy per woman.
Stratified analyses and Cox regression models were
used to adjust for confounding factors, and the results
were reported as HRRs with 95% CIs. The basic model
included maternal age, parity, maternal educational
level, and infant gender as covariates. Preterm delivery,
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multiplicity, and SGA status were then added to the
basic model, separately and together, for evaluation of
the effects of these parameters on the association be-
tween IVF and CP. All variables were tested for mutual
interaction; if results were statistically significant, then
an interaction term was included in the model. Addi-
tional stratified analyses were performed for singleton,
twin, term, and preterm children.
Additional subanalyses (for IVF children only) evalu-
ated the effects of the underlying cause of infertility and
the treatment method on the risk of CP and the risk of
preterm delivery (ie, preterm delivery was considered
the outcome of interest in a separate analysis). For these
analyses with Cox regression models, the CP risk esti-
mates were adjusted for maternal age, preterm delivery,
infant gender, maternal educational level, parity, and
multiplicity. The risk of preterm delivery within this
subcohort was estimated by using a general linear model
with logarithmic link function, with adjustment for ma-
ternal age, infant gender, maternal educational level,
parity, and multiplicity. Stata software (version 8; Stata
Corp, College Station, TX) was used in the analyses.
RESULTS
A total of 403 968 singletons and twins were born in
Denmark between 1995 and 2000, from 307 960 moth-
ers; 9255 (2.3%) of the children were born after IVF,
from 7000 mothers. Of the IVF women, 6535 (93%)
contributed to the cohort with only 1 pregnancy,
whereas 219 529 (73%) of the non-IVF women contrib-
uted to the cohort with 1 pregnancy and 76 646 (25%)
of the non-IVF women contributed to the cohort with 2
pregnancies. Less than 2% of all women contributed
with ⬎2 pregnancies. The percentage of IVF singletons
and twins increased from 1.4% in 1995 to 3.0% in 2000.
In comparison with mothers of non-IVF children,
mothers of IVF children were older (P ⬍ .001), had more
education (P ⬍ .001), and were more often primiparous
(P ⬍ .001). IVF children were more often delivered
preterm (18%, compared with 5% among non-IVF chil-
dren; P ⬍ .001) and were more frequently of multiple
births (P ⬍ .001). The SGA rate was 8.8% among IVF
children and 3.6% among non-IVF children (P ⬍ .001)
(Table 1). In this study, 38.6% of the IVF children were
twins and 2.7% of the non-IVF children were twins. The
preterm rate among IVF twins was 35.9%, similar to the
preterm rate among twins in the non-IVF group
(33.6%). The preterm rate among IVF singletons was
6.5%, compared with 3.7% among non-IVF singletons
(P ⬍ .001). IVF twin pairs were more often of different
gender (871 of 1785 twin pairs, 49%), compared with
non-IVF twins (1865 of 5397 twin pairs, 35%; P ⬍ .001),
and IVF twin pairs had higher rates of discordant birth
weight (393 of 1732 twin pairs, 23%), compared with
non-IVF twins (946 of 5157 twin pairs, 18%; P ⬍ .001).
During the follow-up period, 1048 singletons and
PEDIATRICS Volume 118, Number 2, August 2006 477
 TABLE 1 Demographic and Obstetric Data for Children Born in TABLE 2 Multivariate Models Showing Effects on Risk for CP of IVF
Denmark, 1995–2000, and Their Mothers and Covariates
No. (%) HRR 95% CI P
IVF IVF Non-IVF Non-IVF Basic model
Singleton Twin Singleton Twin IVF 1.61 1.13–2.30 .005
Male gender 1.30 1.15–1.48 ⬍.001
No. of children 5685 3570 383 919 10 794
Primiparous 1.20 1.05–1.38 .008
Age at delivery
Maternal age
⬍30 y 911 (16.0) 703 (19.7) 210 511 (54.8) 4913 (45.5)
⬍30 y 1.00 Reference
30–34 y 2626 (46.2) 1766 (49.5) 125 285 (32.6) 4142 (38.4)
30–34 y 1.18 1.01–1.37 .032
ⱖ35 y 2148 (37.8) 1101 (30.8) 48 123 (12.6) 1739 (16.1)
ⱖ35 y 1.28 1.04–1.57 .016
Educational level
Educational level
Basic 1066 (18.8) 701 (19.6) 95 517 (24.9) 2497 (23.1)
Basic 1.66 1.44–1.91 ⬍.001
Intermediate 2931 (51.6) 1825 (51.1) 192 922 (50.3) 5545 (51.4)
Intermediate 1.00 Reference
University 1636 (28.8) 1018 (28.5) 83 244 (21.7) 2486 (23.0)
University 1.03 0.87–1.22 .740
Primiparous 4447 (78.2) 1369 (38.3) 163 481 (42.6) 2207 (20.4)
Basic model plus preterm
Gestational agea
IVF 1.07 0.76–1.52 .676
⬍33 wk 101 (1.8) 338 (9.5) 3060 (0.8) 884 (8.2)
Preterm (⬍37 wk) 6.22 5.37–7.21 ⬍.001
33–36 wk 269 (4.7) 944 (26.4) 11 172 (2.9) 2710 (25.3)
Basic model plus multiplicity
ⱖ37 wk 5311 (93.5) 2288 (64.1) 366 726 (96.3) 7106 (66.5)
IVF 1.11 0.76–1.63 .554
SGA 250 (4.4) 548 (16.0) 12 266 (3.2) 1623 (16.0)
Twins 2.33 1.79–3.04 ⬍.001
CP 20 (0.35) 20 (0.56) 947 (0.25) 61 (0.57)
Basic model plus SGA
Male gender 2989 (52.6) 1873 (52.5) 197 124 (51.3) 5525 (51.2)
IVF 1.51 1.08–2.16 .024
Diedb 48 (0.8) 61 (1.7) 2004 (0.5) 209 (1.9)
SGA 3.23 2.63–3.40 ⬍.001
Percentages are within outcome categories. Basic model plus preterm plus multiplicity
a Gestational age is in completed weeks.

b Infants died within the follow-up period.

IVF 1.09 0.75–1.59 .617
Preterm (⬍37 wk) 6.27 5.36–7.34 ⬍.001
Twins 0.96 0.72–1.28 .756
Basic model plus preterm plus SGA
twins were diagnosed as having CP. Forty IVF singletons IVF 1.06 0.74–1.51 .755
and twins received a CP diagnosis (40 of 9255 infants, Preterm (⬍37 wk) 6.24 5.30–7.35 ⬍.001
SGA 2.82 2.16–3.68 ⬍.001
0.43%) and 1008 non-IVF singletons and twins received
Preterm ⫻ SGA 0.55 0.36–0.83 .005
a CP diagnosis (1008 of 394 713 infants, 0.26%; P ⬍ Basic model plus multiplicity plus SGA
.001). IVF 1.14 0.78–1.68 .494
The risk of receiving a CP diagnosis for IVF children Twins 2.44 1.82–3.28 ⬍.001
was estimated with a crude HRR of 1.79 (95% CI: 1.28 – SGA 3.46 2.79–4.29 ⬍.001
Multiplicity ⫻ SGA 0.35 0.18–0.68 .002
2.50). Adjustment for maternal age, educational level,
Basic model plus multiplicity plus SGA plus preterm
gender, and parity (the basic multivariate model) re- IVF 1.10 0.76–1.61 .606
duced the estimate to HRR of 1.61 (95% CI: 1.13–2.30); Twins 0.91 0.68–1.22 .548
a HRR of 1.57 (95% CI: 1.10 –2.23) was obtained when SGA 2.16 1.74–2.69 ⬍.001
we included only 1 pregnancy per woman. Maternal Preterm (⬍37 wk) 5.76 4.88–6.79 ⬍.001
age, parity, gender of the child, and educational level All estimates were adjusted for gender, parity, maternal age, and educational level.

also had statistically significant independent associations

with the risk of CP (Table 2).
With stratification with respect to multiplicity and
application of the basic model, the HRR for CP was 1.28
(95% CI: 0.80 –2.03) for IVF singletons, compared with
non-IVF singletons, whereas IVF twins showed a HRR of
1.08 (95% CI: 0.57–2.05), compared with non-IVF
twins. We identified 2 pairs of IVF twins (gestational
ages: 28 and 30 weeks) in which both twins had CP and
3 pairs of non-IVF twins (gestational ages: 32, 35, and 40
weeks) in which both twins had CP. The risk of having
⬎1 twin with CP was increased among IVF mothers,
although not statistically significantly, with a recurrence
risk ratio of 2.15 (95% CI: 0.18 –19). No IVF mothers
with a child with CP (singleton or twin) had a subse-
quent singleton with CP, but 3 non-IVF mothers with a
singleton with CP had a subsequent singleton with CP,
all born at term.
Not surprisingly, multiplicity, preterm delivery, and
SGA status had large and statistically significant inde-
pendent effects on the risk of receiving a CP diagnosis,
when added separately to the basic multivariate analysis
(Table 2). In the cases of preterm delivery and multiplic-
ity, however, the risk of CP from IVF vanished. When
preterm delivery was added to the basic multivariate
model, the risk associated with IVF was HRR of 1.07
(95% CI: 0.76 –1.52); when multiplicity was included,
the HRR was 1.11 (95% CI: 0.76 –1.63). In contrast,
when SGA status was added to the basic multivariate
model, the risk of CP in IVF remained statistically signif-
icant (HRR: 1.51; 95% CI: 1.08 –2.16). We then added
multiplicity, preterm delivery, and SGA status, in all
possible combinations, to the basic multivariate model
and observed that preterm delivery seemed to be the key

478 HVIDTJØRN et al
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factor affecting the risk of CP from IVF. In any model increased risk of CP for IVF twins of opposite gender,
that included preterm delivery, the risk of CP from IVF compared with non-IVF twins of opposite gender (HRR:
disappeared. If a model included multiplicity without 1.49; 95% CI: 0.52– 4.31). IVF twins with discordant
preterm delivery, then the risk of CP from IVF disap- birth weight, compared with non-IVF twins with discor-
peared but, if preterm delivery was included with mul- dant birth weight, did not have increased risk of CP
tiplicity, then the risks for CP from IVF or from multi- (crude HRR: 1.32; 95% CI: 0.48 –3.66).
plicity both disappeared. The inclusion of SGA status in For the subanalyses among IVF children, Table 3 pro-
any model did not seem to affect greatly the risk of CP vides details on the underlying causes of infertility and
from IVF (beyond the effects observed for preterm de- the treatment methods. The most common underlying
livery or multiplicity), and SGA status remained a statis- causes of infertility were tubal factors (4243 of 9255
tically significant independent risk factor for CP in all cases, 46%) or male factors (2796 of 9255 cases, 30%);
model combinations. There was statistically significant 18% of cases (1634 of 9255 cases) had unknown or
interaction between SGA status and both preterm deliv- unspecified causes. Because an individual case could
ery and multiplicity in the risk of CP, but the inclusion of have ⬎1 underlying cause, we included only cases with
the interaction terms also did not affect markedly the a single underlying cause of infertility for the multivar-
risk of CP from IVF. In the models that included preterm iate analyses (6054 of 9255 cases, 65%). Although 23
delivery and/or multiplicity and/or SGA status, the in- (58%) of 40 cases of CP among IVF children were asso-
dependent effects of the other covariates on the risk of ciated with a tubal factor only (underlying cause in 3596
CP were largely unchanged from the basic multivariate of 9255 IVF cases, 39%), we found no statistically sig-
model (data not shown). When we added gestational age nificant association between this or any other single
(as a continuous variable) to the basic multivariate underlying cause of infertility and risk of CP in the IVF
model, the risk of CP for IVF children disappeared (HRR: group (Table 3). With the same analytic approach, we
0.97; 95% CI: 0.69 –1.38). did not find an increased risk of preterm delivery asso-
Apparently, preterm delivery is a step on the causal ciated with any single underlying cause of infertility in
path to CP for IVF children. To investigate more com- models adjusting for maternal educational level, age,
pletely whether IVF had a residual effect on the risk of parity, gender, and multiplicity (results not shown).
CP, we performed a stratified analysis (basic multivariate The vast majority of treatments were conventional
model) with strata of term/preterm and multiplicity. For IVF, but the use of ICSI increased over the years, from
term singletons, the risk estimate for CP from IVF was a 4.7% of treatments in 1995 to 31.0% in 2000. The ICSI
HRR of 0.84 (95% CI: 0.43–1.63); for term twins, the group had a smaller proportion of children with CP,
risk estimate was a HRR of 0.83 (95% CI: 0.27–2.61). For compared with the conventional IVF group, although
preterm singletons, the risk estimate for CP from IVF was this was not statistically significant (HRR: 0.80; 95% CI:
a HRR of 1.91 (95% CI: 1.00 –3.66); for preterm twins, 0.31–2.00) (Table 3). Five hundred sixty children were
the risk estimate was a HRR of 1.15 (95% CI: 0.54 – born after frozen embryo replacement; they had no sta-
2.45). Adding SGA status in the analyses did not change
these results appreciably, and the risk estimates for CP
from IVF remained nonsignificant. TABLE 3 HRR of CP Within IVF Group, for Singletons and Twins
The importance of preterm delivery as an indepen- Combined
dent risk factor for CP was also apparent in the popula- No. of No. of Children Adjusted HHR P
tion-attributable fraction for CP among IVF children due Children With CP (%) (95% CI)
to preterm delivery, which we estimated to be 59.4% Cause of infertility
(95% CI: 58.8%– 60.0%) on the basis of these study Cervical factor total 65 0/65 (0.00)
Cervical factor only 33 0/33 (0.00) Not calculated
data. That means that, if we assume that the association
Male factor total 2796 8/2796 (0.29)
between preterm delivery and CP is causal, then ⬃59% Male factor only 2028 7/2028 (0.25) 1.06 (0.46–2.42)a .894
of CP cases among IVF children may be attributable to Ovulation factor total 814 1/814 (0.12)
preterm delivery. In comparison, we estimated the at- Ovulation factor only 397 0/397 (0.00) Not calculated
tributable fraction for CP among non-IVF children due Tubal factor total 4243 25/4243 (0.59)
Tubal factor only 3596 23/3596 (0.64) 1.47 (0.75–3.00)a .264
to preterm delivery to be 19% (95% CI: 18.9%–19.2%).
Other or unknown 1634 4/1634 (0.24) 0.63 (0.22–1.80)a .384
This difference between IVF and non-IVF children in Treatment method
attributable fraction for CP due to preterm delivery is Conventional IVF 6444 31/6444 (0.48) Reference
largely attributable to the larger proportion of IVF chil- ICSI 1842 5/1842 (0.27) 0.90 (0.36–2.26) .827
dren born preterm (18%), compared with non-IVF chil- Fresh embryo 8878 36/8878 (0.41) Reference
Frozen and thawed embryo 560 4/560 (0.71) 2.32 (0.80–6.76) .122
dren (5%), rather than a difference between the 2
Egg donation 111 0/111 (0.00)
groups in the risk of CP associated with preterm birth.
Results were adjusted for maternal educational level, age, parity, gender, multiplicity, and pre-
In considering twin-specific risk factors and using the term delivery.
basic multivariate model, we did not find a significantly a Reference is all other groups of 1 factor only.

PEDIATRICS Volume 118, Number 2, August 2006 479

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tistically increased risk of CP (HRR: 2.19; 95% CI: 0.77–
6.28), compared with children born after fresh embryo
transfer, but numbers were small (Table 3). Only 111
children were born after egg donation and none of them
had a CP diagnosis, as would be expected from the small
sample size. In assessment of the risk of preterm delivery
associated with a specific type of treatment, only chil-
dren born after egg donation had an increased risk of
preterm delivery (HRR: 1.69; 95% CI: 1.14 –2.50), in
comparison with other types of treatment and with ad-
justment for maternal educational level, age, parity, gen-
der, and multiplicity.
DISCUSSION
Children born after IVF have an increased risk of CP,
primarily because of preterm delivery. Low gestational
age is a major step on the causal path to CP among IVF
children, for singletons as well as twins.
In the basic multivariate model, the risk of CP for IVF
children was increased, compared with non-IVF children
(adjusted HRR: 1.61; 95% CI: 1.13–2.30). When multi-
plicity and preterm delivery were included in the mul-
tivariate models, the risk of IVF disappeared, which in-
dicates that the increased risk of CP for IVF children is
largely attributable to the large proportion of IVF chil-
dren who are born preterm (especially because a large
proportion of IVF children are both born as multiple
births and born preterm) and not to the treatment itself
(Table 2). Moreover, there is no apparent significant
residual risk from IVF for CP among term singletons or
twins; in fact, the direction of the association was some-
what protective, underscoring the importance of pre-
term delivery in the risk of CP after IVF. The increased
risk of CP from IVF among preterm singletons ap-
proached statistical significance (HRR: 1.91; 95% CI:
1.00 –3.66), which warrants additional exploration. Pre-
term births represent a heterogeneous group, and addi-
tional work is needed to understand the IVF-preterm
birth-CP pathway, considering the different conditions
leading to preterm birth.
Because SGA rates are increased with IVF and SGA
status is a risk factor for CP, SGA status also might be
expected to be a step on the causal pathway from IVF to
CP. In this study, inclusion of SGA status in the multi-
variate analyses did not have a marked effect on the risk
of CP among IVF children, unlike preterm delivery. A
test for interaction showed that preterm delivery and
SGA status had mutually modifying effects, and the as-
sociation between SGA status and CP was strongest for
term children. The association between preterm delivery
and CP was much stronger than the association between
SGA status and CP, and it is most likely that being born
preterm overpowers the effect of being SGA among pre-
term children. However, the method used to classify
SGA status in this study was based on a simplified model
of fetal growth with few parameters (weight, gestational
480 HVIDTJØRN et al
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age, and gender), and more-sophisticated measures may
be needed to clarify the associations among IVF, fetal
growth, gestational age, and CP.
In our study, the increased risk of CP for IVF children
was lower than the risk found by Stromberg et al17 but,
in accordance with their findings, the risk attributable to
IVF decreased when preterm delivery was included in
the analyses. Lidegaard et al,19 using a slightly different
Danish cohort for their study (1995–2001, compared
with 1995–2000 in this study), found a statistically sig-
nificantly increased risk of CP for singletons, but they did
not adjust for preterm delivery. In our multivariate anal-
ysis, the risk of CP among IVF singletons was elevated
but not statistically significantly.
More IVF singletons were born preterm (6.5%), com-
pared with non-IVF singletons (3.7%; P ⬍ .001), and the
etiology of preterm delivery among IVF singletons still
needs to be explained. Subfertility has been associated
with preterm delivery7–10 and might be part of the expla-
nation, but we lacked the data (eg, prolonged time to
pregnancy) to investigate this pathway. Another expla-
nation for preterm delivery for IVF singletons could be
the vanishing embryo syndrome. In IVF, commonly ⱖ2
embryos are transferred, which produces a potential risk
of losing a twin or triplet in early pregnancy. Some
authors found an increased risk of preterm delivery and
low birth weight among IVF children born after vanish-
ing of a co-embryo.6,26 Others hypothesized that this
event might damage the surviving fetus and that CP of
unknown etiology could result from the vanishing em-
bryo syndrome, but the literature in this area is
sparse.27,28 An association between CP and IVF pregnan-
cies in which the number of embryos transferred origi-
nally was higher than the number of infants at delivery
was indicated.29
Like the studies by Pinborg et al18 and Stromberg et
al, we found no difference in the risk of CP between
17
IVF twins and other twins. In stratified analyses for twins
only, we excluded same-gender twins (thus monocho-
rionic twins), and the risk estimate for CP from IVF for
different-gender twins was elevated but did not reach
statistical significance. We did not find any difference in
the risk of CP between IVF twins with birth weight
discordance, compared with non-IVF twins with birth
weight discordance. Data on twin-twin transfusion syn-
drome were not available. Additional data on the unique
features of twin pregnancies will be needed to draw
conclusions regarding potential differences in the etiol-
ogy of CP after IVF for some twins, compared with
singletons.
Approximately 59% of CP cases among IVF children
may be attributable to preterm delivery, which under-
scores the importance of minimizing the number of chil-
dren born preterm with IVF. One way to reduce the
overall preterm delivery rate with IVF may be to reduce
the high rates of twins (and higher multiple births),
because twins accounted for 78% of the preterm IVF
children in this study. More-widespread use of single-
embryo transfer might reduce this problem and prevent
some of the adverse outcomes associated with multiple
and preterm births. Evidence regarding pregnancy rates
and neonatal outcomes after transfer of ⱖ1 embryo is
still limited,30,31 but studies from Finland and Sweden,
where single-embryo transfer is used to a greater extent
than in many other countries, show promising results of
high pregnancy rates with single-embryo transfer.32,33
Within the IVF group, we found no independent
association between any single underlying cause of in-
fertility and the risk of CP or the risk of preterm delivery.
Although most cases of CP were associated with a tubal
factor only, this was also the most common underlying
cause. Therefore, the relationship between IVF and CP
does not seem to be influenced significantly by the un-
derlying cause of infertility, although studies with larger
sample sizes for individual causes are needed to confirm
these results.
In accordance with the results of the study by Pinborg
et al,18 no difference in the risk of CP between children
born after conventional IVF and those born after ICSI
treatment was seen. For children born after transfer of
frozen and thawed embryos, we found no statistically
significantly increased risk of CP (HRR: 2.19; 95% CI:
0.77– 6.28), but numbers were small. Additional studies
on the outcomes of frozen embryo replacement are
needed, because the numbers of frozen embryo replace-
ment treatments are increasing. Frozen embryo replace-
ment accounted for 6% of IVF treatments overall in this
study, but the number in Denmark increased to 14% in
2003.34
The present study included all live-born singletons
and twins born in Denmark in a 6-year period, which
reduced any selection bias in the study population to a
minimum. All data in the registers were collected pro-
spectively and were independent of the conduct of the
study. As in the studies by Pinborg et al18 and Lidegaard
et al,19 the diagnosis of CP was retrieved from the NRHD,
and the validity and completeness of CP diagnoses in the
NRHD have been questioned.35 In a validation study, it
was shown that the NRHD includes a number of false-
positive CP diagnoses.35 Furthermore, CP caused by post-
natal events is included in the NRHD, but such cases
account for only 3.2% of CP cases.35 Because neither of
these sources of misclassification is likely to be associated
systematically with IVF exposure, the result in our data
is to bias the estimate of the effect of IVF on CP risk
toward the null hypothesis. A national Danish CP regis-
ter is presently in the process of construction,36 with
expert review of diagnoses, and reproduction of this
study with the CP register, when it is established in a few
years, is needed.
The findings considered only fertility treatments per-
formed in vitro (IVF); therefore, children born after in
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vivo fertilization (hormone stimulation followed by in-
semination or intercourse) were placed in the nonex-
posed group. In vivo fertilization, like IVF, results in a
large proportion of multiple births.3 It is possible that the
risk of CP after in vivo fertilization is also increased,
because of a high proportion of multiple births and
preterm deliveries or for other reasons; therefore, the
risk of CP with artificial reproduction in general may be
even higher than presented here.
CONCLUSIONS
Children born after IVF have an increased risk of CP
because of the association between IVF and preterm
delivery, which was the most powerful predictor of CP
found in this study. The risk was not associated with an
underlying cause of infertility, but it was associated
strongly with preterm delivery, primarily for twins but
also for singletons. These findings, which are consistent
with other studies, are of great public health importance
and call for prevention of the high rate of multiple births
and preterm deliveries in IVF.
ACKNOWLEDGMENTS
Funding was provided by the Centers for Disease Control
and Prevention (Atlanta, GA), the Ludvig and Sara El-
sass Fund, the Aase and Ejnar Danielsens Fund, and the
Else and Mogens Wedell-Wedellsborgs Fund. The fund-
ing sources did not participate in any part of the perfor-
mance of the study.
We thank Lone Mortensen, IVF Register, National
Board of Health, and Søren Leth-Sørensen, Statistics
Denmark, for their assistance during data retrieval. We
thank Vibeke Holsteen, MD, for supervision and advice.
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 Cerebral Palsy Among Children Born After in Vitro Fertilization: The Role of
Preterm Delivery−−A Population-Based, Cohort Study
Dorte Hvidtjørn, Jakob Grove, Diana E. Schendel, Michael Væth, Erik Ernst, Lene F.
Nielsen and Poul Thorsen
Pediatrics 2006;118;475
DOI: 10.1542/peds.2005-2585

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
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 Cerebral Palsy Among Children Born After in Vitro Fertilization: The Role of
Preterm Delivery−−A Population-Based, Cohort Study
Dorte Hvidtjørn, Jakob Grove, Diana E. Schendel, Michael Væth, Erik Ernst, Lene F.
Nielsen and Poul Thorsen
Pediatrics 2006;118;475
DOI: 10.1542/peds.2005-2585

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/118/2/475

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN:
.

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