correspondence

n engl j med

370;10

nejm.org

march

2014

975

To the Editor:

Williams et al. report that chil-

dren born after assisted conception have a risk of

cancer that is similar to that of children born

without such assistance. Assisted conception can

be achieved with in vitro fertilization (IVF), alone

or in combination with intracytoplasmic sperm

injection (ICSI). Notably, couples with male-

factor infertility are more likely to undergo ICSI.

Infertility in a couple could be due to male-factor

infertility in up to 50% of cases. The risk of birth

defects appears to be higher when assisted con-

ception with ICSI is used, but not when only IVF

is used.

Men with azoospermia have an increased risk

of the subsequent development of cancer, which

suggests that severe male-factor infertility and

cancer development may share a common cause.

Epigenetic modifications such as DNA methyla-

tion are important regulators of both spermato-

genesis

and carcinogenesis.

Had the authors

evaluated whether assisted conception occurred

by means of ICSI, it would have been possible

to discern whether genetic abnormalities in the

father could have modified the risk of childhood

cancer.

Ranjith Ramasamy, M.D.

Larry I. Lipshultz, M.D.

Dolores J. Lamb, Ph.D.

Baylor College of Medicine

Houston, TX

ranjithrama@gmail.com

No potential conflict of interest relevant to this letter was re-

ported.

Davies MJ, Moore VM, Willson KJ, et al. Reproductive tech-

nologies and the risk of birth defects. N Engl J Med 2012;366:

1803-13.

Eisenberg ML, Betts P, Herder D, Lamb DJ, Lipshultz LI.

Increased cancer risk and azoospermia. Fertil Steril 2013;

100(3):e12.

Boissonnas CC, Jouannet P, Jammes H. Epigenetic disorders

and male subfertility. Fertil Steril 2013;99:624-31.

Kaiser J. Genes link epigenetics and cancer. Science 2010;

330:577. [Erratum, Science 2010;330:1746.]

DOI: 10.1056/NEJMc1315232

The Authors Reply:

Iliadou et al. comment on

the effect missing data may have on determinis-

tic linkage. Our linkage protocol (see Table S2 in

the Supplementary Appendix of the article, avail-

able at NEJM.org) was designed to overcome this

potential problem by not excluding possible

matches involving missing data. A very large

number of potential linkages (4,677,887) were

generated with the use of this inclusive approach.

Given our exacting protocol and the fact that

linkage involved primarily parental information,

our match rates should be independent of the

child’s age. We are confident that our data link-

age was exhaustive in terms of attempting to

identify cases of cancer.

Previous studies have shown small absolute

increased risks of cancer, specifically leuke-

mia,

1,2

in association with assisted conception.

Our study showed no such increase; however,

our confidence interval for the overall risk of

cancer does overlap with that of an earlier,

smaller, albeit population-based, study.

The

majority of previous studies are too small to

detect rare outcomes, and even the recent meta-

analysis

cited by Iliadou et al. included signifi-

cantly fewer children than our large cohort

study. Furthermore, many previous studies have

methodological limitations. Iliadou et al. refer

to a case–control study

in which children hos-

pitalized with noncancer diagnoses were used as

controls. Such children may not be representa-

tive of the general population. In addition, it is

difficult to estimate the effect of consent bias

in such studies. Our study design, which relied

on population-based registry data, avoids such

biases.

Caution should indeed be exercised when

cancers with different causes are grouped. How-

ever, cancer of any type, or its absence, is a key

marker of long-term health. Couples considering

assisted conception are likely to ask their clini-

cian about increased cancer risk in resulting

offspring but are unlikely to be overly concerned

about an increased risk for one diagnostic sub-

group as compared with another. Therefore, we

presented data for “overall cancer risk” and data

for diagnostic subgroups separately.

In response to Ramasamy et al.: we did inves-

tigate the risk of childhood cancer according to

the type of assisted conception and the infertil-

ity diagnosis. We found no overall increased risk

in children conceived with the use of ICSI (stan-

dardized incidence ratio [SIR], 1.07; 95% confi-

dence interval [CI], 0.53 to 1.49) or in those

conceived to couples with a diagnosis of male-

factor infertility (SIR, 0.92; 95% CI, 0.70 to 1.57)

(Table S4 in the Supplementary Appendix).

Carrie L. Williams, M.B., B.Ch.

University College London

London, United Kingdom

Kathryn J. Bunch, M.A.

University of Oxford

Oxford, United Kingdom

The New England Journal of Medicine

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