Medical and Pediatric Oncology 33:2933 (1999)

Pregnancy Outcome in Long-Term Survivors of Childhood Cancer

Julie Blatt, MD*
Background. By the year 2010, 1/250
young adults will be long-term survivors of
childhood cancer. One of the major concerns is
whether they will be able to have healthy children. Procedure. The literature was reviewed to
determine 1) the extent of intrapartum and perinatal complications experienced by survivors
or their spouses and 2) the risk of congenital
malformations or cancer in their children. Results and Conclusions. Series have reported on
pregnancy complications among approximately 400 female survivors and 300 partners
of male survivors. An increased incidence of
spontaneous abortions, low-birth-weight ba-

bies, and neonatal deaths has been described

for women with Wilms tumor who had received at least 20 Gy abdominal radiation.
Hodgkin disease survivors who had received
both radiation and chemotherapy (but not either alone) also appear to be at increased risk of
spontaneous abortions. Based on several thousand survivor offspring, there is no overall increased risk of either congenital malformations
or childhood cancer. Further studies will define
the outcome of offspring of cancer survivors
treated in the modern era. Med. Pediatr. Oncol.
33:2933, 1999.
1999 Wiley-Liss, Inc.

Key words: pregnancy outcome; childhood cancer; long-term survivors

INTRODUCTION

It has been estimated that by the year 2010, 1/250

young adults (2029 years) will be long-term survivors
of childhood cancer [1]. For this growing cohort of
former patients, one of the major concerns is whether
they will be able to have healthy children. This review
deals with two aspects of this question: 1) the course of
pregnancies in fertile patients, including intrapartum and
perinatal problems, and 2) whether there will be mutagenic effects of parental anticancer therapy such that offspring of childhood cancer survivors will themselves be
at increased risk of cancer or congenital malformations.
Several clinical settings must be considered before
survivors, both female and male, can be counseled effectively with respect to these issues. The most common of
these is pregnancy occurring years after cancer treatment.
However, because pediatric oncologists frequently care
for sexually active adolescents and young adults, outcomes of pregnancies concurrent with therapy also must
be understood. This latter topic is beyond the scope of
this review and has been discussed elsewhere [2].
COMPLICATIONS OF PREGNANCY

Several studies have provided information according

to survivor sex with respect to prenatal and perinatal
morbidity and mortality [315]. These outcomes appear
to vary with cancer diagnosis and with specifics of
therapy (Tables I, II). Among female survivors of Wilms
tumor, one large series by Li et al. [3] noted an increased
risk of intrauterine and peripartum complications. These
included spontaneous abortions, low-birth-weight babies,
1999 Wiley-Liss, Inc.

and neonatal deaths. Whereas about one-half of the patients had received dactinomycin, the risk of these adverse outcomes was restricted to women who had received 2035Gy abdominal radiation (with/without chemotherapy), for whom the incidence was about 30%.
Compared with the general population, their relative risk
of perinatal mortality was 7.9 and of having low-birthweight infants (<2,500 g) was 4.0. Another study has
generally confirmed these results [4]. The pathogenesis
of radiation-associated pregnancy complications in these
patients is unclear but may include uterine vascular insufficiency and radiation-induced structural changes
such as scoliosis or fibrosis. In some cases, adverse pregnancy outcomes may not be treatment-related but may be
due to congenital genitourinary tract malformations,
which sometimes are part of the Wilms tumor complex.
For example, one survivor who had experienced five
miscarriages had a bicornuate uterus [4].
Among survivors of Hodgkin disease whose treatment
had included both radiation and chemotherapy, Holmes
and Holmes [5] found that female patients as well as
partners of male patients were at increased risk of spontaneous abortion. Whether the radiation was above or
below the diaphragm was not a factor. On the other hand,
neither males nor females who received radiation or che-

Division of Hematology-Oncology, Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina
*Correspondence to: Julie Blatt, MD, Division of HematologyOncology, Department of Pediatrics, University of North Carolina
School of Medicine, Chapel Hill, NC 27599-7220.
E-mail: jblat@med.unc.edu

30

Blatt
TABLE I. Perinatal Complications: Female Long-Term Survivors*
Reference
3
4
5
7
10
11
12
13
14
15
18

Diagnosis
WT
WT
HD
HD
ALL
ALL
ALL, ANLL
ALL
ALL, NHL
NB, GN
Mixed

No. survivors/pregnanciesa
65/127
15/30
29/52
15/30
8/17
5/8
8/11
23/40
14/20
19/43
15/15

Fetal deaths
b

11
12b
4b (See text)
6
3c
1
0
0
1
3
1

Neonatal deaths
b

10
1
NA
0
0
0
0
0
0
0
0

LBW, premie
22b, 19
35
NA
10
2 c, 2
0
11
10
0
NA
0

*Includes only those series in which survivors had been treated during childhood and in which results are broken down by
survivor sex. Abbreviations: WT, Wilms tumor; HD, Hodgkin disease; ALL, acute lymphocytic leukemia; ANLL, acute
nonlymphocytic leukemia; NHL, non-Hodgkin lymphoma; NB, neuroblastoma; GN, ganglioneuroma; NA, not available;
LBW, low birth weight (<2,500 g) or small for gestational age.
a
Some of the numbers are best guesses derived from each reference. The number of pregnancies includes live births,
stillbirths, spontaneous abortions (for some series, only those occurring after 20 weeks gestation were noted) but not elective
abortions; Fetal deaths include spontaneous abortions, stillbirths, ectopic pregnancies; LBW babies account for many of the
neonatal deaths in the previous column.
b
Judged to be significant by the authors of the study.
c
Conception after artificial insemination, and not cancer therapy, was considered to be responsible for most of these
complications.
TABLE II. Perinatal Complications: Male Long-Term Survivors*
Reference
3
4
5
7
10
12
13
15
18

Diagnosis

No. survivors/pregnancies

Fetal deaths

Neonatal deaths

LBW, premie

WT
WT
HD
HD
ALL
ALL
ALL
NB, GN
Mixed

34/64
12/26
19/31
7/11
4/10
6/12
4/7
5/5
4/8

0
3
5b (See text)
2
2
0
0
0
1

0
0
NA
0
0
0
0
0
0

2
1
NA
0
0
0
0
NA
0

*See footnotes to Table I.

motherapy alone were at increased risk of pregnancy

complications. Another report (which, however, was
based entirely on patients who had been aged >15 years
at the time of therapy and which did not detail treatment
regimens) also suggested that female survivors of
Hodgkin disease were at increased risk of pregnancy
complications [6]. Of 44 pregnancies, 4 ended in spontaneous abortions, 2 in stillbirths, and 6 in premature or
low-birth-weight babies. Other series [79], although not
confirming these findings, may have been too small or
too heterogeneous with respect to parental diagnoses, age
at cancer diagnosis, and treatment to reexamine these
claims in Wilms tumor or pediatric Hodgkin disease survivors critically.
For other disease categories, the data also are limited.
However, the best evidence suggests that offspring of
survivors of most diseases [1015] (including the large
group with acute lymphoblastic leukemia), when treated
with 1970s1980s therapy do not experience perinatal
problems different from those of other babies.

CONGENITAL ABNORMALITIES

The above-noted studies and others also have provided preliminary data with respect to congenital anomalies in offspring of adult survivors of childhood cancer
[322]. Bearing in mind that major malformations occur
in <4% of the general population and minor malformations in about 10%, three series are unique in having
found what was concluded to be an excess of malformations (not all major)all in offspring of female survivors. Byrne et al. [4] identified anomalies in 6 of 18
newborns born to 12 girls with a history of Wilms tumor.
Several of these malformationscryptorchidism, penile
anomalieslikely were inherited features of the Wilms
tumor spectrum and not effects of maternal therapy.
McKeen et al. [6] reported malformations (hydrocephalus, tracheomalacia, pelvic asymmetry, a sacral dimple,
hairy nevus) in 5 of 75 pregnancies (7.5%, an unspecified
number of which were in women who had been treated as
adults) that occurred following chemotherapy for

Pregnancy and Childhood Cancer

31

TABLE III. Congenital Anomalies in Offspring of Female Long-Term Survivors*

Reference
3
4
5
7
10
11
12
13
14
15
16
17
18
19
20
22

Diagnosis

Survivors (n)

Live offspring +
stillborns (n)

WT
WT
HD
HD
ALL
ALL
ALL, AML
ALL
ALL, NHL
NB, GN
Mixed
Mixed
Mixed
ALL
Mixed
Mixed

65
12
29
15
8
5
8
23
14
20
309
35
15
56
54
626

127
18
52
28
14
8
11
40
20
41
603
63
14
81
92
1,282

Malformations
Major

Minor

<3
4b

NA
2

5
1
1
0
2
0
1
2
2
1
0
1
1
2
0
27
NA
2
3
0
1
5
NA
3
0
51 Major + minor

*See footnotes to Table I; includes only those series in which analyses by patient sex were given for
long-term survivors <15 years at diagnosis. Congenital anomalies are defined differently in references.
References 17 and 20 include some patients reported in references 7 and 10.

Hodgkin disease. Maradi et al. [12] reported that, of 6

infants born to 5 female survivors of childhood ALL, 1
had gastroschisis, and 1 had panhypopituitarism with
midline defects.
In contrast, as shown in Tables III and IV, most other
studies have shown no excess of major or minor malformations in offspring of female or male childhood cancer
survivors. The recent Five Center Study [22], with 2,198
offspring, is the largest series to date and had an 80%
power to detect as little as a 40% increase in the incidence of genetic diseases. Its reassuring conclusion is
supported by several other studies [19,21]. Although several well-characterized anomalies have been reported in
more than one child, these appear to have occurred with
equal frequency in the general population. No highly
penetrant single dominant gene defects have appeared de
novo to suggest the occurrence of germ cell mutations
following anticancer therapy. To the extent that the sex
ratio of offspring may reflect germ cell mutations, it is
reassuring that, overall, the proportion of boys and girls
born to survivors of childhood cancer approximates that
in the population at large.
Congenital anomalies in most of these studies have
been defined based on modified ICD-9 codes and therefore have included major anomalies. However, which
anomalies are considered to be major has varied among
investigators. Although all have attempted to include
problems that require intervention or are in some way
handicapping, some problems (notably congenital hip
dislocations or dysplasias) have been classified as major
in some reports and minor in others. In addition, there has
been no exhaustive look at minor anomalies. These latter
likely have been underreported; most studies have relied

TABLE IV. Congenital Anomalies in Offspring of Male

Long-Term Survivors

Reference
3
4
5
7
10
12
13
15
16
17
18
19
20
22

Diagnosis

Survivors
(n)

Liveborn
+ stillborn
(n)

WT
WT
HD
HD
ALL
ALL
ALL
NB, GN
Mixed
Mixed
Mixed
ALL
Mixed
Mixed

34
9
19
7
4
6
4
4
231
25
4
37
37
436

64
20
32
9
9
12
7
7
432
39
7
59
61
916

Malformations
Major

Minor

<3
NA
0
0
0
1
0
1
0
0
0
0
0
0
0
0
19
NA
0
3
0
2
0
0
2
0
23 Major +
minor

on medical records and parental recall and not on physical examination of offspring. Nonetheless, when children
of long-term survivors have actually been examined with
an emphasis on dysmorphology, unusual problems have
not been uncovered [18].
Because all of these studies suffer either from small
numbers, or heterogeneity with respect to treatment regimen, significant effects of individual agents could have
been masked. The analysis with respect to chemotherapy
is particularly important; a number of agents are known
to be mutagenic in vitro and theoretically might be expected to cause germline mutations. For example, as was
emphasized by Green et al. [17], based on the Ames
Salmonella/microsome assay system [23,24], doxorubi-

32

Blatt

cin, daunorubicin, cyclophosphamide, ifosfamide, carmustine, lomustine, dacarbazine, cisplatin, etoposide,

and mercaptopurine all are candidate mutagens. On the
other hand, a number of other agents that are prominent
components of treatment regimens in survivors nevertheless are unlikely to cause problems in human offspring
based on in vitro assays. These include vincristine, vinblastine, methotrexate, thioguanine, asparaginase, dactinomycin, bleomycin, and cytosine arabinoside.
In one large series that did examine the occurrence of
specific anomalies as a function of past parental therapy
(site and dosage of radiation, type and dose intensity of
chemotherapy), as well as of the age of patients at diagnosis and elapsed time since completion of therapy, no
clear-cut relationships could be demonstrated [17]. Although an association between actinomycin D and cardiac anomalies in offspring of female survivors was suggested by this study, more recent publications by the
same and other investigators [20,22] failed to support this
possibility. In looking specifically at alkylator-exposed
(n 57) or anthracycline-exposed (n 47) survivors,
Green et al. [17] found no influence on the frequency of
birth defects. Similar conclusions with respect to alkylator exposure have been drawn by others [22]. In contrast,
another study has suggested a trend for increased risk of
birth defects in offspring of female survivors of ALL
who had received cyclophosphamide (>1 g/m2 ). However, the numbers are small and confidence intervals too
wide to allow definitive conclusions [19]. Nonetheless,
while the outlook for survivor offspring appears optimistic with respect to birth defects, larger numbers will be
needed to evaluate the possibility of excess malformations related to specific agents.
CANCER

Apart from heritable tumors such as retinoblastoma,

studies uniformly have failed to demonstrate a significantly increased overall risk of childhood cancer in offspring of long-term survivors [20,2528]. In the largest
series to date [28], among 5,487 offspring of some
14,000 childhood cancer survivors treated in Scandinavia, the standardized incidence ratio (sir) of nonheritable
neoplasms was 1.3. That study concluded that there was
fewer than one excess cancer diagnosis for every 1,000
offspring. Apart from the expected single gene inherited
tumors and cancer family syndromes, there have been no
recurrent cancer pairs reported in long-term survivors
and their offspring. Most pairs could represent chance
occurrences.
However, as for congenital anomalies, significant cancer excesses may be masked by heterogeneous groups of
patients and treatment regimens and in most series by the
small numbers of offspring. Thus, in one large retrospective cohort (the Five Center Study) that analyzed cancer

diagnoses in offspring by age of occurrence, 5 of 7 were

found to have been diagnosed at age <5 years [25]. Only
1.7 cancers were expected in this age range, for a risk
ratio of 2.9. Although based on small numbers, male
offspring of female survivors appeared to be at greatest
risk; four of the five young children were boys for whom
the parent survivor was the mother. In the Scandinavian
experience, there was a trend toward increased risk of
cancer in children whose survivor parents had been
younger than 10 years old at diagnosis (sir 3.9).
FUTURE PLANS

The available data tentatively support the conclusions

1) that adverse pregnancy outcomes are limited to select
groups of cancer survivors and 2) that live-born children
of female and male survivors, taken as a whole, are not
at increased risk either of congenital anomalies or of
cancer. Concerns about these data persist for several reasons. Because the latency for development of many cancers is protracted, many offspring might not have had
long enough follow-up to be sure that they are not at
increased risk. Thus, increasing efforts are being directed
at identifying and validating surrogate markers of malignancy in offspring that might appear within a shorter
time frame. The most obvious of these is constitutional
cytogenetics of survivors, with the idea that these would
reflect mutations in germline chromosomes. The results
of Rubin et al. [29] suggest that this is not so; the majority of survivors of childhood ALL (who do not have
abnormal children) harbor a small population of longlived lymphocytes that exhibit stable nonclonal chromosomal abnormalities. Survivors of pediatric cancer have
been shown to have other markers of chromosomal injury in peripheral blood, such as sister chromatid exchanges, and mutations at the glycophorin A, HGPRT,
and T-cell antigen receptor loci [3032]. However,
whether these will translate into cancer or congenital
defects in offspring is not clear.
In addition to concerns about latency, other concerns
raise questions about the optimistic conclusions with respect to offspring. Most of the offspring who have been
studied were born to patients who were diagnosed and
treated at a time when survivorship was low and therapy
was much less intense than it has been over the past
decade. Among survivors, the number of successful
pregnancies has been relatively low. The study of problems in offspring of pediatric cancer survivors also has
been encumbered by the same problems faced in other
areas of late effects. As the children become adults, a
large proportion are lost to follow-up by the pediatric
oncologists who treated them. When patients remain in
contact, they may represent a selected subgroup in whom
the prevalence of late effects may be misrepresented
compared to all survivors.

Pregnancy and Childhood Cancer

The Childhood Cancer Survivor Study (CCSS) is a

retrospective cohort study of patients who have survived
cancer-free for at least 5 years, which was designed to
address some of these concerns. Children diagnosed between 1970 and 1986 when younger than 21 years old
with a malignant tumor at one of 25 institutions were
eligible for this study. Through a combination of institutional tumor registries and data management records,
and a tracking mechanism to capture patients lost to follow-up, more than 20,000 eligible patients have been
identified. To date, current follow-up is available on
more than 3,000 live-born infants. Multivariate analysis
of their risk for congenital anomalies or cancer is ongoing, and results should be published over the next few
years. These results should be definitive for patients
treated in the context of past therapies and should lay the
groundwork for prospective follow-up of offspring of
patients treated in the modern era.
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