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Failure to Lactate: A Possible Late Effect of Cranial Radiation

Karen Johnston, RN, MN, Grad Cert Paed Onc,1* Marcus Vowels, AM, MB, BS, MD, FRACP,1,4

Susan Carroll, MBBS, FRANZCR,3,4 Kristen Neville, MBBS FRACP,2,4 and Richard Cohn, MBBCH FCP (SA) FRACP1,4

INTRODUCTION

Survival rates of patients treated for childhood cancer have

improved significantly [1]. Cranial irradiation has been identified as

being responsible for late endocrine toxicities [2]. Although fertility

and hormone production are affected, many long-term survivors

have produced normal offspring [3]. After noting that two females

who were treated with 24 Gy prophylactic cranial irradiation failed

to lactate postpartum, we reviewed all females who had received

24 Gy cranial radiotherapy as part of treatment for a hematologic

malignancy to determine the frequency of the problem.

MATERIALS AND METHODS

All female patients treated for a hematologic malignancy at the

Sydney Children’s Hospital prior to 1982 were reviewed. During

this period patients received chemotherapy and 24–25 Gy

prophylactic cranial irradiation delivered by megavoltage external

beam apparatus (Supplemental Table I). Sixty of 110 patients aged

between 2 and 16 years at diagnosis survivedbeyond18 years of age.

Sixteen women have been lost to follow-up. Forty-four women

attend the Long-Term Follow-Up Clinic for childhood cancer

survivors. All of these women were contacted to identify those who

had produced offspring. The medical records were reviewed to

obtain information regarding past treatment, current medical status

with particular reference to the hypothalamic–pituitary axis,

including details of menstrual cycle, problems with conception,

pregnancy, and delivery. Information regarding breast development

during puberty and pregnancy, production of colostrum and breast

milk after deliverywere obtained from the patients and confirmedby

attending obstetric staff and lactation nurses.

RESULTS

Twelve of the 44 women survivors produced offspring: 3 have

1 child, 7 have 2 children each and 2 have 3 children each. Eleven

were treated for acute lymphoblastic leukemia (ALL) and one for

acute non-lymphoblastic leukemia (ANLL) (Supplemental

Table II). The median age at diagnosis was 5.25 years (range 2.6–

13.5 years).With the exception of patient four, who had commenced

puberty but had not started menstruating, the remainder were

prepubertal when treated. All remain in remission with a median

follow-up of 28 years (range 25–37 years). All 12 women have

completed secondary education (high school) and 5 have tertiary

qualifications (university).

In 75% (9/12) of the women, the final adult height was >1

standard deviation (SD) lower than their height SD at diagnosis with

final heights>2 SDbelow themean in four (Supplemental Table II).

Three patients had documented endocrine problems prior to

We conducted a retrospective review of the lactation experienceof female survivors who received 24 Gy cranial radiotherapy as CNSprophylaxis for acute lymphoblastic leukemia in childhood prior to1982 and who attend the Long-Term Follow-Up Clinic at SydneyChildren’s Hospital, Randwick, Australia. Median time sincediagnosis is 28 years (range 25–37 years). Twelve have produced

offspring. Ten report minimal or no breast changes during pregnancyand failure to lactate postpartum. All patients remain in remission.These data suggest a high risk of failure of lactation in women treatedduring childhood with 24 Gy cranial irradiation. Awareness of thispossibility can assist in counseling. Pediatr Blood Cancer2008;50:721–722. � 2007 Wiley-Liss, Inc.

Key words: childhood cancer survivors; cranial irradiation; lactation; leukemia; postpartum

——————This article contains Supplementary Material available at http://

www.interscience.wiley.com/jpages/1545-5009/suppmat.

1Centre for Children’s Cancer and Blood Disorders, Sydney Children’s

Hospital, Randwick, NSW, Australia; 2Department of Endocrinology,

Sydney Children’s Hospital, Randwick, NSW, Australia; 3Prince of

Wales Hospital, Randwick, NSW, Australia; 4School of Women’s and

Children’s Health University of New South Wales, Sydney, Australia

*Correspondence to: Karen Johnston, Centre for Children’s Cancer

and Blood Disorders, Sydney Children’s Hospital, High Street,

Randwick, NSW 2031, Australia.

E-mail: karen.johnston@sesiahs.health.nsw.gov.au

Received 28 July 2006; Accepted 22 May 2007

� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21291

Brief Reports 721

pregnancy; one received treatment for hypothyroidism, one for

thyrotoxicosis, and one received growth hormone replacement for

documented growth hormone deficiency (peak GH <10 mU/L).

Menstrual patterns before pregnancy were regular in all. All women

were clinically and biochemically euthyroid. All had tanner stage

V secondary sexual characteristics and all described normal breast

development during puberty. Two women were diagnosed with

polycystic ovarian syndrome (PCOS).

All women became pregnant without assisted reproductive

technology and the pregnancies went to term. One woman was

induced with syntocinon and the remainder went into spontaneous

labor. One required forceps assistance and one had an elective

caesarian section for breech twins. None of the women had retained

placental products. Patient 3 had a postpartum hemorrhage not

requiring a transfusion. All offspring were healthy with no neonatal

or congenital problems.

Ten women reported an inability to breast-feed postpartum.

Three women reported small amounts of colostrum postpartum. All

10 had minimal or no breast changes during pregnancy and none

produced breast milk. Attempts to stimulate milk production using

metoclopramide were not successful in two women in whom this

was tried. Women who delivered more than one child had identical

experiences with each further pregnancy, with the exception of

patient six who had a small amount of colostrum with the second

pregnancy.

All women were aware that infertility might be a problem but

were unaware of the possibility of lactation difficulties and

expressed disappointment at their inability to breast-feed. Three

women reported negative experiences in the maternity units due to

reaction of staff to their inability to establish breast-feeding. One

womanwho participated in the early discharge program represented

to the emergency department at day 3 postpartum with a newborn

who was diagnosed with 10% dehydration due to lactation failure.

The 2 women who did lactate did not have any identifiable

distinguishing features from the 10 who did not lactate. They

experienced normal breast changes during pregnancy, produced

colostrum, had normal amounts of milk and breast fed normally.

DISCUSSION

These data show a failure to lactate postpartum which has not

been previously reported in long-term survivors of childhood cancer

treated with chemotherapy and 24–25 Gy prophylactic cranial

irradiation. Eighty-five percent (10 of 12) of women in our series

failed to lactate. All 10 women reported minimal or no breast

changes during pregnancy or following delivery.While 3/10women

did report the presence of colostrum, all 10 failed to produce milk.

The incidence in the general population of failure to lactate is

reported to be between 2% and 15% [4]. Nowoman in our series had

risk factors cited of cosmetic breast surgery, inverted nipples, and

treatment for breast malignancy. There are reports of lactation

failure associated with PCOS [5]. Lactation failure is also reported

in association with retained placenta, postpartum hemorrhage, and

postpartumpituitary necrosis [6]. Only onewoman (patient 3) in our

series reported an insignificant postpartum bleed. Nothing from the

clinical notes and subsequent consultations suggested that anxiety in

the patients could have been a contributing factor.

Growth hormone is known to play a role in milk production and

mammary development [7]. In a placebo-controlled, double-blind

trial Gunn et al. [8] demonstrated increased milk production with

human growth hormone (hGH) supplementation in womenwho had

insufficient milk supply following the delivery of preterm infants.

Wiren et al. [9] reported failure of lactation in 5/8 growth hormone

deficient women after assisted reproduction with growth hormone

replacement during the first and second trimester only. As many as

50% of children who receive 24 Gy prophylactic cranial irradiation

for ALL develop growth hormone deficiency [2].

All patients in our cohort proceeded through puberty without

problem, established regular menstrual cycles and had no problems

conceiving, suggesting a relatively intact hypothalamic–pituitary–

ovarian axis. Hormonal profiles during pregnancy were not

performed in this retrospective review. Formal GH testing was only

performed in 1 of the 10 women, who was found to be GH deficient

(peak GH<10 mU/L). A significant fall (�1 SD) in height SD from

diagnosis to final height in over three quarters of the women in the

absence of other health problems suggests impaired GH secretion in

at least some of these women. Five women who were treated for

ALL with 18 Gy cranial radiation on a later study at our institution,

have given birth. All five had normal breast development during

pregnancy, normal amounts of colostrum, and lactated normally.

These data suggest a high risk of failure to lactate in women

treated during childhood with 24 Gy cranial irradiation. Lack of

breast development during pregnancy provides a forewarning of the

likelihood of failure to lactate. The negative experiences of these

women inmaternity units highlights the need to informwomenwho

have received 24Gy cranial irradiation of the potential for decreased

or absent milk production and to alert obstetricians and maternity

staff in order to allow a supportive approach to these women. We

postulate that GH insufficiency may contribute to the failure to

lactate. The relationship between pituitary hormones and failure of

lactation requires evaluation.

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Pediatr Blood Cancer DOI 10.1002/pbc

722 Brief Reports