Bereavement in adult life

Full text

Education and debate
Personal paper
Risk of diabetic nephropathy in potential living related
kidney donors
D Simmons, M Searle
Diabetic nephropathy is the leading cause of end stage
renal failure in New Zealand.1Cadaveric organs are in
short supply here, as elsewhere, and we need to
consider living related donation. Kidneys from living
related donors also provide a better graft and
improved survival of transplant patients. However,
donors from ethnic groups who have a high incidence
of end stage renal failure because of diabetes and
glomerulonephritis are also at increased risk of devel-
oping diabetes.2This risk is compounded by environ-
mental factors such as obesity. In New Zealand the
ethics of living related donation within the diabetic
family are being questioned.
Renal transplantation is preferred to dialysis in
diabetic patients who are fit enough for surgery. It is
associated with an improved quality of life, lower
morbidity and mortality, reduced long term costs, and
greater incremental benefit in diabetic patients com-
pared with patients without diabetes.3The main reason
for not transplanting kidneys into suitable candidates is
the low availability of compatible organs for transplanta-
tion. Some ethnic groups object to donating body parts
after death for cultural and spiritual reasons. The result-
ing underrepresentation of these ethnic groups in the
donor pool further reduces the likelihood that patients
with end stage renal failure from these ethnic groups will
receive an organ. Organ donation from living relatives is
therefore particularly encouraged in these groups.
Diabetes and the development of nephropathy
once diabetes has occurred are familial and cluster in
families.45It is therefore important to be able to advise
a potential donor of his or her personal risk of
developing end stage renal failure.
Risk factors for diabetes
Apart from a few rare cases in patients with impaired
glucose tolerance, development of clinical diabetes
precedes the onset of diabetic nephropathy. Undiag-
nosed diabetes may already be present, but if it is not
there are four major predictors of future diabetes
—
ethnic group, previous gestational diabetes, a high titre
of islet cell antibody (for insulin dependent diabetes
mellitus), and impaired glucose tolerance (table). The
underlying prevalence of diabetes is a major determi-
nant of risk for both impaired glucose tolerance and
gestational diabetes. In those aged 30-64 years, the
prevalence of non-insulin dependent diabetes varies
from 1% to 50% between ethnic groups.6The
prevalence also varies within the same ethnic group in
different geographical locations.6The risk of diabetes
in terms of familial relationship and type of diabetes in
different ethnic groups is shown in the table.
Prospective studies have shown that other compo-
nents of the metabolic syndrome are risk factors for
developing diabetes. In the eight year follow up of the
middle aged cohort of the San Antonio heart study,
34% of hypertensive people and 30% of overweight
subjects went on to develop non-insulin dependent
diabetes mellitus or impaired glucose tolerance
(compared with 15% of people without hypertension
and 10% of those with a normal weight).7Other risk
factors for the development of non-insulin dependent
diabetes include the degree of fasting hyperglycaemia
and hyperinsulinaemia after an oral glucose load.89
Among Pima Indians, a family history of diabetic
nephropathy is itself a risk factor for the development
of diabetes.10 The risk of developing non-insulin
dependent diabetes mellitus is three times greater
where both parents have diabetes and one has renal
disease than where both parents are diabetic but
Summary points
Living related kidney donors may have a
pre-existing increased risk of diabetes and
diabetic nephropathy
Undiagnosed diabetes and impaired glucose
tolerance in potential living related kidney donors
need to be excluded by a glucose tolerance test
Clinical risk factors for diabetes and diabetic
nephropathy need to be considered before kidney
donation
The underlying prevalence of diabetes in a given
ethnic group is particularly important
Balancing the immediate benefit of kidney
transplantation to the recipient with the possible
long term harm to the donor may be difficult
University of
Auckland,
Middlemore
Hospital, Private
Bag93311,
Auckland 6,
New Zealand
D Simmons,
senior lecturer in
medicine
M Searle,
renal physician
Correspondence to:
Dr Simmons
BMJ 1998;316:846–8
846 BMJ VOLUME 316 14 MARCH 1998

neither has kidney disease. If this applies to other eth-
nic groups, the people who are most likely to be asked
to give kidneys may be those with the highest chance of
developing diabetes (and possibly nephropathy).
Risk factors for development of
nephropathy
Only a proportion of people with diabetes progress to
nephropathy and then to end stage renal failure. Many
of the modifiable risk factors for diabetic nephropathy
depend upon the quality of health care and self care (for
example, blood pressure, glycaemia, smoking, and obes-
ity).11 Ethnic and familial factors are also important for
determining those with diabetes who will probably
develop nephropathy. While few (around 0.4%) Europe-
ans with non-insulin dependent diabetes mellitus
develop end stage renal failure,12 overt nephropathy
occurs in up to 50% of Pima Indians who have had non-
insulin dependent diabetes mellitus for more than 20
years.13 Ethnic groups at high risk of diabetes related to
end stage renal failure often have a relatively high preva-
lence of microalbuminuria but are not overtly diabetic,
and this should be considered by any potential donor. A
parental history of hypertension is associated with an
increased the risk of microalbuminuria.14
The findings of the study by Seaquist et al are of
particular concern.5The development of nephropathy
and end stage renal failure was compared in the
diabetic siblings of insulin dependent diabetics with
and without end stage renal failure.5Although 17% of
siblings of subjects without nephropathy developed
albuminuria, most of the siblings of patients with
diabetic nephropathy developed either albuminuria
(41%) or end stage renal failure (41%).
Does having only one kidney increase the risk of
nephropathy?
The final and most relevant question is whether having
only one kidney increases the risk of nephropathy
should diabetes develop. The few animal studies
undertaken suggest that the resulting hyperfiltration is
associated with increased renal morbidity.15 16 Clinical
studies are few. Two follow up studies of patients with
either unilateral agenesis or uninephrectomy included
eight patients with diabetes, two of whom experienced
progression of renal disease.17 18 In two studies, one of
363 patients with non-insulin dependent diabetes mel-
litus19 and the other of over 5000 patients with both
non-insulin dependent and insulin dependent diabetes
mellitus,20 the proportions of albuminuric patients with
reduced renal mass were 8% and 3% respectively. None
of the patients without albuminuria was known to have
a reduced renal mass (although these subjects were not
as extensively investigated as the patients with
albuminuria). Unilateral renal agenesis occurs in
approximately 1/1000 births.21 Studies are urgently
needed to investigate this issue further.
Assessment of the potential living related
donor
The clinical information that needs to be collected for
assessment of the potential living related donor is
shown in the box. Clearly, the risk of developing
diabetic nephropathy in relatives of those with insulin
dependent diabetes mellitus complicated by end stage
renal failure incorporates a low risk of developing
diabetes with a high risk of developing nephropathy
should diabetes occur. The risk of diabetic neph-
ropathy in relatives of people with end stage renal fail-
ure caused by non-insulin dependent diabetes mellitus
is especially high in those with impaired glucose toler-
ance and previous gestational diabetes. Some ethnic
groups have a very high risk of developing non-insulin
dependent diabetes mellitus, but a variable risk of
developing end stage renal failure, depending on
ethnic group. Other risk factors, such as obesity and
hypertension, may be cumulative. The final calculation
will be an assessment of clinical risk rather than of a
true actuarial risk.
Conclusion
There may be an increased risk of developing
nephropathy after nephrectomy, but this has not been
quantified. The issues need to be carefully discussed
Risk factors for developing diabetes in various ethnic groups
Risk factor Ethnic group (risk) Rate of progression
Trial
(reference no)
Non-insulin dependent diabetes (NIDDM)
Ethnic group Pima Indians (very high) 64% by age 94 years 22
UK South Asians (high) 30% by age 70 years 23
US whites (medium) 21% by age 89 years 22
Gestational diabetes South Asians (high) 62% after 6 years 24
Europeans (low) 76% after 27 years 25
Impaired glucose tolerance Europeans 1.5% a year 26
Mexican Americans 7.3% a year 26
Monozygous twin with NIDDM Finns 34% over 30 years 27
Dizygous twin with NIDDM Finns 16% over 30 years 27
Offspring with NIDDM US whites 16% over 20 years 28
Insulin dependent diabetes (IDDM)
Relative of patient with IDDM US whites 47% after 7 years 29
Monozygous twin with IDDM Finns 23% over 30 years 27
Dizygous twin with IDDM Finns 5% over 30 years 27
Sibling with IDDM Danes 10% over 60 years 30
Offspring with IDDM Danes 6% over 34 years 30
Benefit to the recipient must be balanced against possible long term harm to the living related
donor
CLAUDIA PAGLIARANI
Education and debate
847BMJ VOLUME 316 14 MARCH 1998

with potential living donors, and clinicians need to bal-
ance the immediate benefit to the intended recipient
with the possible harm, some time in the future, to the
potential donor.
1 Disney APS, ed. ANZDATA report 1994. Adelaide: Australia and New Zea-
land Dialysis and Transplant Registry, 1994.
2 Simmons D. Epidemiology of diabetes and its complications in New Zea-
land. Diabetic Med 1996;13:371-5.
3 Disney APS.ANZDATA report 1993. Adelaide: Australia and New Zealand
Dialysis and Transplant Registry, 1993.
4 Simmons D, Gatland BA, Leakehe L, Fleming C. Frequency ofdiabetes in
family members of diabetic probands. J Intern Med 1995;237:315-21.
5 Seaquist ER, Goek FC, Rich S. Barbosa J. Familial clustering of diabetic
kidney disease: evidence for genetic susceptibility to diabetic nephropa-
thy.N Engl J Med 1989;320:1161-5.
6 McCarty D, Zimmet P. Diabetes 1994 to 2010: global estimates and pro-
jections. Melbourne: International Diabetes Institute, 1994:46.
7 Morales PA, Mitchell BD, Valdez RA, Hazuda HP, Stern MP, Haffner SM.
Incidence of NIDDM and impaired glucose tolerance in hypertensive
subjects: the San Antonio heart study. Diabetes 1993;42:154-61.
8 Nagi DK, Knowler WC, Charles MA, Liu QZ, Hanson RL, McCance DR,
et al. Early and late insulin response as predictors of NIDDM in Pima
Indians with impaired glucose tolerance. Diabetologia 1995;38:187-92.
9 Zimmet PZ, Collins VR, Dowse GK, Knight LT. Hyperinsulinaemia in
youth is a predictor of type 2 (non-insulin-dependent) diabetes mellitus.
Diabetologia 1992;35:534-41.
10 McCance DR,Hanson RL, Pettitt DJ, JacobssonLTH, Bennett PH, Bishop
DT, et al. Diabetic nephropathy: a risk factor for diabetes mellitus in the
offspring. Diabetologia 1995;38:221-6.
11 Klein R, Klein B, Moss SE. Incidence of gross proteinuria in older onset
diabetes: A population perspective. Diabetes 1993;42:381-9.
12 Fabre J, Balant LP, Dayer PG, Fox HM, Vernet AT. The kidney in maturity-
onset diabetes mellitus: a clinical study of 510 patients. Kidney Int
1982;21:730-8.
13 Kunzelman CL, Knowler WC, Pettitt DJ, Bennett PH. Incidence of
proteinuria in type 2 diabetes mellitus in Pima Indians. Kidney Int
1989;35:681-7.
14 Krolewski AS, Canessa M, Warram JH, Laffel LMB, Christlieb AR,
Knowler WC, et al. Predisposition to hypertension and susceptibility to
renal disease in insulin dependent diabetes mellitus. N Engl J Med
1988;318:140-5.
15 Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal
hypertension in the initiation and progression of diabetic and other
nephropathies. Am J Med 1982;72:375-80.
16 Steffes MW, Brown SM, Mauer SM. Diabetic glomerulopathy following
unilateral nephrectomy in the rat. Diabetes 1978;27:35-41.
17 Grossman HB, Sommerfield D, Konnak JW, Bromberg J. Long term
assessment of renal function following nephrectomy for stage I renal car-
cinoma. Br J Urol 1994;74:279-82.
18 Schmitz A, Christensen CK, Christensen T, Solling K. No microalbumin-
uria or other adverse effects of long standing hyperfiltration in humans
with one kidney. Am J Kidney Dis 1989;13:131-6.
19 Nielson FS, Gall M, Parving HH. Acquired oligonephropathy and
diabetic nephropathy. Am J Kidney Dis 1995;26:893-903.
20 Sampson MJ, Drury PL. Development of nephropathy in diabetic
patients with a single kidney. Diabetic Med 1990;7:258-60.
21 Bernstein J. The morphogenesis of renal parenchymal maldevelopment
(renal dysplasia). Pediatr Clin North Am 1971;18:395-400.
22 Meneilly GS, Tessier D. Diabetes in the elderly. Diabetic Med 1995;12:
949-60.
23 Simmons D, Williams DRR. Diabetes in the elderly: an under-diagnosed
condition. Diabetic Med 1993;10:264-6.
24 Ali Z, Alexis SD. Occurrence of diabetes mellitus after gestational diabetes
mellitus in Trinidad. Diabetes Care 1990;13:527-9.
25 O’Sullivan JB. Subsequent morbidity among gestational diabetic women.
In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy
and the newborn. Edinburgh: Churchill Livingstone, 1984:174-80.
26 Harris MI. Impaired glucose tolerance-prevalence and conversion to
NIDDM. Diabetic Med 1996;13(suppl 2):S9-11.
27 Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Erikk-
son J, et al. Concordance for type 1 (insulin dependent) and type 2 (non-
insulin dependent) diabetes mellitus in a population based cohort of
twins in Finland. Diabetologia 1992;36:1060-7.
28 Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glu-
cose removal rate and hyperinsulinaemia precede the development of
type II diabetes in the offspring of diabetic parents. Ann Intern Med
1990;113:909-15.
29 Riley WJ, MacLaren NK, Krischer J, Spillar RP, Silverstein JH, Schak DA,
et al. A prospective study of the development of diabetes in relatives of
patients with insulin dependent diabetes. N Engl J Med 1990;323:1167-72.
30 Lorenzon T, Pociot F, Hougaard P, Nerup J. Long term risk of IDDM in
first-degree relatives of patients with IDDM. Diabetologia 1994;37:321-7.
(Accepted 29 July 1997)
A difficult case
Management of metastatic melanoma during pregnancy
S R D Johnston, K Broadley, G Henson, C Fisher, M Henk, M E Gore
About 35% of women with melanoma are of child
bearing age, and thecoexistence of melanoma and preg-
nancy is increasing.1Many doctors recommend that
women wait two to three years after successful
treatment for melanoma before becoming pregnant as
most recurrences occur during this time. This advice is
inadequate. Doctors need to inform these women
about the considerable problems that may arise if
relapse occurs while they are pregnant. We present our
recent experience of this difficult situation: malignant
melanoma within the maternal intervillous space,
invading into the core of the villus.Immunostaining for
S100 protein and HMB45 was positive, and staining
for human chorionic gonadotropin was negative in the
tumour cells.
Case report
A 41 year old woman presented with left axillary
lymphadenopathy. A superficial spreading melanoma
had been removed from her back two years previously.
Radical lymph node dissection was performed. All
nodes contained metastatic melanoma that stained
positive for S100 and HMB45. There was evidence of
extranodal tumour towards the deep resection margin,
but her chest radiograph and liver ultrasonography
Assessment of the risk of diabetes and
subsequent nephropathy in potential living
related donors
Risk of diabetes
•Age
•Ethnic group
•History of gestational diabetes mellitus
•Impaired glucose tolerance
•Family history of diabetes
•Body mass index
•Two hour oral glucose test to exclude diabetes and
impaired glucose tolerance
•Fasting and two hour insulin measurements
•Islet cell antibody status
•Risk of nephropathy should diabetes develop
Risk of nephropathy should diabetes develop
•History of renal disease or hypertension
•Family history of diabetic nephropathy or
hypertension
•Smoking history
•Blood pressure
•Microalbuminuria
Education and debate
Melanoma Unit,
Royal Marsden
Hospital, London
SW3 6JJ
SRDJohnston,
consultant medical
oncologist
M Henk,
consultant clinical
oncologist
M E Gore,
head of skin and
melanoma unit
continued over
BMJ 1998;316:848–51
848 BMJ VOLUME 316 14 MARCH 1998

were both normal. The woman had a professional
career and had never been pregnant.
The patient presented four months later with a
short history of low back pain. Clinical examination
showed no abnormalities and her neurological signs
were normal. However, plain radiographs of the
lumbar spine and computed tomography showed that
the 8th thoracic vertebra had collapsed, associated with
a soft tissue mass consistent with metastatic melanoma.
The spinal cord was not affected.
The patient reported that she was 12 weeks
pregnant. Termination was discussed and the patient
was counselled, but she and her partner were
determined to continue with the pregnancy. Since she
had no neurological signs of cord compression and
her pain was intense, she was given a single palliative
dose of radiotherapy to the affected vertebra (8 Gy to a
depth of 5 cm). The scatter dose of radiation received
by the uterine fundus was calculated to be 0.0005 Gy,
which represents a small increased risk of fetal malfor-
mation and leukaemia. The use of analgesic drugs in
pregnancy was discussed, but she was reluctant to take
these.
The patient’s pain improved initially, but eight
weeks later she developed bilateral leg weakness and
difficulty in walking. Neurological examination showed
that she had grade 3-4 weakness in her legs and loss of
both ankle jerk reflexes. Magnetic resonance imaging
confirmed that her spinal cord was being compressed
by tumour at D8/9, and that there were several tumour
deposits at other levels. She underwent a decompres-
sive laminectomy and pediculotomy. Histological
examination of the tumour confirmed metastatic
melanoma. During her recovery several skin nodules
developed and splenic metastases were noted on ultra-
sonography. Fetal growth and development seemed
normal at 25 weeks’ gestation. The clinical problem
was how to manage progressive systemic metastases in
a woman expecting her first child.
1 Reintgen OS, McCarthy K, Vollmer R. Malignant melanoma and
pregnancy. Cancer 1985;55:1340-4.
Commentary: Pregnancy should not have affected treatment for
melanoma
Robert Hammond
The occurrence of malignant disease in pregnancy
turns what is usually a happy experience into a poten-
tial nightmare. In no situation in medical practice is the
concept of informed choice more important when con-
sidering management options. As in all problems
related to pregnancy, there are two individuals to con-
sider and it is imperative that the woman and her part-
ner are helped to prioritise their objectives on the basis
of information given in a caring and sympathetic
manner.
The issues
Maternal survival is usually of paramount importance,
and doctors would normally wish to offer the same
treatment they would give to a woman who is not preg-
nant. However, other factors must be considered, such as
the effect of pregnancy on the disease process and vice
versa. The impact of treatment on the fetus must also be
borne in mind as this may result in fetal demise,
congenital abnormalities, or failure of development in
utero. In addition, there may be long term risk to the
fetus after birth if it is affected by metastatic tumour.
The gestational age at which the problem arises is
important, not just from the point of view of risks of
treatment but because the doctor may wish to delay
treatment until fetal viability is reached
—
so long as this
does not compromise maternal survival. There may be
circumstances in which the couple would wish to place
fetal survival above maternal outcome
—
particularly if
they have moral objections to termination or if the
prognosis for the mother is so poor that further
treatment is unlikely to influence the course of the
disease.
Fortunately, malignant disease in pregnancy is
uncommon, but this rarity may cause problems when it
does arise because doctors may not have reliable infor-
mation about some of the issues. In this case, the
mother presented with metastatic malignant
melanoma at 12 weeks of pregnancy. Sutherland et al
reported that malignant melanoma was affected by
hormones, and was stimulated by increasing oestrogen
and progesterone concentrations in pregnancy.1How-
ever, MacKie et al did not find any adverse effect of
pregnancy on the disease.2On balance, there does not
seem to be sufficient evidence to recommend termina-
tion of pregnancy in these cases.
The mother’s median survival with treatment was
about six months, and the time until fetal viability
would be reached was between four and five months.
Haematoxylin and eosin stained section of placenta showing deposit of malignant melanoma
within the maternal intervillous space, invading into core of the villus. Immunostaining for
S100 protein and HMB45 was positive, and human chhorionic gonadotropin negative in the
tumour cells
Education and debate
University Hospital,
Queen’s Medical
Centre, Nottingham
NG7 2UH
Robert Hammond,
consultant
obstetrician and
gynaecologist
Palliative Care Unit,
Royal Marsden
Hospital, London
SW3 6JJ
K Broadley,
consultant in
palliative medicine
Department of
Pathology, Royal
Marsden Hospital
C Fisher,
consultant
histopathologist
Department of
Obstetrics and
Gynaecology,
Whittington
Hospital, London
N19 5NF
G Henson,
consultant
obstetrician
Correspondence to:
Dr Johnston
stephen@icr.ac.uk
849BMJ VOLUME 316 14 MARCH 1998

The risks to the fetus of thoracic radiotherapy and
general anaesthesia for surgical treatment were small,
and data suggested that it would not be affected
adversely by the preferred drug. Indeed, it is possible
that this treatment would reduce the risk of the fetus
being affected by metastatic disease.
Recommendation
In this case information on both parents’ views on ter-
mination of pregnancy, as well as the father’s feelings
about the probability that he would be a single parent
from early in the child’s life, is not reported. Assuming
that the parents found this scenario acceptable, and
they were prepared to take the small but statistically
significant risk that the fetus might develop metastatic
disease after birth, I would not have recommended ter-
mination of pregnancy to them. I would have treated
the patient as I would a woman who was not pregnant
in the hope that she would survive for long enough to
experience some joy from her baby.
1 Sutherland CM, Wittliff J, Mabie WC. The effect of pregnancy on
hormone levels and receptors in malignant melanoma. J Surg Oncol
1983;22:191-2.
2 MacKie RM, Buf alino R, Morabito A, Sutherland C, Cascinelli N. Lack of
effect of pregnancy on outcome of melanoma. Lancet 1991;337:653-5.
Commentary: Self interest is not the sole legitimate basis for
making decisions
Charles Weijer
Treating cancer in pregnancy presents the patient and
doctor with difficult medical, ethical, and, at times, even
legal questions. Should the pregnancy be terminated?
How best should the cancer be treated? How should
potential benefits of treatment to the mother be
balanced against risks to the fetus?
Texts on bioethics help little
Little guidance is found in publications on bioethics.
Discussion to date has focused on cases in which a
mother has refused a potentially life saving treatment
for the fetus, for example, caesarian section.1The best
known case is that of Angela Carter, a terminally ill
cancer patient who was 26.5 weeks pregnant.2Close to
death, Carter refused a caesarian section and
demanded that comfort measures be continued, even if
the delay in surgery resulted in the death of her fetus.
The hospital consulted the court, which ordered that a
caesarian section be performed and, unfortunately,
neither Carter nor her child survived. Review by a
higher court found that the court erred in its decision:
“We hold that in virtually all cases the question of what
is to be done is to be decided by the patient
—
the preg-
nant woman
—
on behalf of herself and the fetus. If the
patient is incompetent . . . her decision must be
ascertained through . .. substituted judgement.3”
The case at hand is the mirror image of the Carter
case. We are told that the patient determined to
continue with the pregnancy. Her actions bespeak a
willingness to sacrifice her own comfort, and perhaps
her chances of survival, to protect her unborn child.
Even when she developed bone metastases she was
reluctant to use analgesics. Continuing the pregnancy
precluded treatment options such as high dose or
multiagent chemotherapy, which is associated with
higher response rates than chemotherapy with a single
agent.4
Selfless decisions in others make us
uncomfortable
Decisions in which one person sacrifices her own well-
being for the sake of a loved one, a fetus in this case,
make us uncomfortable. The temptation is to regard
these decisions as not voluntary, as the result of “inter-
nal coercion.”5This temptation ought to be resisted.
The problem is not with the decision as such but rather
with the prevalent view of human agency in bioethics
that proceeds as if self interest is the only legitimate
basis for decision making. The fact is that people make
sacrifices for loved ones all the time:parents get by with
less so their children may go to a better school, and
spouses turn down lucrative job offers to remain with
their mate. Our interests, and those of the patient in
this case, therefore comprise both self interest and
interest with regard to others. The patient’s decision to
proceed with the pregnancy is thus voluntary and
valid.
A muted victory
Whatever moral discomfort we might feel in such cases
in general is alleviated by the particular circumstances
of this case. There is no convincing evidence that
therapeutic abortion improves the cure rate of
melanoma in pregnancy.6Dacarbazine is the most
effective single agent regimen, and can be safely given
in the second and third trimesters. Furthermore, while
high dose and multiagent regimens are promising,
none have yet been proved better than dacarbazine
alone in a prospective randomised controlled trial.4
Finally, no currently available regimen is likely to pro-
vide cure or even long term survival. In this context,
salvaging a healthy child seems like a victory, albeit a
muted one, for the mother and her doctors.
1 Mahowald MB. Women and children in health care:an unequal major ity. New
York: Oxford University Press, 1993:131-47.
2 Annas GJ. Foreclosing the use of force: AC reversed. Hastings Center
Report 1990;20:27-9.
3In re: AC. District of Columbia Court of Appeal, April 26, 1990.
4 Houghton AN, Meyers ML, Chapman PB. Medical treatment of
metastatic melanoma. SurgClinNAm1996;76:1343-4.
5 Siegler M, Lantos JD. Commentary: ethical justification for living donor
transplantation. Cambridge Q Healthcare Ethics 1992;1:320-5.
6 Kjems E, Krag C. Melanoma and pregnancy. Acta Oncologica
1993;32:371-8.
Education and debate
Mount Sinai
Hospital, Toronto,
Ontario M5G 1X5,
Canada
Charles Weijer,
bioethicist
cweijer@mtsinai.
on.ca
850 BMJ VOLUME 316 14 MARCH 1998

Commentary: Management of the patient
S R D Johnston, K Broadley, G Henson, C Fisher, M Henk, M E Gore
Because of the progressive metastases, systemic
chemotherapy was started with single agent dacar-
bazine (250 mg/m2given intravenously for three days
every 21 days). After two courses, which were tolerated
well, metastatic spread halted. However, at 31 weeks’
gestation the patient’s back pain increased and was not
relieved by opioid analgesics. She became confused
and was hypercalcaemic (calcium 3.04 mmol/l). An
elective caesarian section was performed and a live girl
(1.22 kg) was delivered. Unfortunately, the mother’s
condition deteriorated and she died four days later.
Histological examination of the placenta showed
evidence of melanoma deposits, which again stained
positive for S100 and HMB45. Metastases seemed to
breach the single layer of syncytial cells and extend into
the chorionic villous space in places. One year later the
infant remains well and has no signs of metastatic
melanoma.
In retrospect—ethical and clinical issues
Whether pregnancy influences the natural history of
malignant melanoma has been debated. Primary
melanomas in pregnant women were thicker than
melanomas in matched control women who were not
pregnant, but whether this was because of late diagnosis
or hormonal or growth factor stimulation during
pregnancy is unclear.1When corrected for tumour
thickness, no adverse effect of pregnancy on overall sur-
vival in women of childbearing age treated for stage I
primary cutaneous disease has been shown.1However,
patients with metastatic melanoma confined to the
regional lymph nodes (stage II) who have disease recur-
rence or who need treatment during pregnancy may
have a shorter survival than either nulliparous or parous
women with no disease recurrence during pregnancy.2
Difficult ethical and clinical issues arise. Firstly, the
question of terminating the pregnancy may be raised in
light of a median survival of only six months in these
patients. The expectant mother may become seriously ill
before term, putting the life of the fetus at risk, or she
may die soon after delivery, leaving a child without a
mother. Secondly, cancer treatment may affect the fetus.
In our patient the risk of radiotherapy was considered
low. In addition, dacarbazine is the most active
chemotherapeutic agent in melanoma and can be given
safely during the second and third trimesters. In Hodg-
kin’s disease, where dacarbazine was used as part of the
regimen, no long term effects were seen in children fol-
lowed for up to 19 years.3Finally, the risk of transplacen-
tal spread of melanoma to the fetus has been perceived
to be low up to now.4In a recent report of 16 cases of
placental metastases, however, 25% of the infants devel-
oped metastatic melanoma (mainly skin and liver) at 1-8
months of age, with a mortality of 100%.5Maternal fac-
tors associated with an unfavourable outcome for the
infant were: age less than 30 years, nodal metastases
before pregnancy, primiparity, onset of disease more
than three years before pregnancy, more than three sites
of metastases before the third trimester, and maternal
death within one month of birth.
All these issues need to be considered when coun-
selling women who develop regional (stage III) or
metastatic (stage IV) recurrence of malignant
melanoma during the early stages of pregnancy, espe-
cially in view of the difficult clinical and ethical
decisions which may need to be taken if they develop
progressive disease.
1 MacKie RM, Buf alino R, Morabito A, Sutherland C, Cascinelli N. Lack of
effect of pregnancy on outcome of melanoma. Lancet 1991;337:653-5.
2 Shiu MH, Schottenfeld D, Maclean B, Fortner JG. Adverse effect of preg-
nancy on melanoma. Cancer 1976;37:181-7.
3 Aviles A, Diaz-Maqueo JC, Talavera A, Guzman R, Garcia EL. Longterm
follow-up of 43 children exposed to chemotherapy in utero. Am J Hematol
1991;36:243-8.
4 Ross MI. Melanoma and pregnancy: prognostic and therapeutic consid-
erations. Cancer Bull 1994;46:412-7.
5 Anderson JF, Kent S, Machin GA. Maternal malignant melanoma with
placental metastases: a case report with literature review. Pediatric Pathol
1989;9:35-42.
Fifty years ago
The new NHS: Statement by the B.M.A. Council to every member of the medical profession
We are now on the eve of a decision of the profoundest
importance to the public and to the medical profession. For years
the British Medical Association has been working for the
extension, improvement,and consolidation of the country’s health
services, publishing its constructive proposals in a series of reports.
It is now confronted with an Act of Parliament directed to the
establishment of a comprehensive health service but embodying
forms of organisation which are in conflict with the principles of
the profession. The conflict is based on the profession’s conviction
that the Act leads unmistakably towards a whole-time State
medical service, and that such a service would be harmful to
medicine. This conviction is strengthened by the knowledge that
the Act of 1946 is in the hands of those who profess as their
objective a whole-time salaried State medical service.
We have sought a number of changes, some of principle, some
of detail. The answer has been a refusal to modify one word of the
Act. The Council recognises that some points of the profession’s
case make a stronger appeal to some members of the profession
than to others. But it firmly believes that,viewed as a whole, the
Act in its present form is in conflict with the best interests of the
community and the profession.
After years of discussion the time has come for the profession
to translate words into actions. The issue is one not of money or
compensation but of the intellectual freedom and integrity of a
great profession. The Council of the Association will abide by the
result of the plebiscite, as defined on the plebiscite form. It would
be lacking in its duty, however, if it did not make abundantly clear
to every member of the profession its carefully considered and
determined view that the profession should not take service
under the Act in its present form. (BMA statement, 31 January
1948, p 207. See also editorial by Gordon Macpherson, 3 January
1998, p 6.)
Education and debate
Melanoma Unit,
Royal Marsden
Hospital, London
SW3 6JJ
SRDJohnston,
consultant medical
oncologist
M Henk,
consultant clinical
oncologist
M E Gore,
head of skin and
melanoma unit
Palliative Care Unit,
Royal Marsden
Hospital
K Broadley,
consultant in
palliative medicine
Department of
Pathology, Royal
Marsden Hospital
C Fisher,
consultant
histopathologist
Department of
Obstetrics and
Gynaecology,
Whittington
Hospital, London
N19 5NF
G Henson,
consultant
obstetrician
851BMJ VOLUME 316 14 MARCH 1998

The new genetics
Genetic testing and public policy
Neil A Holtzman, David Shapiro
The increasing rate of discovery of genes related to
disease and the development of tests for them has
fostered the idea that healthy people will be able to
prevent future disease by undergoing genetic testing.
The genetics of many diseases are such that tests have
only a limited ability to predict the clinical outcome
accurately.Nevertheless, the benefits of some predictive
genetic tests can be substantial, such as screening new-
borns for phenylketonuria and sickle cell anemia and
testing of older children at risk of familial medullary
thyroid carcinoma and multiple endocrine neoplasia
type 2a.1The fact remains that relatively few interven-
tions have yet been devised to improve the outcome of
most mendelian disorders.2When no treatments are
available, genetic testing can be used to avoid the con-
ception or birth of affected offspring. Carrier screening
in Sardinia, Cyprus, and elsewhere in the Mediterra-
nean has led to an appreciable reduction in the birth of
infants with thalassaemia through the use of prenatal
diagnosis in couples at high risk and their selective ter-
mination of affected fetuses.3
Genetic testing (box), including prenatal testing,
also carries the risks of inducing psychological
sequelae4and of making individuals vulnerable to dis-
crimination and diminishing their privacy. Additional
benefits of testing in refining clinical diagnosis and tai-
loring treatent may be in the offing,5but these remain
to be shown.
Government involvement
Both the American and British governments have rec-
ognised at least some of these problems, but solutions
have been slow in coming. The United States started
earlier to create a structure to consider the problems,
but at present no federal committee is dedicated to
addressing issues of genetic testing (box). In its final
report, the Task Force on Genetic Testing reviewed
many of the problems of genetic testing and laid out
specific recommendations6; the Secretary of Health
and Human Services is considering how they should
be implemented. The major stakeholders in genetic
testing were represented on the task force.
In Britain, in response to the House of Commons
Select Committee on Science and Technology,7–9 the
Conservative government set up two committees (box).
Both committees contain clinical geneticists, other
professionals concerned with genetic applications,
media representatives, and consumers. Each committee
has now addressed one issue in genetic testing.
Predicting genetic risks
Without sufficient data, there is no assurance that
genetic tests will predict disease accurately. Although
the quality of test performance is a factor, the genetics
of the disorder often explains most of the difficulty.
Variable expressivity, incomplete penetrance, and
genetic heterogeneity all reduce the ability of genetic
tests to predict future disease accurately, even when
single genes have a prominent role (box). For many
common disorders, including insulin dependent
diabetes, hypertension, and schizophrenia, it seems
likely that in the vast majority of cases, no single gene
will be prominent but multiple genes will be
implicated. However, different combinations of alleles
at multiple loci and environmental factors will each be
capable of increasing the risk of disease. Testing for any
one of the possible combinations, which is not yet pos-
sible, will account for only a small proportion of
patients. Unless a test detects most of the necessary
alleles, it will have low predictive value.
Despite these limitations, exaggerated claims are
made for genetic testing,21 and providers and the pub-
lic are given incomplete and sometimes misleading
information about tests (B Wilfond, unpublished
data).622
In the United States, the Task Force on Genetic
Testing recommends requiring organisations develop-
ing new genetic tests to submit protocols for establish-
ing the clinical validity (including sensitivity and
positive predictive value) and utility of the tests to insti-
tutional review boards,6equivalent to local research
ethics committees in the United Kingdom. Once data
are collected, the task force calls for review of the data
by an independent body including consumer repre-
sentatives. The task force recommends using the results
of review to consider whether the test should be intro-
duced into practice and become the “standard of care.”
The Food and Drug Administration will perform the
review for genetic tests marketed as tangible products,
such as kits. For genetic tests marketed as services, as
many genetic tests are, the Food and Drug Administra-
Summary points
The genetic components of many diseases are
responsible for the predictive limitations of
genetic tests
The validity and benefits of predictive genetic tests
need to be established before these tests enter
clinical use
Adverse social consequences of genetic tests,
including discrimination and possible breaches of
confidentiality, are barriers to testing; policies to
minimise them need to be developed before
testing will be widely accepted
Laboratories performing genetic tests require
special quality assurance procedures. Further
assurance of the quality of pretest and post-test
education and counselling is also needed
Government policies are needed to assure the
safe and effective use of genetic tests
Education and debate
This is the last
of four articles
discussing the
broader
implications of
advances in
genetics
Genetics and Public
Policy Studies,
Johns Hopkins
Medical Institutions,
550 N Broadway,
Suite 511,
Baltimore, MD
21205, USA
Neil A Holtzman,
professor
Woodstock Lodge,
London W4 1DS
David Shapiro,
consultant in bioethics
Correspondence to:
Dr Holtzman
holtzman@welchlink.
welch.jhu.edu
BMJ 1998;316:852–6
852 BMJ VOLUME 316 14 MARCH 1998

tion has elected not to perform the review, although it
has the legal authority to do so.6The Task Force on
Genetic Testing indicated it was “concerned about the
quality of information made available to providers and
consumers” and emphasised the role of the provider in
ensuring that potential test users receive accurate
information.6
In the United Kingdom, the terms of reference of
the Advisory Committee on Genetic Testing include:
“to establish requirements, especially in respect of effi-
cacy and product information to be met by
manufacturers and suppliers of genetic tests.”12 This
could lead the committee to examine the need for
review of genetic testing protocols by research ethics
committees. It has published a policy for genetic
testing without the involvement of a doctor; this was
prompted by a company that offers cystic fibrosis
carrier screening directly to the public for a fee of £95
per couple. The policy states that carrier testing for
inherited recessive disorders with childhood onset, like
cystic fibrosis, can be obtained directly by individuals
without the intervention of a healthcare provider
unless there is a family history of the disorder.12 (On
the matter of direct testing, the United States’s Task
Force on Genetic Testing proceeds more cautiously:
“The Task Force discourages advertising or marketing
of predictive tests to the public.”6)
Improving laboratory quality
In both the United States and the United Kingdom it is
generally agreed that laboratories performing clinical
tests should be subject to external quality control. In
the United States, the Clinical Laboratory Improve-
ment Amendments passed by Congress in 1988
provide some control but none specifically for genetic
tests. Laboratories can voluntarily participate in
proficiency testing and inspection programmes for
genetic tests offered by professional associations.A few
laboratories do not participate in any proficiency test-
ing programmes.23 The Task Force on Genetic Testing
recommends the creation of a genetics specialty under
the amendments. Once it is established, every
laboratory performing genetic tests will have to comply
with the specialty requirements.
In the United States, most clinical laboratories are
private and many are run for profit, but most of those
in the United Kingdom are associated with health
authorities and are subject to Department of Health
rules. The Clinical Molecular Genetics Society estab-
lished a quality assurance scheme, now operated by an
independent body.By 1995 it was assessing the quality
of testing for eight specific genetic disorders.24
Assessment has now been considerably extended to
more diseases. A proposed European Union directive
on in vitro diagnostic medical devices provides greater
assurance of the quality of tests marketed as kits and
reagents.25 As is the case in the United States, this
Directive does not extend to tests provided as services.
The therapeutic gap
It has proved far easier for scientists to develop tests for
genetic diseases than to devise effective interventions
to prevent manifestations in people who are born
affected. This therapeutic gap has already lasted over
10 years for Huntington’s disease, Duchenne muscular
dystrophy, and cystic fibrosis. For all three of these dis-
orders, prenatal diagnosis and termination of preg-
nancy can be used to avoid the birth of an affected
child. This option is not acceptable to people who
oppose abortion on religious or moral grounds.
Among those who do not oppose abortion entirely,
questions still arise about pregnancy termination for
adult onset disorders, like Huntingdon’s disease, or for
disorders whose prognosis is improving, like cystic
fibrosis, and for which gene therapy is already being
A person’s genetic test results may have bearing on relatives’ risks of
future disease
AKG PHOTOS
Definition of genetic tests
“The analysis of human DNA, RNA, chromosomes,proteins, and certain
metabolites in order to detect inherited disease-related genotypes,
mutations, phenotypes, or karyotypes, for clinical purposes. Such purposes
include predicting risk of disease, identifying carriers, establishing prenatal
and clinical diagnosis or prognosis. Prenatal, newborn, and carrier
screening, as well as testing in high risk families, are included. Tests for
metabolites are covered only when they are undertaken with high
probability that an excess or deficiency of the metabolite indicates the
presence of inherited mutations in single genes” (Task Force on Genetic
Testing6).
This definition excludes tests conducted purely for research, tests for
somatic (as opposed to inherited) mutations, and testing for forensic
purposes; it also excludes eliciting genetic information from a family history.
Government responses to the implications of genetic testing
In the United States, a joint working group of the National Institutes of
Health and the Department of Energy on ethical, legal, and social
implications of human genome research was created in 1990.10 It has now
been disbanded. This group created two task forces to make policy
recommendations on the implications of genetic testing.611In the United
Kingdom, a non-statutory Advisory Committee on Genetic Testing was
created in 1996. It has issued a report on offering genetic tests direct to the
public.12 The government established the Human Genetics Advisory
Commission in 1996 to review scientific progress, report on issues that have
“social, ethical, and/or economic consequences,for example in relation to
public health, insurance, patents and employment” and to “advise on ways
to build public confidence in, and understanding of, the new genetics.”13 It
has recently published a report on the implications of genetic testing for
insurance.14
Education and debate
853BMJ VOLUME 316 14 MARCH 1998

attempted. Marteau and Croyle have discussed issues
related to the therapeutic gap.5
Although treatments are available for some of the
common, complex disorders, such as breast and colon
cancer, their safety and effectiveness in asymptomatic
people found to have genetic susceptibilities to these
disorders have not been established.26 27 In families in
which disease is known to be associated with a specific
inherited susceptibility mutation, a negative test result
greatly lowers the chance of future disease and could
help dispel concerns about the need for special
surveillance or prophylactic surgery.28 In the absence of
a known inherited susceptibility mutation in the family,
a negative test result for genetic susceptibility to a com-
mon disorder affects risk estimates negligibly.
Interest in some predictive genetic tests wanes as
people are told of their limitations,29 30 but people are
not always fully informed. The American task force
emphasises that information on the risks and benefits
of tests must be presented “fully and objectively” and
that informed consent should be obtained.6Genetic
testing could be inflicted on ethnic minorities when
they are not informed of the implications of testing.31
In the United Kingdom, there is evidence that patients
with haemoglobinopathies, many of whom come from
minority groups, are not always looked after in the best
possible way.32
Discrimination and breaches of
confidentiality
In the United States, some people cannot afford health
insurance and others are denied coverage (or covered
only if they can pay very high premiums) because of
past illness. Asymptomatic people have been denied
insurance (or charged higher premiums) because they
were at risk of genetic conditions,33–35 although it is dif-
ficult to gauge the extent of the problem. The ability of
genetic tests to predict future risks could also be used
to deny insurance. The solution to this problem has
taken two forms, both involving legislation. The first is
to deny health insurers the opportunity to use genetic
test results, or knowledge that a person has had a
genetic test, to deny insurance to healthy people. In
some cases, the denial extends to genetic information
as embodied in a family history. The second is to deny
health insurers access to genetic test results or
information without the explicit consent of the person
being tested even though insurers will often pay for
these tests. Both approaches would help reduce
people’s apprehension that having genetic tests would
cause them to lose their insurance.36 Over the opposi-
tion of the insurance industry, 26 states in the United
States have passed laws barring health insurance
discrimination on the basis of genetic testing or infor-
mation.37 38 At the federal level, the Health Insurance
Portability Act and Accountability of 1996 specifically
prohibits the use of genetic information to deny group
health insurance coverage when workers switch from
one job to another.37 The second approach, which is
part of the bigger picture of assuring the privacy of
medical records in general, is currently being explored
at the federal level.
With the NHS assuring everyone some care in the
United Kingdom, more attention has been focused on
discrimination in life insurance. The recently published
Association of British Insurers Code of Practice
addresses these issues for all types of insurance (box).39
Refusal to hire workers because testing shows they are
at increased risk of disease is also a concern. American
employers can no longer decline to hire someone on
the basis of genetic information as long as the person
can perform the essential functions of the job without
threat to himself or herself or to others. After workers
are employed, employers can exclude from their health
insurance disorders whose future occurrences are pre-
dicted by genetic testing, as long as there is an actuarial
basis for doing so.41 Thus far in the United Kingdom
terms of employment seem not to have been a
constraint on health care, nor has health care
constrained people to refrain from moving jobs. Only
one employer’s genetic screening programme could be
identified in 1993 and it seemed to meet the very strin-
gent conditions that had been suggested by the
Nuffield Council on Bioethics.42
A person’s genetic test results may have a bearing
on relatives’ risks of future disease. Until recently, there
seemed to be a strong consensus in both the United
States and Britain that health providers had a duty to
protect the confidentiality of genetic information
obtained from patients and not to convey it to relatives
Genetic limitations of genetic testing
For single gene (mendelian) diseases, the finding that a
healthy person possesses a disease causing genotype
will be highly predictive that future disease will occur,
but:
•Expression cannot be forecast with great accuracy
(variable expressivity). For instance, the severity of the
lung disease in cystic fibrosis cannot be predicted very
well by the genotype15
•Not all disease causing genotypes will be detected
because many mendelian diseases can each result
from several different inherited mutations at one gene
locus (allelic diversity) or several loci (genetic or locus
heterogeneity). Often, current technology cannot
detect all of them. Over 600 mutations cause cystic
fibrosis,15 but the best technology available for clinical
testing can detect no more than 90% of white carriers;
the percentage is smaller in other racial groups
In contrast with the mendelian diseases, in common
disorders, usually of adult onset, in which a genetic
role has been identified:
•Inheritance of a relatively rare mutation may
increase risk but does not always result in the disease
(incomplete penetrance). For instance, the lifetime risk
of breast cancer among a relatively unselected group
of Ashkenazi Jewish women with the susceptibility
conferring BRCA1 or BRCA2 alleles is less than
60%.16 The risk is higher when multiple cases occur in
families, suggesting that other gene loci as well as
environmental factors influence the appearance of
disease
•Genetic polymorphisms, which occur in 1% or more
of the population, may contribute to the appearance
of disease, but most people with the risk-increasing
form of the polymorphism will never develop the
diseases. For instance,fewer than 30% of people with
the apolipoprotein E4 polymorphism develop
Alzheimer’s disease17
•Alleles of single genes play a significant role in only
a small proportion (usually less than 5%) of all people
with common diseases. This is the case for breast18 and
colon cancer19 and Alzheimer’s disease20
Education and debate
854 BMJ VOLUME 316 14 MARCH 1998

except when, in the most dire circumstances, the tested
relative refused to do so.42 43 In a recent case in New Jer-
sey, an appeals court seemed to take a more permissive
view: when a woman with familial adenomatous polypo-
sis brought suit against the estate of her deceased father’s
deceased doctor for not warning relatives of their risk 20
years earlier, the court remanded the case for trial to
determine whether the duty to warn relatives was
breached.44 Meanwhile, the House of Commons Select
Committee veered in the other direction, maintaining
that if counselling cannot persuade someone to share
genetic risk information with his or her relatives, then
the individual’s decision to withhold information should
be respected.7The law on this matter in the United
States is far from settled. The Task Force on Genetic
Testing emphasised that in offering genetic tests
“providers must make clear that they will not communi-
cate results to relatives, except in extreme circum-
stances,”which the provider should define.6
Conclusions
Both the British and American governments have
been slow to respond to issues raised by the potential
spread of genetic testing. Current policies do not
assure that sufficient data on the predictability of
genetic tests will be collected before they enter clinical
practice, that laboratory quality will be high once tests
are used clinically, and that test results will be useful to
those who are tested. Confidentiality of test results and
specimens, psychological problems, and discrimina-
tion based on test results are likely to be problems.
Once these problems are satisfactorily addressed, the
public will be assured that the genetic tests available
will truly be to their benefit.
In both countries, the efforts to address the problems
of genetic testing have started with non-statutory
advisory committees. The United Kingdom is now
further advanced than the United States in establishing a
governmental framework; two 1997 reports12 14 marked
the first use of that framework. The United States has
considered many of the substantive issues in greater
depth, as evidenced by the report of the Task Force on
Genetic Testing,6recent analyses and policy statements
regarding genetic discrimination in health insurance45
and employment,46 and the passage of laws at the state
and federal level to reduce the danger of genetic
discrimination. These issues cut across government
agency and departmental lines, making action difficult.
New legislation may be needed. Each country could
benefit from examining the course taken by the other.
This series was edited by Theresa Marteau.
1 Holtzman NA, Murphy PD, Watson MS,Barr PA. Predictive genetic test-
ing: from basic research to clinical practice. Science 1997;278:602-5.
2 Treacy E, Childs B, Scriver CR. Response to treatment in hereditary
metabolic disease: 1993 survey and 10-year comparison. Am J Hum Genet
1995;56:359-67.
3 Cao A, Saba L, Galanello R, Rosatelli MC. Molecular diagnosis and
carrier screening for âthalassemia. JAMA 1997;278:1273-7.
4 Marteau TM, Croyle RT. Psychological responses to genetic testing. BMJ
1998;316:693-6.
5 Bell J. The new genetics in clinical practice. BMJ 1998;316:618-20.
6 Task Force on Genetic Testing. Promoting safe and effective genetic testing in
the United States. Final report. Baltimore: Johns Hopkins University Press
(in press).
7 House of Commons Select Committee on Science and Technology. Third
report. Human genetics: the science and its consequences. London: HMSO,
1995. (HC41.)
8 Dickson D. MPs challenge rejection of genetics panel. Nature
1996;379:195.
9Government response to the Third Report, Science and Technology Committee,
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10 Juengst ET. Self-critical federal science? The ethics experiment within the
U.S. Human Genome Project. Social Philosophy and Policy 1996;13:63-95.
11 Task Force on Genetic Information and Insurance. Genetic Information
and Health Insurance. Rockville, MD: National Institutes of Health, 1993.
(Publication 93-3686.)
12 Advisory Committee on Genetic Testing. Code of practice and guidance on
human genetic testing services supplied direct to the public. London: HMSO,
1997.
13 Human Genetics Advisory Commission. London: Office of Science and
Technology, 1997.
14 Human Genetics Advisory Commission. The implications of genetic testing
for insurance. London: Office of Science and Technology, 1997.
15 Cutting G. Cystic fibrosis. In: Rimoin DL, Connor JM, Pyeritz RE, eds.
Principles and practice of medical genetics. London: Churchill Livingstone,
1996.
16 Str uewing JP,Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, et
al. The risk of cancer associated with specific mutations of BRCA1 and
BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401-8.
17 Seshadri S, Drachman DA, Lippa CF. Apolipoprotein E e4 allele and the
lifetime risk of Alzheimer’s disease. What physicians know, and what they
should know. Arch Neurol 1995;52:1074-9.
18 Healy B. BRCA genes
—
bookmaking, fortune telling, and medical care. N
Engl J Med 1997;336:1448-9.
19 Toribara NW, Sleisenger MH. Screening for colorectal cancer. Current
concepts. N Engl J Med 1995;332:861-7.
20 Mor rison-Bogorad M, Phelps C, Buckholtz N. Alzheimer disease research
comes of age. The pace accelerates. JAMA 1997;277:837-40.
21 Holtzman NA. Testing for genetic susceptibility: what you see is not what
you get. Accountability in Research 1996;5:95-101.
22 Cho MK, Arruda M, Holtzman NA. Informational materials about
genetic tests. In: Holtzman NA, Watson MS, eds. Task force on genetic testing:
promoting safe and effective genetic testing in the United States. 1997:125-35.
23 Holtzman NA, Hilgartner S. State of the art of genetic testing in the
United States: survey of biotechnology companies and nonprofit clinical
laboratories and interviews of selected organizations. In: Holtzman NA,
Watson MS, eds. Promoting safe and effective genetic testing in the United
States. Final report of the Task Force on Genetic Testing. Bethesda: National
Institutes of Health, 1997:99-124.
24 Mountford R. Molecular genetics quality assurance. 1995 report of the Molecu-
lar Genetics Quality Assurance Committee. Liverpool: Liverpool Women’s
Hospital, 1996.
25 Commission of the European Communities. Proposal for a European Par-
liament and Council Directive on in vitro diagnostic medical devices. Brussels:
CEC, 1995..
26 Burke W, Petersen G, Lynch P, Botkin J, Daly M, Garber J, et al.
Recommendations for follow-up care of individuals with an inherited
predisposition to cancer. I. Hereditary nonpolyposis colon cancer. JAMA
1997;277:915-9.
27 Burke W, Daly M, Garber J, Botkin J, Kahn MJE, Lynch P, et al.
Recommendations for follow-up care of individuals with an inherited
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28 Holtzman NA. Testing for genetic susceptibility to common cancers:
clinical and ethical issues. Adv Oncol 1997;13:9-15.
29 Lerman C, Biesecker B, Benkendorf JL, Kerner J, Gomez-Caminero A,
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Am J Hum Genet 1996;59:A56.
Genetic testing and life insurance
Early in 1997, the Association of British Insurers adopted a two year
moratorium on asking people to take genetic tests when applying for life
insurance. The association also said that genetic test results will not be used
in providing life insurance of up to £100 000 that is directly linked to new
applications for home mortgages; family history and other medical
information will continue to be used. Decisions about use of genetic tests
for other policies are up to individual companies. The association will
continue to expect people to report the results of reliable and relevant
genetic tests, and these results can affect the premium if the result indicates
an increased risk.39 Some major life insurance companies, however,have
announced they will not require such reporting.40
The Human Genetics Advisory Commission has concluded that “it is
unlikely that actuarially important genetic predictions of common causes of
adult death will be available and validated for some time to come. . . . On
balance . .. the life insurance industry could currently stand limited adverse
selection. .. . Concern about the perceived threat of discrimination by
insurers . .. remains an important issue and . .. the Advisory Committee on
Genetic Testing should keep the situation under review. .. . We recommend
that for the time being the insurance industry should respect a moratorium
on requiring disclosure of results of genetic tests.”14
Education and debate
855BMJ VOLUME 316 14 MARCH 1998

31 Press NA, Browner CH. Collective silences, collective fictions: how prena-
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Rothenberg KH, Thomson EJ, eds. Women and prenatal testing. Facing the
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1994:201-18.
32 Department of Health. Sickle cell, thalassemia and other hemoglobinopathies.
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don: Department of Health, 1993.
33 Billings PR, Kohn MA, de Cuevas M, Beckwith J, Alper JS, Natowicz MR.
Discrimination as a consequence of genetic testing. Am J Hum Genet
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34 Geller LN, Alper JS, Billings PR, Barash CI, Beckwith J, Natowicz MR.
Individual, family, and societal dimensions of genetic discrimination: a
case study analysis. Sci Eng Ethics 1996;2:71-88.
35 Lapham EV, Kozma C, Weiss JO. Genetic discrimination: perspectives of
consumers. Science 1996;274:621-4.
36 Ler man C, Narod S, Schulman K, Hughes C, Gomez-Caminero A, Bon-
ney G, et al. BRCA1 testing in families with hereditary breast-ovarian
cancer. A prospective study of patient decision making and outcomes.
JAMA 1996;275:1885-92.
37 Rothenberg KH. Genetic information and health insurance: state legisla-
tive approaches. J Law Med Ethics 1995;23:312-9.
38 Pear R. States pass laws to regulate use of genetic testing. New York Times
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—
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genetic risks: implications for health and social policy. Washington, DC:
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44 Safer v Pack. 1996;677 2D 1188 NJ.
45 Hudson KL, Rothenburg KH, Andrews LB, Kahn MJE, Collins FS.
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46 Rothenberg KH, Fuller B, Rothstein M, Duster T, Kahn MJE, Cumming-
ham R, et al. Genetic information and the workplace: legislative
approaches and policy challenges. Science 1997;275:1755-7.
Coping with loss
Bereavement in adult life
Colin Murray Parkes
Doctors are well acquainted with loss and grief. Of 200
consultations with general practitioners, a third were
thought to be psychological in origin; of these, 55
—
a
quarter of consultations overall
—
were identified as
resulting from types of loss.1In order of frequency the
types of loss included separations from loved others,
incapacitation, bereavement, migration, relocation, job
losses, birth of a baby,retirement, and professional loss.
After a major loss, such as the death of a spouse or
child, up to a third of the people most directly affected
will suffer detrimental effects on their physical or men-
tal health, or both.2Such bereavements increase the
risk of death from heart disease and suicide as well as
causing or contributing to a variety of psychosomatic
and psychiatric disorders. About a quarter of widows
and widowers will experience clinical depression and
anxiety during the first year of bereavement; the risk
drops to about 17% by the end of the first year and
continues to decline thereafter.2Clegg found that 31%
of 71 patients admitted to a psychiatric unit for the
elderly had recently been bereaved.3
Despite this there is also evidence that losses can
foster maturity and personal growth. Losses are not
necessarily harmful.
Yet the consequences of loss are so far reaching
that the topic should occupy a large place in the train-
ing of health care providers
—
but this is not the case.
One explanation for this omission is the assumption
that loss is irreversible and untreatable: there is
nothing we can do about it, and the best way of dealing
with it is to ignore it. This attitude may help us to live
with the fact that, despite modern science, 100% of our
patients still die and that before they die many will suf-
fer lasting losses in their lives. Sadly, it means that, just
when they need us most, our patients and their
grieving relatives find that we back away.
Recent approaches to loss
A 1944 study of bereaved survivors of a night club fire
focused attention on the psychology of bereavement,
and led to the development of services for the bereaved
and to other types of crisis intervention services.4It
established grief as a distinct syndrome with recognis-
able symptoms and course, amenable to positive or
negative influences. This, in turn, fuelled interest in the
new fields of preventive psychiatry and community
mental health. Elizabeth Kubler Ross’s studies
extended this understanding to dying people,5and
helped to provide a conceptual framework for the
humanitarian work of Dame Cicely Saunders and the
other pioneers of the hospice movement.
More recently the improvements in palliative care
have led to improvements in home care for the dying.
Home care nurses have bridged the gap and general
practitioners have had a central role, not only in caring
for dying patients and their families but also in
supporting people through many other losses. This is
Summary points
Losses are a common cause of illness; they often
go unrecognised
Conflicting urges lead to a variety of expressions
of grief; even so there is a pattern to the process
of grieving
A knowledge of the factors that predict problems
in bereavement enables these to be anticipated
and prevented
Grief may be avoided or it may be exaggerated
and prolonged
Doctors can help to prepare people for the losses
that are to come
People may need permission and encouragement
to grieve and to stop grieving
Education and debate
This is the first
in a series of 10
articles dealing
with the
different types
of loss that
doctors will
meet in their
practice
St Christopher’s
Hospice, Sydenham,
London SE26 6DZ
Colin Murray
Parkes,
consultant psychiatrist
cmparkes@aol.com
Series editor: Colin
Murray Parkes
BMJ 1998;316:856–9
856 BMJ VOLUME 316 14 MARCH 1998

the main theme of this series, which draws together
authorities with special knowledge of the losses which
afflict our patients and their families and looks at the
practical implications for doctors.
The components of grief
Three main components affect the process of grieving.
They include the urge to look back, cry, and search for
what is lost, and the conflicting urge to look forward,
explore the world that now emerges, and discover what
can be carried forward from the past. Overlying these
are the social and cultural pressures that influence how
the urges are expressed or inhibited. The strength of
these urges varies greatly and changes over time, giving
rise to constantly changing reactions.
Most adults do not wander the streets crying aloud
for a dead person. Bereaved people often try to avoid
reminders of the loss and to suppress the expression of
grief. What emerges is a compromise, a partial expres-
sion of feelings that are experienced as arising compel-
lingly and illogically from within.
Much empirical evidence supports the claims of
the psychoanalytic school that excessive repression of
grief is harmful and can give rise to delayed and
distorted grief
—
but there is also evidence that
obsessive grieving, to the exclusion of all else, can lead
to chronic grief and depression. The ideal is to achieve
a balance between avoidance and confrontation which
enables the person gradually to come to terms with the
loss. Until people have gone through the painful proc-
ess of searching they cannot “let go” of their
attachment to the lost person and move on to review
and revise their basic assumptions about the world.
This process, which has been termed psychosocial
transition, is similar to the relearning that takes
place when a person becomes disabled or loses a body
part.
The normal course of grief
Human beings can anticipate their own death and the
deaths of others. Unlike the grief that follows loss,
anticipatory grief increases the intensity of the tie to
the person whose life is threatened and evokes a strong
tendency to stay close to them.
Although the moment of death is usually a time of
great distress, this is usually quickly repressed and, in
Western society, the impact is soon followed by a
period of numbness which lasts for hours or days.
This is sometimes referred to as the first phase of
grieving.6It is soon followed by the second phase,
intense feelings of pining for the lost person accompa-
nied by intense anxiety. These “pangs of grief” are
transient episodes of separation distress between
which the bereaved person continues to engage in the
normal functions of eating, sleeping, and carrying out
essential responsibilities in an apathetic and anxious
way.
All appetites are diminished, weight is lost, concen-
tration and short term memory are diminished, and
the bereaved person often becomes irritable and
depressed. This eventually gives place to the third
phase of grieving, disorganisation and despair. Many
find themselves going over the events which led up to
the loss again and again as if, even now, they could find
out what went wrong and put it right. The memory of
the dead person is never far away and about a half of
widows report hypnagogic hallucinations in which, at
times of drowsiness or relaxation, they see or hear the
dead person near at hand. These hallucinations are
distinguished from the hallucinations of psychosis by
the circumstances in which they arise and by their
transience
—
they disappear as soon as the bereaved
arouse themselves. A sense of the dead person near at
hand is also common and may persist.
As time passes the intensity and frequency of the
pangs of grief tend to diminish, although they often
return with renewed intensity at anniversaries and
other occasions which bring the dead person strongly
to mind. Consequently the phases of grief should not
be regarded as a rigid sequence that is passed through
only once. The bereaved person must pass back and
forth between pining and despair many times before
coming to the final phase of reorganisation.
After a major loss such as the death of a loved
spouse or partner, the appetite for food is often the
first appetite to return. By the third or fourth month of
bereavement the weight that was lost initially has
usually returned, and by the sixth month many people
have put on too much weight. It may be many more
months before people begin to care about their
appearance, and for sexual and social appetites to
return. Most people will recognise that they are
recovering at some time in the course of the second
year.
Assessing the risk
Much research, in recent years, has enabled us to identify
people at special risk after bereavement either because
the circumstances of the bereavement are unusually
traumatic or because they are themselves already vulner-
able (box). These risk factors can give rise to complicated
forms of grief that can culminate in mental illness. A
ADRIANA DORSETT
The course of grief
•Numbness
•Pining
•Disorganisation and despair
•Reorganisation
Education and debate
857BMJ VOLUME 316 14 MARCH 1998

clear understanding of these factors will often enable us
to prevent psychiatric disorder in bereaved patients.
Complicated grief
Bereavement has physiological as well as emotional
effects (lower box). It also affects physical health: after
bereavement, the immune response system is tempo-
rarily impaired78 and there are endocrine changes
such as increased adrenocortical activity and increases
in serum prolactin and growth hormone,2as in other
situations that evoke depression and distress.
A variety of psychiatric disorders can also be caused
by bereavement, the commonest being clinical depres-
sion, anxiety states, panic syndromes, and post-traumatic
stress disorder. These often coexist and overlap with
each other, as they do with the more specific morbid
grief reactions. These last disorders are of special interest
for the light that they shed on why some people come
through bereavement unscathed or strengthened by the
experience while others “break down.”
It is a paradox that people who cope with bereave-
ment by repressing the expression of grief are more
likely to break down later than are people who burst
into tears and get on with the work of grieving. The
former are more liable to sleep disorders, depression,
and hypochondriacal symptoms resembling the symp-
toms of the illness that caused the bereavement (“iden-
tification symptoms”). Not all psychogenic symptoms,
however, are a consequence of repressed or avoided
grief. Some reflect the loss of security which often fol-
lows a major loss and causes people to misinterpret as
sinister the normal symptoms of anxiety and tension.
At the other end of the spectrum of morbid grief
are people who express intense distress before and
after bereavement. Subsequently they cannot stop
grieving and go on to suffer from chronic grief. This
may reflect a dependent relationship with the dead
person, or it may follow the loss of someone who was
ambivalently loved. In the former case the bereaved
person cannot believe that he or she can survive with-
out the support of the person on whom they had
depended. In the latter, their grief is complicated by
mixed feelings of anger and guilt that make it difficult
for them to stop punishing themselves (“Why should I
be happy now that my partner is dead?”).
Some degree of ambivalence is present in all
relationships. To some degree its effects can be
assuaged by conscientious care during the last illness,
and many people will recall “We were never closer.” If
members the family have been encouraged and
supported so that they have been able to care, and the
death has been peaceful, anger and guilt are much less
likely to complicate the course of grieving.
These two patterns of grieving often seem to occur
in “avoiders” (people with a tendency to avoidance)
and “sensitisers” (those with a tendency to obsessive
preoccupation), respectively.9
Preventing and treating complicated grief
Doctors are in a unique position to help people
through the turning points in their lives which arise at
times of loss. In order to fulfil this role we need
information and skills. One of our problems as
caregivers is our ignorance of our patients’ view of the
world. Not only do we seldom know what they know or
think they know about the situation they face, we do
not even know how that situation is going to change
their lives. It follows that we need to find out these
things and, where possible, add to their knowledge or
correct any misperceptions, taking care to use
language that they can understand. (This is easier said
than done when words like “cancer” and “death”mean
different things to doctors than they do to most
patients.) Above all, we should spend time helping
them to talk through and to make sense of the implica-
tions of the information we have given. If need be, we
should see them several times to facilitate this process
of growth and change. General practitioners, because
they are likely to know the person, are often well placed
to provide this “trickle” of care. For most bereaved
people the natural and most effective form of help will
come from their own families, and only about a third
will need extra help from outside the family.
Anticipatory guidance
Members of health care teams can often prepare people
for the losses that are to come. People need time to
Factors increasing risk after bereavement
Traumatic circumstances
Death of a spouse or child
Death of a parent (particularly in early childhood or adolescence)
Sudden, unexpected, and untimely deaths (particularly if associated
with horrific circumstances)
Multiple deaths (particularly disasters)
Deaths by suicide
Deaths by murder or manslaughter
Vulnerable people
General:
Low self esteem
Low trust in others
Previous psychiatric disorder
Previous suicidal threats or attempts
Absent or unhelpful family
Specific:
Ambivalent attachment to deceased person
Dependent or inter-dependent attachment to deceased person
Insecure attachment to parents in childhood (particularly learned fear
and learned helplessness)
Complications of bereavement
Physical
•Impairment of immune response system
•Increased adrenocortical activity
•Increased serum prolactin
•Increased growth hormone
•Psychosomatic disorders
•Increased mortality from heart disease (especially in
elderly widowers)
Psychiatric
Non-specific:
•Depression (with or without suicide risk)
•Anxiety or panic disorders
•Other psychiatric disorders
Specific:
•Post-traumatic stress disorder
•Delayed or inhibited grief
•Chronic grief
Education and debate
858 BMJ VOLUME 316 14 MARCH 1998

achieve a balance between avoidance and confrontation
with painful realities, and we need to take this into
account when we impart information that is likely to
prove traumatic. One way is to divide the information
that needs to be confronted into “bite sized chunks.”
Doctors do this when we break bad news a little at a time,
telling a patient as much as we think he or she is able to
take in. Patients seldom ask questions unless they are
ready for the answers, and they will usually ask precisely
what they want to know and no more. It follows that we
should invite questions and listen carefully to what is
asked rather than assuming that we know what the
patient is ready to know. By monitoring the input of
information, a person can control the speed with which
they process that information.
Although a little anxiety increases the rate and effi-
ciency with which we process information, too much
anxiety slows us down and impairs our ability to cope,
our thought processes become disorganised and we
“go to pieces.” Anything that enables us to keep anxiety
within tolerable limits will help us to cope better with
the process of change. If we are breaking bad news
(box) it helps to do so in pleasant, home-like surround-
ings and to invite the recipient to bring someone who
can provide emotional support. A few minutes spent
putting people at their ease and establishing a relation-
ship of trust will not only make the whole experience
less traumatic for them but it will increase their chance
of taking in and making sense of the information
which we then provide.
Supporting bereaved people
A visit from the general practitioner to the family
home on the day after a death has occurred enables us
to give emotional support and to answer any questions
about the death and its causes that may be troubling
the family. Newly bereaved people often feel and
behave, for a while, like frightened and helpless
children and will respond best to the kind of support
that is normally given by a parent. A touch or a hug will
often do more to facilitate grieving than any words.
During the next few weeks bereaved people need
the support of those they can trust. We can often reas-
sure them of the normality of grief, explain its
symptoms, and show by our own behaviour and
attitudes that it is permissible to express grief. If we feel
moved to tears at such times there is no harm in show-
ing it. Bereaved people may need reassurance that they
are not going mad if they break down, that the
frightening symptoms of anxiety and tension are not
signs of mortal illness, and that they are not letting the
side down if they withdraw, for a while, from their
accustomed tasks.
As time passes people may also need permission to
take a break from grieving. They cannot grieve all the
time and may need permission to return to work or do
other things that enable them to escape, even briefly,
from grief. It is only if they get the balance between
confrontation and avoidance wrong that difficulties are
likely to ensue.
The first anniversary is often a time of renewed
grieving, but thereafter the need to stop grieving and
move forward in life may create a new set of problems.
People may need reassurance that their duty to the dead
is done, as well as encouragement to face the world that
is now open to them. The most important thing we have
to offer is our confidence in their personal worth and
strength. We should beware of becoming the “strong”
doctor who will look after the “weak” patient for ever,but
this does not mean that we become angry and
dismissive, reprimanding the patient for becoming
“dependent.” In the end, most bereaved people come
through the experience stronger and wiser than they
went into it. It is rewarding to see them through.
Appendix
In the acute stages it is usually best to give support by
personal contact, preferably in the client’s home. Later
the help of a group in which bereaved people can learn
from each other, as well as a counsellor,may be helpful.
Organisations such as Cruse Bereavement Care and
the member organisations of the National Association
of Bereavement Services may be able to provide either
of these types of help. The Compassionate Friends (for
bereaved parents), Lesbian and Gay Bereavement,
Support after Murder and Manslaughter (SAMM), and
the Widow-to-Widow programmes that exist in the
United States and other parts of the world provide
mutual help by bereaved people for others with the
same types of bereavement.
Further reading
Markus AC, Parkes CM, Tomson P, Johnstone M. Psychological
problems in general practice. Oxford: Oxford University Press,
1989.
Parkes CM. Bereavement:studies of grief in adult life. 3rd ed. Har-
mondsworth: Pelican, 1998.
Funding: No additional funding.
Conflict of interest: None.
1 Clark S. Loss and grief in general practice: a pilot study. National conven-
tion of the Royal Australian College of General Practitioners, 1986.
2 Jacobs S. Pathologic grief: maladaptation to loss. Washington,DC: American
Psychiatric Press, 1993.
3 Clegg F. Grief and loss in elderly people in a psychiatric setting. In:
Chigier E, ed. Grief and mour ning in contemporary society. Vo l 1.
Psychodynamics. London: Freund, 1988:191-8.
4 Lindemann E. The symptomatology and management of acute grief . Am
J Psychiatry 1944;101:141.
5 Ross EK. On death and dying. London: Tavistock, 1970.
6 Bowlby J, Parkes CM. Separation and loss within the family. In:Anthony
EJ, ed. The child in his family. New York: Wiley, 1970.
7 Bartrop RW, Lazarus L, Luckhurse E, Kiloh LG, Pennry R. Depressed
lymphocyte function after bereavement. Lancet 1977;i:834-6.
8 Schleiffer SJ, Keller SE, Camerino M, Thornton JC, Stein M. Suppression
of lymphocyte stimulation following bereavement. JAMA 1983:
250:374-7.
9 Horowitz, M. Stress response syndromes. Northvale, NJ: Aronson, 1986.
Breaking bad news
•Consider social support (who to ask to be present)
•Consider setting (where to meet)
•Try to establish a relationship of mutual respect and trust
•Discover what the patient or the family knows or think they know already
•Invite questions
•Give information at a speed and in a language that will be understood
•Monitor what has been understood
•Recognise that it takes time to hear and understand bad news
•Give the patient or the family time to react emotionally
•Give verbal and non-verbal reassurance of the normality of their reaction
•Stay with the patient or the family until they are ready to leave
•Offer further opportunities for clarification, information, or support
The articles in this
series are adapted
from Coping with
Loss, edited by
Colin Murray
Parkes, which will
be published in
May.
Education and debate
859BMJ VOLUME 316 14 MARCH 1998