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| Journal of the New Zealand Medical Association,
29-July-2011, Vol 124 No 1339
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Peter Moodie, Richard Jaine, Jason Arnold, Scott Metcalfe,
Mike Bignall, Bruce Arroll
Oral isotretinoin is a highly-effective treatment for severe
refractory cystic and conglobate acne that has been available for over 20 years.
It is also highly teratogenic. Given that the medication was difficult to use
and the risk of teratogenicity, until recently, funded access in New Zealand has
been available only for prescriptions written by vocationally registered
dermatologists. Despite this funding restriction, other prescribers have always
been allowed to issue prescriptions, albeit with a patient having to pay the
full direct cost of isotretinoin along with pharmacy markups and dispensing
fees. Several other countries, including the United Kingdom and Australia, have
similar restrictions.
In April 2009, the agency that manages New Zealand’s
community pharmaceutical budget, PHARMAC (Pharmaceutical Management Agency),
widened funded access to oral isotretinoin such that vocationally trained
general practitioners and nurse practitioners acting within their scope of
practice were able to write fully subsidised scripts for their patients.
The main impetus behind this decision was to address the
inequities of access present under the funding restriction: those living in more
deprived areas and Māori and Pacific people were less likely to access
isotretinoin.1
Those opposed to widening funding cited several concerns
including:
In response to these concerns, PHARMAC stated
that: GPs would receive training in managing isotretinoin; although there is the
potential to increase absolute numbers of affected pregnancies, the proportion
of affected pregnancies may not increase; and prescribing pressure may be
present for any type of doctor.2
Isotretinoin is teratogenic at all therapeutic doses.
Malformations—characteristically ear defects, central nervous system
defects and/or cardiovascular defects—have been reported following a
single dose of the pharmaceutical.3
Malformation rates for pregnancies that end in birth range from 11% to 30%, with
most estimates at the upper end of this
range.4–7
Most research on the pregnancy rate of women on isotretinoin
has been completed in North America. One of the early studies reported a
pregnancy rate of 8.8 per 1000 person-years of
treatment.5 Other figures quote a pregnancy
rate for women taking isotretinoin of 0.04% in 1989 dropping to 0.02% in
1999.8 However, given the not insignificant
limitations of some of this research (such as self-reported surveys and
spontaneous reporting of pregnancies), these rates are expected to be
underestimates.7,9
A more recent retrospective cohort study found a pregnancy
rate of 32.7 per 1000 person-years of treatment: a rate four times greater than
what has been previously published.7 Elective
termination of pregnancy rates vary greatly from 36% to
84%.4–7
In New Zealand, there is very little data about pregnancy
rates while on isotretinoin. An informal voluntary survey undertaken by
dermatologists in New Zealand identified approximately 60 at risk pregnancies
over a 20-year period (personal communication, 2008).
There is a lack of New Zealand-specific data on this issue
and the current international literature (mostly from North America) is unlikely
to be generalisable to New Zealand given differences in prescribing
restrictions, pharmaceutical costs, pregnancy prevention programmes and overall
demographics. As such, this study aims to report on terminations of pregnancy
occurring while using isotretinoin in New Zealand.
MethodsIsotretinoin prescription
data—Once a funded prescription is dispensed in New Zealand the
data is collected in a national repository and available for analysis. In
addition to prescriber details, the medication name, strength, quantity and
dosage are recorded, along with an encrypted National Health Index (NHI) number
where this is available.
The NHI number is a unique identifier for virtually
everybody in New Zealand who has ever had contact with the health service. As
previously reported1 only 60% of isotretinoin
prescriptions had an NHI attached (potentially due to the non-routine use of NHI
numbers by private specialists).
Prescription data for isotretinoin for the period year
ending June 2008 was accessed through PharmHouse. The PharmHouse database is a
subset of the New Zealand Health Information Service (NZHIS) database that
contains records of all the claims for medicines dispensed within New
Zealand.
Termination of pregnancy
data—All public hospitals report to the NZHIS on surgical
procedures carried out which are recorded as "disease related groups" (DRGs).
All terminations of pregnancy carried out in a public hospital are recorded in
this way along with an NHI number.
All legal terminations of pregnancy must be reported to
the New Zealand Abortion Supervisory Committee. Termination of pregnancy data
was obtained for this study for year ending June 2008. Not all records in this
database have an NHI number available. By example, in 2008 the Abortion
Supervisory Committee identified 18,382 terminations of pregnancy. However, 1592
(or 8.7%) were performed at a private clinic in Auckland and these cases would
not have been identified in the NZHIS database. Therefore, no NHI data was
available for these women.
Matching datasets—With the
available NHI numbers, an attempt was made to match termination of pregnancy
admissions obtained with recent (i.e. within the last 6 months) isotretinoin
prescriptions using NHI numbers. A prescription within the preceding 6 months
was chosen as the period during which a possible link between isotretinoin use
and wish to terminate pregnancy could most likely be made. This period takes
into account prescription length, one month post medication period, time to
awareness of pregnancy and time to organise termination.
Deprivation level—Individuals
were assigned the deprivation level of their area of residence based on the New
Zealand Deprivation Index (NZDep). The NZDep Index is a population level index
based on nine variables recorded on the 2001 New Zealand
census.10
Analysis—Simple descriptive
analysis of isotretinoin prescriptions and terminations of pregnancy by
deprivation level were completed. Total number of terminations of pregnancy for
those who had been given a prescription of isotretinoin in the preceding 6
months are given.
Ethics—Ethics approval was not
sought as this work fits the exception criteria for secondary use of data
without consent according to the Ethical Guidelines for Observational
Studies: Observational Research, Audits and Related Activities
(2006).
ResultsIn the year ending June 2008, there were 27,056 funded
isotretinoin prescriptions (approximately 3,000,000 capsules) dispensed. Over
the same timeframe, there were 14,793 terminations of pregnancy identified from
the databases.
Isotretinoin use was not evenly distributed across the
deprivation quintiles (Figure 1). Those from the least deprived quintile are
more than twice as likely to access isotretinoin compared with people from the
most deprived quintile.
The opposite effect is present when terminations of
pregnancy are analysed. There were three times as many terminations of pregnancy
performed on individuals from the most deprived areas compared to those living
in the least deprived areas (Figure 2).
Figure 1. Isotretinoin prescription rates by
deprivation level, year ending June 2008
 Figure 2. Total number of terminations of
pregnancy by deprivation level, year ending June 2008
 This study identified 39 patients who had a termination of
pregnancy as well as an isotretinoin prescription within the preceding 6 months.
This gives a crude termination of pregnancy rate of 73 per 10,000 females aged
10–44 years. The crude termination of pregnancy rate for the total
population of females aged 10–44 years is 139 per 10,000. The monthly
distribution is shown in Figure 3.
Figure 3. Monthly total and cumulative number
of terminations of pregnancy by months following isotretinoin prescription, year
ending June 2008
 DiscussionThis study has identified a far greater number of
pregnancies related to isotretinoin use than was previously suspected. A total
of 39 terminations of pregnancy were identified where a prescription of
isotretinoin had been given in the previous 6 months.
While the termination of pregnancy rate for those taking
isotretinoin was approximately half that for the total population, it is still
higher than previously assumed. There had been concern that early estimates of
pregnancy rates for people using isotretinoin had been significantly
underestimated.7,9
The results of this study support this concern in the New
Zealand setting and are consistent with recent international
literature.7 We suspect that, on an
international scale, pregnancy rates while using isotretinoin are far higher
than previously recognised.
There are some limitations to this analysis. Both datasets
used were incomplete. Forty percent of the isotretinoin prescriptions did not
have an NHI number attached, while almost 9% of the termination of pregnancy
data did not have an NHI number. However, if the percentage of isotretinoin
prescriptions or terminations of pregnancy with NHI numbers increased, it would
be expected that there would have been a greater absolute number of terminations
of pregnancy associated with isotretinoin use identified. Hence these results
are almost certainly an underestimate of the number of at risk pregnancies. It
is unknown how an increase in NHI recording would affect the termination of
pregnancy rate.
A further limitation of this study is the use of
isotretinoin prescriptions in the 6 months preceding a termination of pregnancy.
Not all of these pregnancies would necessarily have been at risk and could have
occurred later than a month after stopping therapy. It is also possible that
terminations may have resulted for other reasons independent of known
isotretinoin usage and associated risks of teratogenicity.
This study only examined terminations of pregnancy and does
not attempt to identify other pregnancies, such as spontaneous abortions and
pregnancies carried through to birth, that may have occurred while using
isotretinoin. Given that previous international studies identify that elective
terminations of pregnancy account for between 36% and 84% of all pregnancies
related to isotretinoin use, this study is very likely an underestimate of the
total number of pregnancies occurring while using isotretinoin. There was also
no attempt to identify reasons for the terminations of pregnancy.
Given these results, what effect may the widening of funded
access to isotretinoin have on the number of pregnancies occurring while using
the pharmaceutical? It is expected that widening funding access will increase
the total number of people using isotretinoin, particularly those living in the
more deprived areas, and potentially Māori and Pacific
people.1
Further analysis of the termination of pregnancy data showed
that those in the most deprived areas were overrepresented in termination of
pregnancy figures overall. This suggests that if access is widened such that
those in the more deprived areas achieve greater access, there is also a greater
risk not only in absolute numbers of pregnancies but also in relative numbers.
This will be a very real challenge for primary care providers to ensure that
contraception is managed well in this group. However the new decision support
mechanism and the GP experience with birth control could potentially reduce the
relative pregnancy numbers.
In attempting to effectively manage contraception in those
using isotretinoin several countries have implemented risk management
approaches.5,11 These programmes have tended to
differ in their complexity and approach used.11
Unfortunately, there is limited evidence of the effectiveness of some risk
management approaches in preventing
pregnancies.11,12
In New Zealand, current recommendations for starting and
maintaining a patient on isotretinoin include: obtaining a current sexual
history; giving appropriate advice and information on contraception and the
risks of isotretinoin; the use of two forms of contraception; and pregnancy
tests prior to initiating and monthly at each prescription. It will be important
to audit or monitor prescribers and their adherence to these recommendations.
This will help in assessing the effectiveness of these recommendations and
whether further pregnancy prevention approaches would be required.
The funding for isotretinoin was initially restricted due to
the potential difficulty in managing this highly teratogenic pharmaceutical.
However, given the results of this study, it appears that restricting access may
not have prevented unwanted pregnancies as much as had been anticipated.
Although primary care has not had a great deal of experience in the management
of patients using isotretinoin, they have a great deal of experience and
understanding of the management of contraception.
Primary care clinicians are also well placed to have an
excellent understanding of the overall clinical and social circumstances of
their patient. Now that funding has been widened to primary care, it will be
vital that they are alert to the risks of isotretinoin use and gain experience
in its day-to-day usage, while appropriately applying their broad experience in
contraception management and their understanding of patients’ clinical
circumstances. It will be equally important for dermatologists to act as a
backup to primary care in this area. To add further support to primary care,
PHARMAC has arranged for training seminars along with a number of publications
on the matter.
Now that funding has been widened, it is vital to robustly
monitor isotretinoin use. To this effect, PHARMAC requires that funded access to
isotretinoin be recorded on a “Special Authority” database. This
will guarantee that NHI numbers are recorded on prescriptions and allow
prescribing data to be accurately correlated to New Zealand termination of
pregnancy data. It will be important to regularly review this data to ensure
that the widening of funded access does not have any unexpected negative effects
on the health of the population.
As a final step it would seem sensible to require private
termination of pregnancy clinics to supply not only termination of pregnancy
numbers to the Abortion Supervisory Committee but also include NHI numbers. In
this way accurate statistics can be kept for the whole country.
Competing interests: None, including
no external funding sources.
Author information: Peter Moodie, Medical
Director PHARMAC, Wellington; Richard Jaine, Public Health Physician, Department
of Public Health, University of Otago, Wellington; Jason Arnold, Senior Analyst,
PHARMAC, Wellington; Scott Metcalfe, Chief Advisor Population Medicine/Public
Health Physician, PHARMAC, Wellington; Mike Bignall, Therapeutic Group Manager,
PHARMAC, Wellington; Bruce Arroll, Head of Department, Dept of General Practice
and Primary Health Care, School of Population Health, University of
Auckland
Acknowledgements: Dilky Rasiah (PHARMAC)
assisted in finalising the manuscript. Coonwa Emmanuel Jo (NZ Ministry of
Health) provided the data matching.
Correspondence: Peter Moodie, PHARMAC, PO
Box 10-254, Wellington 6011, New Zealand. Fax: +64 (0)4 4604995; email: peter.moodie@pharmac.govt.nz
References:
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