Risk management
Measures to minimise foetal exposure to potential teratogens
investigated in this review were based on components of Risk Evaluation
and Mitigation Strategies (REMS) with Elements to Assure Safe Use
(ETASU). These measures were: teratogenic counselling, contraceptive
counselling, pregnancy testing before or at start of treatment,
pregnancy testing while on treatment, use of contraception before or on
starting treatment, and use of contraception during treatment. Since
2007, implementation of REMS with ETASU have been required by the FDA
for medications with serious safety issues like teratogenic medications
to ensure that the benefits of a medication outweigh the risks to
patients [83].
Isotretinoin was the most commonly prescribed teratogenic medication
covered by the studies included in this review (n= 16; 29.1%) [22,
30, 31, 33, 34, 47, 53, 63, 64, 66, 67, 71, 73-75, 77]. This may be
because of two reasons. Firstly, isotretinoin is a relatively old
medication that has been in the market since 1982-1983, and has been
prescribed under a pregnancy prevention programme since 1988 [84].
Secondly, it is one of the most cost-effective acne treatments used by
patients from different age groups including women of child bearing age
[4, 77, 85].
By contrast, it was observed that there were fewer publications on
medications prescribed under more recent risk management programmes such
as thalidomide, lenalidomide, and valproic acid [18, 21, 41, 45, 59,
61, 70], indicating a need for further investigation of the safety of
these medications in terms of adherence to risk management measures for
such medications. Good practice guidance suggests that ensuring safe use
of medications can have a number of positive effects on treatment
outcomes. For teratogenic medications in particular, this includes
reducing the incidents of medication- induced foetal harm and empowering
patients to make the most of their treatment [11].
Results of teratogenic risk management implementation showed a wide
variation among studies. Some studies reported surprisingly low rates of
implementation. For example, only 9.5% of women of child bearing age
using valproate received teratogenic counselling in the study by Mulryan
et al. [70], and 6.1% of women using medications of class D or X
received contraceptive counselling in the study by Schwarz et al.
[17]. Additionally, rates of pregnancy testing before starting
treatment with valproate or thalidomide were as low as 0% in two
studies [59, 70], and pregnancy testing during treatment with
acitretin was 12.7% in the study by Raguideau et al. [72]. Low
rates of contraceptive use were also reported. Uuskula et al. reported
that 15.7% of women of child bearing age on isotretinoin treatment in
their study used a contraceptive before starting treatment [22], and
Tsur et al. reported that only 1.7% of women in their study group used
contraception during treatment with isotretinoin [75].
The wide variation in the results of implementing risk management
measures can be discussed in the light of several factors. One factor
could be the data sources used by the different studies. Some studies
relied on medical records as their source of data [17, 19, 21, 22, 31,
32, 34, 36, 37, 40, 41, 43, 44, 46, 49, 54, 57, 58, 60, 61, 65-67, 70,
72, 78], while others used patients surveys [18, 20, 30, 33, 35, 39,
45, 47, 48, 52, 53, 55, 56, 62, 64, 69, 71, 74-77], a combination of
medical records and patient surveys [38, 50, 63, 68, 73], or other
sources (patient logs [42], reproductive life plans [51], and
physician surveys [59]). Having patients as the only source of
information can lead to several forms of self-reporting bias [86].
Recall bias can lead to an erroneous estimation of risk management
variables if the patient’s recall of information is inaccurate [87].
Another form of self-reporting bias associated with the disclosure of
sensitive data is the social desirability bias [86]. Social
desirability bias might have led to an overestimated adherence to risk
management and pregnancy prevention measures [88]. On the other
hand, if data were extracted from the medical records, several issues
like incomplete records, non-captured data, and low quality data might
have an effect on the research outcomes [89, 90]. Therefore, it is
important to bear in mind the possible types of bias associated with
each source of data.
Another well recognised variable leading to variations in the
implementation of risk management for the different teratogenic
medications is the availability of risk management programmes. For
certain medications like thalidomide, linaledomide, and isotretinoin,
detailed risk management programmes that aim to prevent foetal exposure
to the drug are in place [4, 8]. However, for other teratogenic
medications, managing their risk is limited to the use of product
labelling and patient information leaflets rather than rigorous
monitoring [91]. The effectiveness of drug labelling as a risk
management tool has been a matter of debate as research suggests a lack
of effect on physicians’ prescribing behaviours or patients’
understanding of instructions [91].
Results of the current review can be considered as a compliance
assessment of teratogenic risk management (whether through existing risk
management programmes or through labelling recommendations) [91].
Based on the findings of this review, safety of the utilisation of
teratogenic medications is sub-optimal, and entails a risk of foetal
exposure to the harmful effect of potential teratogens. Consequently, it
is recommended that the implementation of the existing teratogenic risk
management programmes be monitored more carefully, and the criteria for
the optimal management of teratogenic risk for potential teratogens be
reviewed and revised based on the available evidence.
Exploring the implementation of risk management for teratogenic
medications can help to develop interventions designed to minimise
foetal exposure to cytotoxic effects, and thus future research utilising
multiple data sources is needed. Drawing on the strengths of data
extracted from medical records and patient reported data, mixed methods
research that utilises quantitative and qualitative methods could yield
more rigorous results than research utilising quantitative or
qualitative methods alone [92, 93].
Consequently, results of this review raise two important issues. First,
the review uncovers deficiencies in the implementation of risk
management of teratogenic medications which constitutes a serious public
health concern that needs further investigation. Second, it highlights a
potential need to reinforce policies and regulations that aim to reduce
foetal exposure to the cytotoxic effects of teratogenic medications.