Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5238_Библиотеки_им_академика_М_И_Перельмана.pdf
46
Y. C. Kaplan et al.
Table 3.1
States, and Australia
Category
Sweden
A No known risk
B Human data insufcient
B1 no fetal effects in animal data
B2 incomplete animal data
B3 fetal effects in animal data
C Pharmacological effects on fetus
D Causes or is suspected of causing fetal damage in humans
United States
A Controlled studies show no risk
B
C Risk cannot be ruled out
D Positive evidence of risk but potential benet may outweigh potential risk
X Contraindicated in pregnancy
Australia
A-D As in Sweden
X Should not be used in pregnancy
From Källén (1999) with permission
Short summary of pregnancy warning classication systems in Sweden, the United
No evidence of human risk (controlled studies show no risk or animal studies indicate no
risk)
(Källén 1999). Category A denotes the safest drugs and the possible risk of the
medication is expected to increase from A to D.Category B comprises 3 subgroups
(B1, B2, B3).
The following year (1979), the US Food and Drug Administration (FDA) introduced its own pregnancy risk categorization system which was composed of 5 subgroups. Similar to the FASS system, categories ranged from A to D, with the
additional subgroup, Category X, which represents contraindicated drugs (Addis
etal. 2000). The Australian Drug Evaluation Committee (ADEC) classication was
developed in 1989. ADEC can be regarded as a combination of both previous categories since it comprises subcategories B1, B2, B3, and X (Addis etal. 2000).
Table3.1 presents a short summary of these 3 systems. Signicant differences in the
classication of similar medications between these 3 systems were previously
reported by Addis etal. in 2000 (Addis etal. 2000).
3.3 Criticisms Regarding theFDA Pregnancy
Risk Categories
The primary aim of the FDA pregnancy risk categorization system was to provide
evidence-based risk assessment to help physicians in counseling the women who
are planning a pregnancy. However, it was generally misunderstood by the healthcare providers, as a tool for assessing exposure risks that happened during an inadvertent pregnancy. At the time the risk categories were designed, pregnant women
were generally considered to be young, healthy individuals who were free of
3 Safety Parameters and Risk Categories Used for Psychotropic Drugs in Pregnancy…
47
diseases. However, this perception has been changed since the last two decades
witnessed an increasing rate of pregnancy in women aged 35 and older (Dunlop
etal. 2008), which consequently led to an increase in the number of pregnant women
who are entering pregnancy with a pre-existing chronic disease that necessitates
pharmacotherapy. For instance, approximately 40% of women in reproductive age
(19–45) are reported to be diagnosed with a chronic disease in the United States
(Chatterjee etal. 2008) and one in ve pregnant women is reported to have at least
one chronic disease in Germany (Kersten etal. 2014).
Toward the end of the 1990s, the FDA recognized the important limitations and
shortcomings of the 1979 categorization system which may misguide clinical practice. A public hearing resulted in the following implications (Feibus 2008):
1. Categories are inadequate in conveying the risk because of the oversimplied
narrative.
2. Categories indicate that the teratogenic potencies of drugs in the same category
are similar, which is a false perception.
3. Categories do not differentiate between the possible severity and incidence of
the fetal adverse effects. They also do not distinguish between the time, dose,
route, duration, and frequency of the exposure.
4. Categories focus on drug use in planned pregnancies. They are insufcient in
identifying risks for the exposures during an inadvertent pregnancy.
5. Categories lack sufcient distinction to provide meaningful interpretations
between animal and human data.
Following extensive reviews and thorough discussions with key stakeholders, the
FDA decided to remove the pregnancy letter categories A, B, C, D and X from the
product labeling and replace with the Pregnancy and Lactation Labeling Rule
(PLLR) which is the narrative summary of the risk associated with the use of a
medication during pregnancy and lactation. The new pregnancy labeling includes
three sections: (1) Fetal Risk Summary, (2) Clinical considerations, and (3) Data
(Frederiksen 2011). Each pregnancy label begins with contact information for relevant pregnancy exposure registries and, when available, includes a standard statement about the baseline risk of major congenital malformations and other adverse
pregnancy outcomes that exist for all pregnancies regardless of medication exposure (Feibus 2008). The Fetal Risk Summary section also provides a conclusion
describing the likelihood that the medication increases risk to the fetus. It covers the
possible fetal adverse effects of the medication such as structural malformations,
fetal and infant death, physiological dysfunctions, and fetal growth abnormalities
and their incidence, seriousness, reversibility, and correctability. The summary also
considers possible fetal risks with regard to the dose, duration, and time window of
the medication exposure (Frederiksen 2011). The Clinical Consideration section
includes information regarding inadvertent exposure such as dose, critical time window for the possible risks, and the possible risks of underlying maternal clinical
condition, if present. It also addresses neonatal concerns, and their severity and
reversibility, associated with the use of medication. The possible effects of the
48
medication on the duration of labor and birth will also be included. Finally, the data
section discusses available human and animal data. Animal data are reviewed in
terms of species, dose ranges, human dose equivalents, and possible mechanisms of
action (Feibus 2008).
This rule took effect on June 30, 2015, and requires medications and biological
products approved after June 30, 2001, to revise the information found in the
Pregnancy and Nursing Mothers subsections of product labeling (Sahin etal. 2016).
Between 2000 and 2022, 488 new drug applications (NDAs) approved by the FDA
were assessed for post-marketing commitments, breastfeeding, and pregnancy
requirements. Of the 59 approved NDAs, 41 included requirements for pregnancy,
4 for lactation, and 14 for both (Avachat etal. 2023).
The new PLLR labeling was evaluated in a survey carried out in 2018. The
results of this survey indicate that despite the extremely low response rate, the
majority of clinicians were unaware of the new PLLR format and were still utilizing
the pregnancy letter category system (Namazy etal. 2020).
Y. C. Kaplan et al.
3.4 Assessing thePossible Teratogenic Risk ofMedications
3.4.1 Variables Related with the Administration
of the Medication
3.4.1.1 Time ofAdministration
The time after conception to implantation (8–10days) is considered as the “all or
none” period which implies the exposure to any harmful agent of the embryo would
either yield to spontaneous abortion or intact survival. The embryonic period, in
which the organogenesis takes place, starts after the implantation and lasts
54–60days after conception. This period where a set of complex cellular events take
place, such as cellular migration and differentiation, is the most sensitive period of
embryo to teratogenic insults resulting in structural malformations. The fetal period
just starts after the organogenesis and continues to term. Growth and functional
maturation of organs occur in this phase and teratogenic exposure during this period
usually ends up with the disruption in function or size of the organs rather than
structural anomalies.
For most drugs, the main concern is the rst trimester of pregnancy (Brent
2004a), however there may be exceptions. For instance, exposure to selective sero-
tonin reuptake inhibitors (SSRIs) in late pregnancy was shown to be signicantly
associated with persistent pulmonary hypertension of the newborn whereas a signicant association with early pregnancy exposure was not apparent (Grigoriadis
etal. 2014).
3.4.1.2 Dose ofMedication
Valproic acid (VPA) constitutes an important example of dose-related teratogenicity. Studies report different dose categories in which the rates of structural malformations with VPA monotherapy are signicantly increased; the largest increased
risk is demonstrated with doses greater than 1000mg per day (Diav-Citrin etal.
3 Safety Parameters and Risk Categories Used for Psychotropic Drugs in Pregnancy…
49
2008; Kaneko etal. 1999). Tomson etal. reported the malformation rates regarding
VPA monotherapy in pregnancy as 5.6%, 10.4%, and 24.2% with doses <700mg/
day, ≥ 700 to <1500, and≥1500mg per day, respectively (Tomson etal. 2011).
Regarding the neurodevelopmental abnormalities, a VPA dose greater than 900mg
per day and 1000mg per day is associated with a decreased total development score
and IQ, respectively (Bromley etal. 2010; Meador etal. 2009).
3.4.1.3 Route ofAdministration
Route of administration is one of the major determinants of drug bioavailability,
which is the ability of a drug to reach the systemic circulation and therefore the
fetus. Retinoids are potent and well-established teratogens which constitute a good
example for this issue. Systemic retinoid exposure has been demonstrated to
increase the rates or major malformations up to 35% (Lammer etal. 1985). This
high gure, which is only comparable to that of thalidomide, and some case reports
with major malformations (Lipson etal. 1993; Camera and Pregliasco 1992) in the
1990s led to an increased teratogenic risk perception regarding topical retinoids.
However, cohort studies (Panchaud etal. 2012; Loureiro etal. 2005; Shapiro etal.
1997; Jick etal. 1993) and a recent meta-analysis (Kaplan etal. 2015b) demon-
strated that inadvertent exposure to topical retinoids does not seem to increase the
rate of major malformations which is in line with invivo and invitro pharmacokinetic data suggesting that their dermal absorption is minimal and unlikely to result
in fetal harm (Jensen etal. 1991; Lehman etal. 1988). However, a rare association
suggested by the case reports still cannot be excluded and contraindicates their use
during pregnancy.
3.4.1.4 Monotherapy Versus Polytherapy
Psychotropic drug polytherapy in pregnant women is a common practice (Sadowski
et al. 2013). However, data regarding the teratogenicity risk of polytherapy vs
monotherapy with psychotropic drugs are very limited, however, a few studies are
worth mentioning. Tomson etal. reported that VPA is a primary determinant of the
risk of major malformations regarding the combination therapy in pregnant women
using antiepileptic drugs (Tomson etal. 2011). This nding conrmed the results of
the previous studies which suggested that it was VPA and not the number of antiepileptic drugs in the combinations that was associated with the increased risk for
major malformations (Vajda 2010; Vajda etal. 2010). However, a recent study questioned this nding and suggested that topiramate, when used in polytherapy, is also
associated with an increased risk of major malformations (Vajda et al. 2016).
Second-generation antipsychotic monotherapy appears to pose less risk to the fetus
when compared with polytherapy (Sadowski etal. 2013). Nevertheless, this area
remains to be further investigated.
3.4.2 Evaluating theData
As previously mentioned, lack of available data regarding a particular drug’s effects
during pregnancy is one of the biggest challenges we face in the clinical setting.
50
Y. C. Kaplan et al.
Because ethical concerns limit the availability of pregnant women for randomizedcontrolled trials, data regarding the effects of a drug on fetus is not usually available
at the time of its launch. It has been shown that 92.1% of the drugs which have been
approved by FDA between years 1980 and 2000, and 97.7% of the drugs that have
been approved between 2000 and 2010 lack adequate data at the time of their
approval (Adam etal. 2011; Lo and Friedman 2002). It takes at least 6.0±4.1years
to determine the teratogenic effect of a drug after its approval, while ruling out even
takes much longer (9.1±4.5years) (Lo and Friedman 2002). Knowing how to interpret animal and human data therefore becomes more critical.
3.4.2.1 Experimental Studies
Animal Studies
Although there are difculties in extrapolating the results to humans, animal studies
can provide important information regarding the teratogenic effects of drugs.
However, their protocols should be well-planned and results need to be reported and
interpreted carefully in order to rule out any bias (Brent 2004b). Detected malformations should be interpreted regarding the type and rate, since some malformations are common in some species. Variations, denition of which depends on
different factors such as animal species, strain, supplier, and laboratory environment, should not be reported and/or interpreted as major malformations. It should
also be kept in mind that excessive maternal toxicity induced by the drug may lead
to non-specic developmental toxicity in the offspring (Guittina etal. 2000).
3.4.2.2 Human Studies
Case Reports
Case reports are very useful tools in the eld of teratology if used properly.
Observation of a repetitive “rare defect” appearing after a “rare environmental
exposure” (Shepard 1994) by the “astute clinicians” (Carey etal. 2009) has been a
very effective way to detect teratogens. The identication of warfarin (Holzgreve
et al. 1976; Fourie and Hay 1975), diethylstilbestrol (Herbst and Scully 1970),
isotretinoin (Rosa 1983), uconazole (only with high dose and prolonged use for
systemic infections) (Pursley et al. 1996; Lee et al. 1992), and mycophenolate
mofetil (Sifontis etal. 2006; Le Ray etal. 2004) as human teratogens was originally
based on case reports. However, case reports cannot provide any estimates regarding the absolute risk since they lack a denominator. Because it is quite common to
report and publish the positive ndings (Song etal. 2013), case reports trying to
associate drug exposure in pregnancy with relatively common major malformations, the background risk of which is 3% in the general population regardless of
any exposure, exist in the literature. The clinician should be careful in interpreting
those ndings and should only consider the ones reporting a unique and repeating
pattern of malformations with a particularly rare exposure during pregnancy as
a signal.
3 Safety Parameters and Risk Categories Used for Psychotropic Drugs in Pregnancy…
51
Epidemiologic Studies
The ethical barriers that exist for enrolling pregnant women in randomizedcontrolled trials make the observational cohort and case-control studies the primary
sources of information for drug use during pregnancy. Both studies are mutually
complementary in assessing the teratogenic risk of drugs.
The development of teratology information services (TISes), which counsel hundreds of pregnant women every year about drug use in pregnancy, and their networks such as MotherToBaby (formerly OTIS, Organisation of Teratology
Information Services) (Leen-Mitchell et al. 2000) and European Network of
Teratology Information Services (ENTIS) (Schaefer 2011) contributed signicantly
to the eld of teratology by enabling the implementation of multicentral prospective
cohort studies. Prospective cohort studies undertaken by TISes have important
strengths such as assigning the subjects before the outcome is known, identifying
the precise exposure time and minimizing the risk of recall bias by prospectively
collected data, and being able to match the subjects in the exposed and control
groups with regard to potential confounders mentioned below (Källén 2012; Irl and
Hasford 2000).
Recent developments in the information technology have also enabled national
medical databases and birth registries as sources of data for conducting prospective
cohort studies. Medicaid and private insurance claims databases in the United
States, Saskatchewan Health Services Database in Canada, The General Practice
Research Database in UK and Population Medical Databases in Nordic Countries
are important examples which enables relatively quick and inexpensive analysis of
a data from a large population that is prospectively collected for routine purposes
(Ehrenstein etal. 2010). Among other things, pregnancy registries may be productor disease-specic, like the “Epilepsy Pregnancy Register” or the “National
Pregnancy Registry for Atypical Antipsychotics” (EMA 2012).
Case-control studies are designed to assess whether a specic type exposure is
associated with a specic outcome by evaluating both subjects with and those without the specic outcome. A major strength of these studies is their increased statistical power which is usually adequate to detect moderate increases in the rate of
specic malformations (Mitchell 2003). Case-control surveillance systems offer a
convenient approach to carry out these studies. “Slone Epidemiology Unit Birth
Defects Study” in the United States and Canada, “National Birth Defects Prevention
Study” in the United States, and “Hungarian Case-control of Congenital
Abnormalities Study” in Hungary are noteworthy surveillance systems (EMA 2012).
Meta-Analysis
Meta-analysis emerged as a powerful tool of epidemiology enabling the pooling of
results from individual, yet comparable, studies (Egger etal. 2002). This method is
useful in assessing the possible teratogenic effects of drugs, by combining the data
from observational studies, with an increased sample size and power. It may also
offer subgroup analyses, such as organ-specic malformations, which are reported
but not evaluated in individual studies.
52
Y. C. Kaplan et al.
3.4.2.3 Methodological Issues
Sample Size, Characteristics, Follow-Up
The background rate for major congenital malformations is 3%. Very few teratogens
(thalidomide, isotretinoin, valproic acid) increase this rate by a factor of more than
two, while most only increase a specic malformation rate. At least 220 exposed
and controlled (unexposed) pregnancies will be required to show that the major
congenital malformation risk is increased by a factor of 2.5, with a power of 80
percent. Prospective cohort studies, which are usually conducted by TISes, include
a relatively small number of patients (<300). Although this number makes it difcult to detect a specic malformation rate, it is adequate to rule out the particular
drug being a major teratogen. Another issue with these studies is that the pregnant
women who call TISes voluntarily may not be the representative of the general
population. The follow-up period of the infants is usually 1 year and limits the inclusion of the malformations which are identied later. The loss-to-follow-up of pregnant patients due to technical reasons may also be a concern in some of these studies
(Chambers 2011).
Recall Bias
Recall of drug use is a potential limitation of case-control studies due to the reason
that mothers with malformed children may be better at remembering their drug use
and course of pregnancies (Mitchell 2003). Selecting the children with different
malformations in the control group is suggested to overcome this problem.
Confounders
Maternal age, parity, gestational week, previous miscarriages or birth of malformed
infants, folic acid use, body mass index, maternal smoking, alcohol or illicit drug
use are important confounders in studies evaluating the association of structural
malformations with drugs used in pregnancy (Källén 2012). Maternal and paternal
IQ, socioeconomic status, and level of education are important for the studies which
assess long-term neurodevelopmental outcomes in children. A recent study suggested that severity of maternal depression, and not selective reuptake inhibitor antidepressants, was a signicant predictor of a decreased behavioral score in infants
aged 3–6years (Nulman etal. 2015).
Confounding by Indication
The risk of major and/or organ-specic congenital malformations has been demonstrated to increase in some chronic diseases regardless of drug use. For instance,
diabetes and chronic hypertension in the mother have been associated with an
increased rate of congenital malformations (Bateman et al. 2015; Correa et al.
2008). Studies evaluating the possible teratogenic medications should consider and
control, if possible, the effect of underlying diseases. Including an untreated disease
3 Safety Parameters and Risk Categories Used for Psychotropic Drugs in Pregnancy…
53
group may be benecial, however the severity of the disease in such a group may
also be lower since treatment is not required (Källén 2005).
Meta-Analysis
Although considered as the evidence of highest quality, meta-analysis may include
different forms of bias and limitations (Egger etal. 2002). Search should include
different medical databases and languages while validated methods of quality
assessment for the included studies should be chosen. In the context of observational studies, a rigorous systematic review of the included studies should be conducted, and results of the meta-analysis should be discussed with regard to possible
confounders and limitations. It is now generally accepted that studies reporting
positive ndings are more likely to get published than studies reporting negative
ones, which is called publication bias or bias against the null hypothesis and discussed elsewhere (Koren etal. 2014; Song etal. 2013), and may lead to erroneous
interpretations regarding drug safety.
3.4.2.4 Important Points toConsider forMedication Use
During Pregnancy
The background frequency of major congenital malformations is approximately 3%.
Unfortunately, no consensus is available in scientic literature regarding the safety of
a drug during pregnancy in terms of the exposed number of pregnancies without a
detectable teratogenic signal. As Larsen etal. pointed out in their recent review, 200
rst trimester exposures without any signs of increase in risk of malformations (80%
power, 5% level of signicance) would mean that the real risk is not more than three
times higher than the background risk (Larsen etal. 2015). If the exposure number is
increased to 700, the real risk factor would decrease to two. In order to provide a real
risk factor of 1.5, the number of exposed pregnancies without any detectable increase
in risk would be 2000. However, these numbers of exposures are not available for
most of the drugs on the market. Further complicating the issue is that those estimates
are identied for the general risk and specic rare malformations, neonatal complications, and possible long-term effects are not considered in the computations above.
Nevertheless, the European Medicine Agency considers 1000 prospective exposed
pregnancies with known outcome in the rst trimester without any detectable signal
as strong evidence suggesting that the malformation risk is unlikely (EMA 2008). If
this data volume cannot be reached, then the risk assessment should be made according to the available amount of data. The clinician should always weigh the possible
fetal risks of the medication against the consequences of untreated maternal psychiatric illness. A discussion regarding those issues, as well as the medical and personal
priorities should be held between the physician and pregnant patient before deciding
to start, continue, or quit the pharmacotherapy.
54
Y. C. Kaplan et al.
3.5 Lactation
3.5.1 Factors Influencing thePassage oftheMedication into
theBreastmilk andInfant Exposure
3.5.1.1 Maternal Plasma Concentration andPlasma Protein Binding
Because passive diffusion is the primary pathway of medications entering the breast
milk, the maternal plasma concentration of the medication usually shows good correlation with the concentration of the medication in the breast milk depending on
the other pharmacokinetic variables such as the plasma protein binding. A high
volume of the distribution and plasma protein binding leads to a lower maternal
plasma concentration and unbound (free) medication levels which results in lower
breast milk concentrations. For instance, sertraline has a relatively high volume of
distribution and plasma protein binding which leads to a lower maternal plasma and
breast milk concentration (LactMed 2018). On the other hand, lamotrigine’s lower
volume of distribution and plasma protein binding capacity leads to higher breast
milk levels (LactMed 2018).
3.5.1.2 Size oftheMolecule
Most medications, and so do the psychotropic drugs, are small enough to enter the
breast milk. Exceptions are the larger molecules such as heparin.
3.5.1.3 Degree ofIonization
Medications should be nonionized in order to cross membranes and enter the milk.
Of importance, breast milk is relatively more acidic (pH7.2) compared to the maternal plasma (pH7.4) (Hotham and Hotham 2015). Weak bases such as codeine and
amphetamines become ionized at this pH and may accumulate in the milk (Hotham
and Hotham 2015; Hale 2012).
3.5.1.4 Lipid Solubility
Mature milk, which has a relatively stable composition and is produced by
2–3weeks after birth, is composed of ions, proteins, and lipids. Some lipid-soluble
drugs, such as citalopram, may become dissolved in the lipid droplets and be cosecreted which may lead to a higher concentration in a milk with high fat content
(hind-milk) compared to the milk with low fat content (fore-milk) (Ilett and
Kristensen 2005). However, the practical implications of this issue are unclear and
unlikely to inuence the choice of pharmacotherapy (Hotham and Hotham 2015).
3.5.1.5 Pharmacogenomics
Pharmacogenomics of mother and the infant may affect the exposure of the infant
to the drugs in breast milk. This is particularly highlighted for opioids (Madadi etal.
2012). As one study reported, the adverse outcomes in the breastfeeding mother-
infant pairs are signicantly associated with the maternal risk genotypes in CYP2D6
and ABCB1 (Sistonen etal. 2012). However, this domain should be further explored.
3 Safety Parameters and Risk Categories Used for Psychotropic Drugs in Pregnancy…
55
3.5.1.6 Oral Bioavailability
A drug with low bioavailability in adults is usually expected to behave similarly in
neonates. For instance, drugs with large molecules, protein or peptide drugs (unstable in the gut) exhibit limited transfer to the milk and therefore suggest limited
bioavailability of the orally ingested drug in the infant through the breast milk (Ilett
and Kristensen 2005).
3.5.1.7 The Age oftheInfant
The rst 3 days of postpartum is the period in which many drugs and immunoglobulin, lymphocyte, leukocyte, macrophage, and maternal proteins are able to pass to
the colostrum due to alveolar intercellular gaps. These gaps are closed after a week,
and passage of most drugs and molecules is reduced. Although colostrum is able to
contain higher drug concentrations than the mature milk, the amount of colostrum
produced in the early postpartum period is expected to be low (30–100ml/day).
Clinicians should be more careful at this stage, because of the possibility of the high
drug concentration in the milk and premature or unstable newborns may have insufcient capacity to metabolize medications. The amount of milk taken by babies over
1year of age is usually reduced, and consequently the drug intake will be less (Hale
and Rowe 2017). In a review investigating the adverse drug reactions seen in the
breastfed infants whose mothers are using medications, 63% of the cases were
observed in the rst month (newborn) and 16% were in the second month of life
which means that almost 80% of the adverse events occurred during the rst
2 months. Therefore, careful monitoring is particularly needed for this period
(Anderson etal. 2016).
3.5.2 Effect ofMedications onMilk Production
Prolactin released from the anterior pituitary gland is the most important hormone
that provides milk production. Drugs may cause an increase in milk production
through dopamine-blocking actions which result in stimulation of prolactin production and release. Amisulpiride, phenothiazines, and risperidone are the antipsychotics with potent dopamine blocking actions which may cause galactorrhea (Ilett and
Kristensen 2005). In addition, TRH, serotonin, vasopressin, oxytocin, prostaglandins, opioids, histamine, and noradrenaline stimulate prolactin secretion (Richards
and Williams 1976). On the other hand, drugs may interfere with the milk production through decreasing prolactin release or local blood ow to the breast tissue.
Bromocriptine, cabergoline, ergotamine, estrogens, and pseudoephedrine can cause
a reduction in breast milk supply.