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36
N. Kokras et al.
than in the maternal plasma (Babu etal. 2015; Patton etal. 2002). Very few and
inconclusive data exist on amisulpride, aripiprazole, ziprasidone, asenapine, and
sertindole (Babu etal. 2015; Kronenfeld etal. 2017). A note of concern is that following an evaluation by Hummels etal., very few studies regarding antipsychotics
and lactation correctly reported the M/P ratio, the Absolute Infant Dose (AID), and
the Relative Infant Dose (RID), thus raising some concerns about the quality of the
evidence so far (Hummels etal. 2016). Moreover, a most recent systematic review
by Schoretsanitis etal. reports that there is a variability on milk penetration ratio for
many antipsychotics. This might be explained by the differences between foremilk
and hindmilk drug concentrations, as well as differences/errors in sample collection. Caution is required when using this pharmacokinetic evidence to assess infant
antipsychotic exposure. The weight-adjusted relative infant dose and the infant
serum drug concentration are expected to be more relatable indicators of infant drug
exposure (Schoretsanitis etal. 2020b).
2.2.7 Pharmacokinetics ofMood Stabilizers During Lactation
The free, unbound fraction of mood stabilizing drugs can be excreted into breast
milk, where no protein binding occurs (Johannessen 1992). Importantly, if a lactating mother is treated with lithium, the drug is detected in both breast milk and infant
serum. Milk levels highly correlate with plasma levels in low lithium concentrations, but can reach 1.5 times the plasma level, in higher concentrations.
Consequently, mean breast milk levels are approximately 40% of the maternal
serum levels, but levels higher than 50% have also been observed. Accordingly,
infant plasma concentrations are between 10% and 50% of maternal levels, and
80% of the weight-adjusted dose. In addition, infants might lack the ability to
excrete large lithium quantities, and infection or dehydration can exacerbate this
inability, thereby increasing lithium concentrations (Iqbal etal. 2001a, b; Spigset
and Hägg 1998; Craig and Abel 2001). However, a recent study on breastfeeding
neonates (mothers on lithium therapy) showed that even after 53–60days of exclusive breastfeeding, lithium did not accumulate in the infants and, during the lactation follow-up, there was no acute growth or developmental delay (Imaz etal. 2021).
Overall, lithium’s relative infant dose has been reported to be 12.2% (ranging
between 10 and 25%) and the average M/P ratio is 0.49 (Imaz etal. 2019).
Valproate levels in breast milk are low, corresponding to 5% or less of maternal
serum concentrations, as shown by various studies (Grover and Avasthi 2015; Von
Unruh etal. 1984; Nau etal. 1981). The dose found in infants corresponds to less
than 6% of the initial pediatric dose for epilepsy (Spigset and Hägg 1998). Despite
low levels of valproate, there is some risk involved, because of potential fetal hepatotoxicity (Goldberg and Nissim 1994). Regarding carbamazepine, the milk-toplasma ratios are found between 0.4 and 1.8, and infant blood levels range from 6%
to 65% of maternal blood concentration (Grover and Avasthi 2015; Yoshida etal.
1999). However, carbamazepine is considered to have a more favorable pharmaco-
kinetic prole than lithium, as the nal exposure of the lactating infant corresponds
2 Maternal and Infant Pharmacokinetics of Psychotropic Medications…
37
to only a fraction of the lowest therapeutic dose after weight-adjustment (Iqbal etal.
2001b; Spigset and Hägg 1998). Finally, lamotrigine is also excreted, and the breast
milk/maternal plasma ratio may vary considerably, between 40% and 60%, and
even as high as 150%, as shown by several studies (Iqbal etal. 2001a; Ohman etal.
2000; De Haan etal. 2004; Grover and Avasthi 2015). Lactating infants eliminate
lamotrigine slower, therefore are prone to display enhanced lamotrigine levels.
Moreover, it should be highlighted that lamotrigine serum levels in the mother
undergo a rapid increase immediately after delivery, thus loading the breast milk
with high lamotrigine concentrations (Ohman etal. 2000).
2.2.8 Opioid Pharmacokinetics During Lactation
Opioid relative infant dose is generally low (1–5%), however long-term maternal
use (more than 3–4days) potentially leads to drug accumulation in the infant, especially if the newborn’s renal clearance is impaired. Morphine and M6G are excreted
into milk and can be detected in the colostrum. Without counting in MG6, the relative infant dose of morphine is 2–3% of the weight-adjusted maternal morphine
dose. However, MG6, especially in the early postpartum period, might reach high
maternal plasma levels and its bioavailability in the infant still remains unknown
(Ito 2018). Regarding codeine, the related infant dose is 1.2% of the maternal
codeine dose. Despite the apparent safety of codeine and morphine, caution should
be exerted as a rapid/ultrarapid metabolizing mother can transform increased
amounts of codeine to morphine, thus overdosing the lactating infant which has low
capacity of morphine glucuronidation. CYP2D6 genotype status crucially affects
codeine/morphine disposition in milk making it difcult to predict. Moreover, these
relative infant dose calculations for codeine do not include MG6 infant exposure.
Overall, short-term postpartum administration of morphine is compatible with
breastfeeding, but codeine should be avoided according to the FDA (Madadi etal.
2012; Ito 2018). Fentanyl excretion in the colostrum is very low both after epidural
and intravenous administration during delivery. Following transdermal fentanyl
administration to the lactating mother, fentanyl and its metabolite, norfentanyl, are
undetectable in the infant’s blood (relative infant dose 2–3%). Fentanyl exposure of
the lactating infant corresponds to 10% of the one-time oral dose recommended for
anesthesia in children. Such low doses are unlikely to exert any effects, and shortterm fentanyl use during breastfeeding is considered relatively safe (Ito 2018;
Cohen 2009). Tramadol is frequently used for labor analgesia, and its kinetics in the
newborn and breast milk are relatively well-studied. The relative infant dose of tramadol and its metabolite, O-desmethyltramadol combined, is calculated to approximately 3% (Salman etal. 2011). Tramadol metabolism in the neonate is adequate
and becomes substantial over the rst year of life, but in return, accumulation of its
metabolite can take place due to its limited excretion (Bloor etal. 2012). Overall,
tramadol, due to its complex mechanism of action and its contraindication for children younger than 12years of age, is not yet recommended for breastfeeding women
(Ito 2018). Regarding methadone, its breast milk levels are modest. Ingested
38
N. Kokras et al.
methadone through breastfeeding is calculated to be 0,1–0.3 mg daily, and the
weight-adjusted dose for the infant is low, approximately 2,8% of the maternal dose.
However, there have been scarce reports of neonatal abstinence syndrome after
breastmilk feeding was discontinued (Jansson etal. 2008; Jansson etal. 2004). The
relative infant dose of buprenorphine has been reported less than 1–2% of the maternal sublingual dose. For both methadone and buprenorphine, uneventful breastfeeding cases have been reported, although close infant monitoring should take place to
treat infant opioid withdrawal syndrome (Ito 2018). There is limited evidence of
oxycodone milk pharmacokinetics. The relative infant dose might vary from 0.1%
to 3%. However, oxycodone can accumulate in breast milk if the nursing mother
uses the drug for a prolonged period of time (more than 3days) and/or if the newborn’s drug clearance is impaired (Ito 2018).
2.3 Conclusions
Pregnancy results in a myriad of physiological changes, and unavoidably this leads
to signicant changes in the pharmacokinetics of nearly all psychotropics.
Unfortunately, whether these changes are clinically important or not has not been
claried yet (Pariente etal. 2016). Moreover, it becomes immensely more difcult
to clarify the nal net effect of those changes, as many alterations have effects that
cancel each other. Notably, although the placenta barrier normally protects the fetus,
this does not apply to psychotropic medications, which are designed to penetrate
human barriers, such as the blood-brain barrier and thus also the placenta. As a
result, there is no “safe” drug in pregnancy, and pharmacokinetic data should merely
be interpreted as aids in the “risk to benet” decision-making processes made by
clinicians. Randomized trials and well-designed pharmacokinetic studies in pregnant and lactating women would signicantly improve our knowledge. Both kinds
of studies are unlikely to occur, even for psychotropic medications routinely or
widely used, as the pharmaceutical industry lacks the nancial incentive to study
those special populations and the regulatory framework is, righteously, very strict.
Even if all these obstacles were overcome, the recruitment for such studies would
be very problematic (Thomas and Yates 2012).
Based on current limited data, some prescribing strategies based on pharmacokinetics can be concluded: dose reduction during pregnancy is not always as attractive
a strategy as it intuitively sounds, except for very specic cases. Pregnancy itself
results in a reduced bioavailability of many medications and for many psychotropics there is not a clear or linear dose-response curve (W’t Jong and Einarson 2017).
As a result, clinicians should carefully assess the risk of disease exacerbation or
recurrence, and even consider a dose increase if required. From a pharmacokinetics
point of view, in order to minimize the exposure of the fetus to a psychotropic medication, higher protein binding, smaller distribution volume, shorter half-life, and
ideally good afnity with efux transporters are characteristics that would make
one psychotropic medication more suitable than others for pregnant women. In any
case, combinations of drugs should be avoided, especially those involving extensive
2 Maternal and Infant Pharmacokinetics of Psychotropic Medications…
39
P450 metabolism, as the cytochrome is heavily modulated by pregnancy and interactions cannot be easily predicted.
Regarding breastfeeding, traditionally women on psychotropic medications were
discouraged from it, a recommendation mostly based on principle rather than rm
evidence. Alternatively, psychotropic medications were discontinued if breastfeeding was chosen, but this practice also ignores the individual characteristics and
pharmacokinetic prole of each psychotropic medication. It is considered that
infant drug concentration of 10% or less of the maternal drug therapeutic dose is a
safe infant exposure, and for several psychotropic medications there is evidence
(though still not unequivocally rm) that they have nearly undetectable levels in the
lactating infant (W’t Jong and Einarson 2017). A word of caution for those drugs
that display low to moderate levels in the systemic circulation of a lactating infant
is that brain concentrations can be signicantly higher, or more impactful, due to the
immature blood-brain barrier and brain tissue (Craig and Abel 2001). Specic strategies can be implemented to further reduce the exposure of the infant, i.e., selection
of psychotropics with shorter half-life, administration at the lowest effective dose,
breast-feeding and/or pumping milk (for later feeding), just before the scheduled
time to take the medication (Menon 2008; Burt etal. 2001).. Pharmacogenomic
considerations may enter clinical practice in the future, as, for example, CYP
metabolizer status could guide drug dose adjustments during pregnancy and lactation (Betcher and George Jr. 2020). Breastfeeding mothers should be well-informed
and educated, in order to observe for potential adverse effects (Harding and Timko
1999; Fortinguerra etal. 2009). Infant age should also be taken into consideration,
as the potential risks progressively diminish with the maturation of the infant’s
hepatic metabolism and renal clearance. In any case, premature infants should not
be exposed to psychotropics (Craig and Abel 2001).
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N. Kokras et al.
Safety Parameters andRisk Categories
Used forPsychotropic Drugs
inPregnancy andLactation
YusufCemKaplan, HilalErol, andElifKeskin-Arslan
3.1 Introduction
The perinatal period is associated with an increased risk of psychiatric disorders
which may necessitate maternal pharmacotherapy. In this chapter, we aim to provide the reader with the basics of safety assessment regarding medication use during
pregnancy and breastfeeding.
3.2 Pregnancy Risk Categories
The Thalidomide disaster of the 1960s caused a drastic change in our understanding
of risks associated with medication use during pregnancy. One of the key consequences of this incident, apart from the changes in regulations regarding preclinical
trials, was the emergence of a need to develop a categorization for the medications
based on the risks they pose to the fetus and this need led to the introduction of the
various pregnancy risk categories across different countries.
The rst risk categorization system regarding medication use in pregnancy was
developed and introduced in Sweden in 1978, named as The Swedish Catalogue of
Approved Drugs (FASS) and 4 risk categories (A, B, C, D) have been proposed
3
Y. C. Kaplan (*)
Department of Pharmacology, Izmir Katip Celebi University Faculty of Medicine,
Izmir, Turkey
Terafar– Izmir Katip Celebi University Teratology Information, Research and Training
Center, Izmir, Turkey
H. Erol
Independent Researcher, Izmir, Turkey
E. Keskin-Arslan
Department of Pharmacology, Izmir Bakırcay University Faculty of Medicine, Izmir, Turkey
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
F. Uguz, L. Orsolini (eds.), Perinatal Psychopharmacology,
https://doi.org/10.1007/978-3-031-99720-4_3
45