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282
S. Grover et al.
11.4.4 Oxcarbazepine
Oxcarbazepine, a congener of carbamazepine, has been used for the treatment of
BD. There is a lack of data on the use of oxcarbazepine during breastfeeding. A case
report suggests a low milk plasma ratio (0.5) and a low concentration in human milk
(<11μg/mL) with a low relative infant dose (1.5–1.7%) (Lutz etal. 2007). A case
report documented normal development in the infant exposed to oxcarbazepine
through breast milk during the rst month of life (Gentile 2003).
11.4.5 Lamotrigine
Available data in the form of case reports and case series suggests mean milk/
plasma ratios for lamotrigine to range from 0.40 to 0.61 (Liporace et al. 2004;
Ohman etal. 2000; Page-Sharp et al. 2006; Rambeck etal. 1997). A study that
involved 30 breastfeeding mothers receiving lamotrigine (50–800 mg/d;
mean=386.5) and their infants reported a mean milk/plasma ratio of 41.3% with a
range of 5.7 to 147%. Lamotrigine concentrations were higher in the breast milk
4hours after the intake of the drug by the nursing mother, although the nding was
not statistically signicant. Infant plasma concentrations were 18.3% of that
reported for nursing mothers. However, except for mild thrombocytosis in 7 out of
8 infants, no other adverse events were observed (Newport et al. 2008). A case
report documented multiple episodes of apnea in the newborn while the mother was
receiving lamotrigine, which improved completely when breastfeeding was terminated (Nordmo et al. 2009). A recent relatively large sample size study, which
included data from 158 women and 143 breastfed newborns collected between the
second and fth postnatal days, showed that the median lamotrigine concentrations
in mg/L were 2.7, 1.4, and 1.7in maternal serum, milk, and newborn serum, respectively. The median milk/maternal serum concentration ratio and newborn/maternal
serum concentration ratio were 0.6, and the median newborn serum/milk concentration ratio was 1.00. A signicant correlation was observed between milk and maternal serum concentrations and between newborn serum and milk concentrations,
maternal serum concentrations, maternal daily dose, and dose-related to maternal
body weight. Based on these ndings, the authors concluded that exposure to
lamotrigine among breastfed newborns was lower than that exposure during pregnancy (Kocirova et al. 2022). LactMed considers the use of lamotrigine during
breastfeeding to be relatively safe and recommends evaluating the plasma levels and
monitoring the platelet count of infants.
11.4.6 Topiramate
A small sample study involving 5 mother-infant pairs reported very low topiramate
concentrations in the infants, with no adverse effects seen among the infants (Ohman
etal. 2002). The mean milk/maternal plasma concentration ratio was 0.86 (range,
11 Mood Stabilizers During Lactation
283
0.67–1.1) at 2–3weeks and 1month and 0.69 at 3months after delivery. Two out of
the 3 infants who were breastfed had detectable topiramate levels, i.e., >0.9 microM
concentrations, however, this was lower than the limit of quantication (2.8
microM), and one infant had an undetectable concentration (Ohman etal. 2002).
There are other case reports of safe use of topiramate during lactation (Gentile
2009). However, a case report documented the association of diarrhea with topira-
mate, while breastfed by a mother who was receiving topiramate (Westergren
etal. 2014).
11.4.7 Gabapentin
The mean milk/maternal plasma concentration ratio of gabapentin in milk has been
estimated to be 1 (range, 0.7–1.3) from 2weeks to 3months. Accordingly, the mean
infant dose is reported to be 0.2–1.3mg/kg/day, which is much lower (1.3–3.8%)
than the maternal dose. In terms of plasma concentrations, plasma concentration in
breast-fed infants has been estimated to be 12% of the mother’s plasma levels. No
adverse effects were observed with low plasma concentration in the breastfed
infants (Ohman etal. 2005). In a case report, the relative infant dose was estimated
to be 2.34%, with the absolute infant dose being approximately 3% of the recommended children’s dose for gabapentin, and the infant plasma level was 0.4mg/L,
which was about 6% of the maternal plasma drug concentration. No adverse events
were reported in the infant (Kristensen etal. 2006).
11.5 Recommendations forUse ofMS During Puerperium
andLactation
Table 11.1 summarizes expert recommendations on the use of MS during the lactation period. There is a high risk of relapse among patients with BD during the puerperium. Hence, reinitiating the MS in the immediate post-partum period is
Table 11.1 Expert recommendations based on scientic evidence and clinical experience
High risk of relapse in the post-partum period
Initiation and continuation of MS must be considered
The decision to breastfeed the newborn must consider the risks & benets
Baseline and regular evaluation of the newborn by a pediatrician is a must, with close
monitoring for side effects
The lowest effective dose of MS should be used
Medications must be timed according to the neonates’ feeding pattern
Valproate is considered safe; monitoring of infant liver function test is recommended
Breastfeeding should be done with caution in mothers receiving lithium; regular monitoring of
electrocardiogram, lithium levels, and blood counts to be done; information to be given to
parents regarding warning signs in the newborn
Lamotrigine is considered safe, however, data is sparse
Carbamazepine may be used with caution and monitoring
284
S. Grover et al.
recommended for patients at high risk of relapse. Available data suggests that the
use of lithium as a prophylactic agent in the post-partum period brings down the
relapse rate from nearly 50% to less than 10% (Cohen etal. 1995).
Starting an MS during the post-partum period for the rst episode of hypomania/
mania/mixed episode is a tricky one, and this must be based on the consideration of
the severity of symptoms and risk of continuation of symptoms to the mother and
the fetus, including mother-child bonding. If the symptoms are severe enough, the
use of MS needs to be considered.
If the MS is started, then whether to allow breastfeeding or not should take the
risk and benets into account. The risk-benet analysis should take into consideration the benets of breastfeeding (both physiological and psychological), the
desires of the mother, the risk of infant exposure to the medication, and the possibility of refusal to treatment by a severely ill mother in favor of giving up breastfeeding
(Gartner etal. 2005).
If the decision is made to continue breastfeeding while using MS, the newborn
should be evaluated at the baseline and also must be monitored closely to minimize
the risk. The newborn should be examined by a pediatrician for baseline behavior
and other parameters like sleep, feeding, and alertness. The newborn should be evaluated from time to time by the pediatrician to ensure normal development. The
parents need to be informed about the possible side effects of the medication
being used.
Certain physiological changes that occur during infancy must be remembered,
which can help minimize the negative effects of MS on the infant, who is continuing
breastfeeding. Older infants metabolize and eliminate various drugs more efciently
than younger infants, and they generally sleep for longer durations. The long duration of sleep can help in planning the dosing of the mother. It is generally recommended to administer the dose to the mother immediately after breastfeeding and
just prior to the baby’s longest sleep interval (Grover and Avasthi 2015). While
allowing breastfeeding, a close liaison needs to be maintained with the pediatrician
and the discussions need to include sharing information about potential side effects
of medication exposure to the newborn and possible drug interactions with other
commonly prescribed medications to infants (e.g., antibiotics, nonsteroidal antiinammatory agents, acetaminophen).
If the MS is used during breastfeeding, the dose must be kept at the lowest effective dose. However, such an attempt must not lead to ineffective dosing, poor symptom control, and resultantly unnecessary exposure to the neonate.
In terms of selection of the MS, valproate is considered to be safer than lithium.
AAN and AAP support breastfeeding if the mother is taking valproate (Harden etal.
2009; Sachs and Drugs 2013). However, monitoring of liver function tests and blood
counts for the newborn is recommended. Accordingly, if a clinician needs to start
MS for the rst time during the post-partum period and parents/mothers wish to
continue breastfeeding, valproate needs to be considered as the preferred agent.
The American College of Obstetricians and Gynecologists (ACOG) categorizes
the risk of continuing psychotropic medications during lactation into ve categories
(L1 = Safest; L2 = Safer; L3 = Moderately safe; L4 = Possibly hazardous;
11 Mood Stabilizers During Lactation
285
L5=Contraindicated). Among the currently available MS divalproex (L2), and carbamazepine (L2) are considered to be safer than other options. Lithium is placed in
the L4 category and lamotrigine is placed in the L3 category. Among the antipsychotics olanzapine is placed in the L2 category; risperidone, aripiprazole, and clozapine are placed in the L3 category, and quetiapine and ziprasidone are placed in
the L4 category (ACOG Clinical Practice Guideline 2007).
Another categorization of medications according to the lactation risk includes
the Hales categorization. According to this categorization, the available medications
are divided into ve categories, i.e., L1- Safest; L2- Safer; L3-Moderately Safe; L4Possibly Hazardous; and L5- Contraindicated. This categorization is updated every
2 years. According to this, carbamazepine and valproate are placed in the L2 category. Lithium is placed in the L4 category and lamotrigine is placed in the L3 category. Among the antipsychotics, olanzapine and quetiapine are placed in the L2
category; risperidone and clozapine are placed in the L3 category, and quetiapine
and ziprasidone are placed in the L4 category.
Accordingly, if someone has to start a MS for the rst time during the post-partum period, valproate and carbamazepine are considered to be most compatible with
breastfeeding. However, it is important to note that it is recommended to monitor
the liver function tests of newborn while using valproate. Among the antipsychotics,
olanzapine and quetiapine are considered to be most compatible with breastfeeding.
In recent times data has also emerged on the safety of lurasidone during lactation.
However, this is only in the form of case reports and not sufcient to make any
specic recommendations.
According to the recommendations of AAP, breastfeeding should be done with
caution while using lithium in mothers, and if this is permitted then the breastfed
infant needs to be monitored for serum lithium levels, ECG, and complete blood
counts from time to time (Sachs and Drugs 2013). Accordingly, lithium needs to be
used when this has been used during pregnancy or the patient has a past history of
response to lithium. If there are no contraindications, the mother may be given an
option to switch to valproate. It is important to remember that mothers may require
lower doses of lithium during the post-partum period when compared to those
required during pregnancy. Hence, the maternal lithium dose needs to be reduced to
the pre-pregnancy level, immediately after delivery, and serum lithium levels must
be monitored. Further, the mother must be informed to monitor the newborn for
signs of dehydration, lethargy, and feeding problems. The newborn must be screened
for thyroid and renal functions, and maternal and infant serum lithium levels must
be done if clinically indicated. The renal functions of the newborn must be monitored closely, especially during the rst 6weeks of life. The newborn must also be
monitored for subtle neurological signs and needs to be referred for early intervention when indicated (Viguera etal. 2007b; Ugaz and Sharma 2016).
Lamotrigine is also considered safe during breastfeeding. However, it should be
used during lactation when other safer options are not available. If carbamazepine
is used, then the infant should be monitored closely for jaundice, drowsiness, adequate weight gain, and developmental milestones (Davanzo etal. 2013). LactMed
286
S. Grover et al.
database also recommends similar monitoring of breastfeeding infants, whose
mothers are receiving carbamazepine. Data for other anticonvulsants is cursory.
11.6 Conclusion
The issue of the safety of the use of MS during lactation is far from being resolved.
Accordingly, the decision to prescribe while continuing breastfeeding should be
taken in the light of the severity of mental disease, and MS should be considered
only when the potential risk to the fetus from exposure to medication outweighs the
risk of untreated maternal mental disorder. The selection of the medication depends
on the balance between safety and efcacy prole. Whenever MS is started during
lactation, the newborn must be monitored closely.
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Benzodiazepines andZ-Drugs
inPregnancy
CesarioBellantuono
12.1 Introduction
Psychiatric disorders during pregnancy and postpartum are common and often need
to be treated with psychotropic drug treatment. Benzodiazepines (BDZs), together
with the so-called hypnotic Z-drugs, are one of the most widely prescribed psychotropic treatments, not only in psychiatric practice but also in several medical elds,
for the treatment of several psychopathological conditions, particularly concerning
acute anxiety and relevant sleep disorders. It has been estimated that from 5% to
15% of the adult general population have received a prescription of BDZs and
Z-drugs, in many cases even for a long period of time (Galbally etal. 2014). It was
documented that approximately 50% of adults report a difculty in initiating or
maintaining sleep or having unrefreshing sleep, whereas upwards of 20% of adults
meet strict diagnostic criteria for a diagnosis of clinically relevant insomnia.
Insomnia is also the most prevalent sleep disorder experienced in women during
pregnancy, affecting a signicant number of pregnant women. The prevalence of
insomnia during pregnancy is usually high from the start, and two-thirds of pregnant
women suffer from insomnia in the later months of their pregnancy. Results emerging from a recent meta-analysis conrm that the prevalence of insomnia is higher
during pregnancy, particularly in the third trimester; the overall prevalence during
the antenatal period was estimated to be 38% (Sedov etal. 2021). It is well established that insomnia is related to several potential maternal and infant health risks,
such as adverse pregnancy outcomes (e.g., hypertension, gestational diabetes mellitus). Disturbed sleep in early and late pregnancy may also increase the risk of
cardio-metabolic disorders, which are associated with maternal and infant morbidity.
12
C. Bellantuono (*)
DeGra Clinic for Perinatal Mental Disorders, Verona, Italy;
http://www.depressionegravidanza.it
© 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_12
289
290
C. Bellantuono
Insomnia is also frequently related during pregnancy and postpartum to several
psychiatric disorders, such as major depression, general anxiety, and post-traumatic
stress disorders. In addition, sleep loss during pregnancy has been associated to fetal
intrauterine growth retardation and longer duration of delivery (Wang etal. 2020).
During the last two decades, with a parallel increased focus in the clinical research
and development of newer antidepressants and antipsychotics, we assisted to a
reduced interest in BDZs, generating therefore the false impression that these drugs
represent an outdated issue in the eld of clinical psychopharmacology, despite
their current widespread utilization in general population. On the other hand, the
prescription of anxiolytic and sleep-promoting drugs may be responsible for their
uncontrolled, long-term use, with a higher potential for abuse, misuse, and dependence, particularly among polysubstance users (Walton et al. 2016). However, it
should also be said that the above-mentioned risks need to be always carefully balanced with the clinical benets that many patients may experience with a short or
intermittent use of these drugs taken at therapeutic dosages.
Many expert opinions support the use of BDZs and Z-drugs as treatments of
choice for acute situational anxiety, anxiety disorders associated with depressive
episode, insomnia, and alcohol withdrawal syndromes. Tolerance can develop to
sedation and possibly to psychomotor impairment, but not to the anxiolytic effect.
Moreover, in contrast to commonly held opinion, BDZs are not frequently misused
or at risk of misuse of other substances in patients without substance use disorders
who are prescribed these drugs for appropriate indications and at lowest effective
therapeutic doses with regular clinical monitoring by the attending physician
(Dubovsky and Marshall 2022). It is also well known that BDZs and Z-drugs are
usually not lethal in overdose, except when ingested with other substances, such as
alcohol, opioids, and CNS depressant drugs. The mechanism of action of BDZ at
CNS level is clearly delineated as well as their pharmacokinetic properties, metabolic pathways, and risk of drug interaction, allowing for greater precision in their
routine clinical use. Moreover, the continued widespread use of antianxiety and
hypnotic medication for several clinical conditions testies their usefulness for
many patients, but at same time strongly recommend that these drugs must be prescribed and used in agreement with the rules of good clinical practice.
The common assertion that the prescription of these drugs leads by default to the
abuse of other substances or misuse seems therefore not supported by clinical experience and observational studies. In any case, considering the current widespread
prescriptions of BDZs and Z-drugs both in general practice and in specialist psychiatric and non-psychiatric setting, it is advisable for an appropriate use to encourage
the implementation of specic training interventions concerning their prescriptions
in clinical setting; this strategy is considered a useful tool to minimize the risk of
abuse and/or misuse by some patients as well as the risk of malpractice by physicians’ prescribers. Finally, it is worthwhile to remember that since 2–3% of pregnant women take a BDZ and/or a Z-drug, the issue concerning their prescription in
the perinatal period is not trivial, still remaining a topic for future clinical and epidemiological studies (Bellantuono etal. 2014; Bais etal. 2020).
12 Benzodiazepines andZ-Drugs inPregnancy
291
12.2 Pharmacological Profile ofBenzodiazepines
andZ-Drugs
Benzodiazepines (BDZs) are a pharmacological class of drugs including agents
that work on the CNS, by selectively acting on gamma-aminobutyric acid alfareceptors (GABA-A). GABA is a neurotransmitter that inhibits or reduces the
activity of neurons within the brain, particularly in the amygdala and prefrontal
cortex. BDZs open GABA-activated chloride channels and allow chloride ions
to enter the neurons. This makes the neuron negatively charged and resistant to
excitation. Even though all BDZs work in a similar way at CNS level, there are
relevant differences in the way in which a specic BDZ acts on different
GABA-A receptor subtypes. In addition, some BDZs are more “potent” than others and are eliminated from the plasma more slowly than others; some BDZs can
also generate active metabolites, as in the case of diazepam, which generates the
desmethyl-diazepam, also called “nordiazepam”. Since the introduction of the
rst BDZ, the chlordiazepoxide in 1962, many other compounds were introduced into the pharmaceutical market. These drugs have been usually classied
according to their length of elimination plasma half-life (t½), hepatic metabolic
pathways, the formation of active metabolites, and the interactions with other
drugs. All BDZs are commonly considered very safe drugs, as no fatalities have
been associated in patients taking these drugs in overdoses; symptoms observed
after overdose of BDZs alone include usually deep drowsiness, sedation, and
muscle relaxation. Moreover, BDZs do not cause in huge overdosages severe
respiratory, cardiovascular, and CNS depression. Their side effects prole is
well known (e.g., mild worsening of psychomotor performance and sleepiness),
and it is dose-dependent, therefore these drugs must be prescribed in each
patient using the lowest effective dosage for the treatment of anxiety conditions
as well as sleep problems (Bellantuono etal. 1980). This is particularly relevant
to avoid or minimize a withdrawal reaction in newborns exposed to such medication during pregnancy. Table12.1 summarizes the most relevant pharmacological characteristics of BDZs.
Z-Drugs are a non-benzodiazepine class of drugs commonly prescribed in clinical practice for the short-term treatment of insomnia. Z-drugs, also dened as “hyp-
notic benzodiazepine receptor agonists” (HBRA), include the following agents:
zolpidem, zopiclone, and zaleplon. HBRA binds to the BDZ receptor subunit of the
GABAThese agents are metabolized by the liver, have a short elimination half-life ranging
from 2 to 6h, are generally well tolerated by the patients, and are usually considered
to be less addictive and/or habit-forming than BDZs. However, a number of cases of
dependence, abuse, and misuse have also been reported in many patients treated
with these drugs for a long time.
as an anxiolytic (low dose) or hypnotic (high dose). Therefore, in routine clinical
practice, the dosage must always be “individualized” in each patient to nd the lowest
receptor. The peak plasma concentration is attained 1–2 h after intake.
A
Overall, it is worthwhile to remember that each BDZ can act at different dosages