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A.-L. Sutter-Dallay and F. Gressier
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A.-L. Sutter-Dallay and F. Gressier
Mood Stabilizers During Lactation
11
SandeepGrover, DevakshiDua, andNidhiYadav
11.1 Introduction
Bipolar disorder (BD) usually starts in the late teens and early twenties and because
of this, women suffering from this ailment remain at risk of an episode throughout
their reproductive life (Yonkers etal. 2005). Further, available data suggests that
most of the affective disorders, which are post-partum in onset, usually turn out to
be BD in the longitudinal course (Munk-Olsen etal. 2012).
Mood stabilizers (MS) form an integral part of the management of BD. Due to
the severity of the illness, many women continue on MS during pregnancy, which is
carried through into the post-partum period. MS is also often started in the immediate post-partum period in women in whom these medications were withheld during
the pregnancy or at the time of delivery. These medications are also often considered for post-partum onset BD. Continuation or discontinuation of MS during pregnancy and lactation requires appropriate knowledge about the risks and benets of
these medications, both for the mother and the baby (Grover and Avasthi 2015). In
this chapter, we discuss the risks and benets of the use of MS during the postpartum period, both for the mother and the newborn.
In general, the conventional MS includes lithium, sodium valproate, and its congeners, lamotrigine, and carbamazepine. In recent times, other antiepileptic agents
like gabapentin, and atypical antipsychotics like aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, lurasidone, etc. have also been considered to have
mood stabilizing properties (Smith and Dubovsky 2017). Medications like clonazepam, calcium channel blockers, etc., have also been evaluated as MS. In this
S. Grover (*) · N. Yadav
Department of Psychiatry, Postgraduate Institute of Medical Education and Research,
Chandigarh, Punjab, India
D. Dua
Midlands Partnership Foundation Trust, Stafford, UK
© 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_11
275
276
S. Grover et al.
chapter, we will mainly focus on the conventional agents, as information on other
agents is presented in other chapters. Issues related to the use of MS during pregnancy and delivery are not addressed in this chapter.
Available data suggests that there is a high risk of relapse during pregnancy
(Freeman etal. 2002; Jones and Craddock 2005; Viguera etal. 2007b) and the early
post-partum period for BD (Kendell etal. 1987; Terp and Mortensen 1998; Viguera
etal. 2000). While the risk of relapse during pregnancy has been estimated to be
50% or more (Freeman etal. 2002; Jones and Craddock 2005; Viguera etal. 2007b),
with 2.3 times higher risk of recurrence on discontinuation of MS.A prospective
study showed that compared to women who continued the MS during the pregnancy, those who stopped the MS during pregnancy spent about 5 times longer
duration (8.8% versus 40%) of their pregnancy, in the episode (Viguera etal. 2007b).
The risk of episodes during the post-partum period has been estimated to be 40–70%
higher among women with untreated BD (Jefferson etal. 1987) and the risk is
higher in those who discontinue prophylactic treatment (Viguera et al. 2000).
Among the various risk factors for relapse, the rate of discontinuation of MS is an
important marker, with higher risk of relapse associated with rapid discontinuation
of MS (Viguera etal. 2007b). A recent systematic review and meta-analysis that
included data from 37 studies involving 5700 deliveries in 4023 patients estimated
the risk of post-partum relapse to be 35% (95% CI= 29 to 41) (Wesseloo etal.
2016). Another systematic review that included data from 16 studies involving 6064
deliveries of 3977 women estimated the overall risk of post-partum relapse to be
36.77% (Javier Conejo- Galindo 2022). It was further shown that the risk of relapse
during the post-partum period was signicantly higher among those who were medication-free during pregnancy (66%, 95% CI=57 to 75) than those who used prophylactic medication (23%, 95% CI=14 to 37) (Wesseloo etal. 2016). In terms of
clinical variables, available data suggests that the risk of post-partum episodes is
higher when the age of onset of BD is lower, a longer duration of the episode, a history of prior episodes of similar polarity, a family history of BD, history of psychiatric hospitalizations before the pregnancy and absence of prophylaxis (Javier
Conejo- Galindo 2022).
Considering these facts, the selection of appropriate MS for women of reproductive age group, especially during pregnancy and post-partum, requires weighing all
the pros and cons of the use of these drugs. The treating clinicians often face the
challenge of minimizing the risk to the fetus along with minimizing the impact of
maternal morbidity. Clinicians often have to consider either using or not using MS
and determine the reasonable risk with both strategies. It is suggested that considering something as a reasonable risk during pregnancy involves shared responsibility
between the patient and the treating clinician, but it is important to remember that
the nal decision about treatment lies with the informed patient.
11 Mood Stabilizers During Lactation
277
11.2 Beneficial Effects ofBreastfeeding
The post-partum period is associated with the additional clinical dilemma of lactation and breastfeeding. The benecial effect of breastfeeding for both infant and
mother cannot be underscored. Breast milk is considered an ideal form of nutrition,
which confers many advantages to the newborn. As per the American Academy of
Paediatrics, besides being an important contributor to the establishment of emotional bonds and attachment between the mother and the infant (Britton etal. 2006),
breast milk is known to reduce the incidence and/or severity of a wide range of
infectious diseases (Department of Health and Human Service Ofce on Women’s
Health 2003), post-neonatal infant mortality rates, sudden infant death syndrome in
the rst year of life, the incidence of insulin-dependent (type 1) and non–insulindependent (type 2) diabetes mellitus, hematological malignancies (i.e., lymphoma,
leukemia, Hodgkin disease), overweight and obesity, hypercholesterolemia and
asthma in older children and adults (Britton etal. 2006). Breastfeeding has also
been reported to be associated with slightly better performance on tests of cognitive
development (Horta etal. 2018). In terms of maternal benets, breastfeeding has
been reported to decrease post-partum bleeding, lead to faster uterine involution,
decrease menstrual blood loss, child spacing by lactational amenorrhea, earlier
return to pre-pregnancy weight, reduce in the risk of breast and ovarian cancer, and
possibly decreased risk of hip fractures and osteoporosis in the postmenopausal
period (Gartner etal. 2005). Considering these benets, in general, breastfeeding is
recommended for all newborns, with very few absolute contraindications. The use
of medications and drug use are considered as relative contraindications for breastfeeding (Lawrence 2013).
Accordingly, continuing or discontinuing breastfeeding while continuing MS is
often associated with an ethical dilemma and difcult decision-making. The riskbenet should be evaluated by considering physiological and psychological benets
of breastfeeding, the potential negative impact of untreated maternal mental illness
on the infant, maternal-child bonding, the negative consequences of MS on the cognitive and behavioral development of the newborn, and the consequences of
untreated mental illness on the mother (Burt etal. 2001). In general, all efforts must
be made to continue breastfeeding, while minimizing the negative consequences of
the use of MS and other psychotropics. This requires some understanding of physiology of the breast milk secretion.
11.3 Understanding thePhysiological Aspects ofBreast Milk
Secretion andUse ofMS During Lactation
Breast milk secretion can be broadly understood as fore milk and hind milk. Fore
milk is expressed during the rst half of a feed and has lower lipid content, whereas
hind milk, that is secreted during the second half of a feed, is rich in lipid content.
Due to higher lipid content, hind milk contains a higher quantity of lipid-soluble
psychotropic medications compared to the milk secreted in the rst half (Burt etal.
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S. Grover et al.
2001). Additionally, the exposure of newborns to medications is inuenced by the
rate of absorption of medications into the maternal circulation, diffusion of medications from the maternal circulation to the breast milk, and absorption of the medications in the infant. It is important to understand that the concentration of a medication
in breast milk depends on the non-protein-bound concentration of the drug in maternal plasma. Accordingly, the factors are taken into account to determine the concentration of the medication in breast milk, plasma protein binding, the volume of
distribution, lipid solubility, molecular weight, and pka-pH.Medications that have
high plasma protein binding will have low secretion in breast milk, for example,
selective serotonin reuptake inhibitors (SSRIs) have high plasma protein binding,
whereas venlafaxine has low plasma protein binding. Accordingly, the concentration of venlafaxine is expected to be more than that of SSRIs. Medications that have
large volumes of distribution will get sequestered in different uid compartments
leading to low maternal plasma levels and thus low levels of breast milk. Medications
that have high lipid solubility, such as majority of the psychotropic medications,
easily pass through the alveolar cells and thus have more secretion into breast milk.
Drugs with higher molecular weight have a slower diffusion rate and transfer into
the breast milk. The pKa-pH value of a particular drug is the pH at which the medication is equally ionic and nonionic. Ion trapping occurs when pKa is more than 7.2,
leading to high concentrations in breast milk (Ito and Lee 2003).
In clinical and research practice, the relative infant dose is an estimate of the
amount of drug dose of the breastfeeding infant. Usually, milk to plasma ratio is
considered an indicator of the secretion of the medication in the breast milk. The
relative infant dose is calculated as dose in the infant in mg/kg/d/dose in the mother
in mg/kg/d. Dose in an infant is the concentration of the medication in the breast
milk divided by the volume of breast milk consumed daily. Practically relative
infant dose of <10% is considered acceptable, whereas drugs that have a relative
infant dose of>25% are considered to have a therapeutic effect if absorbed and are
accordingly unacceptable (Ito and Lee 2003). However, it is important to remember
that absorption of medication also depends on the oral bioavailability in the infant.
Limited data is available on the oral bioavailability of drugs in infants. In addition,
inadequate information is available regarding how much infant plasma concentration has the potential to harm (Grover and Avasthi 2015).
Factors that inuence the quantity of medications in breast milk include serum
albumin, lactose, lysozyme, and other enzymes, prolactin levels, and minerals like
calcium and phosphates (Burt etal. 2001). It is also important to understand the factors that inuence the excretion of various medications from the body of the neonates. Neonatal cytochrome P-450 activity is about half of that seen in adults. Most
of the neonates take about 2weeks to develop from minimal levels to almost adult
levels, the capability to conjugate various compounds (Beath 2003). The kidneys of
the neonates are also functionally immature, hence, various medications that are
primarily eliminated through kidneys tend to accumulate. Effects of various medications on the brain also depend on the blood-brain barrier (BBB) and it is well
known that, compared to adults, the BBB in neonates is also immature, which leads
to a higher concentration of lipid-soluble agents (10–30 times) in the CSF than in
11 Mood Stabilizers During Lactation
279
serum. Additionally, compared to older infants, fat storage sites are relatively lower
in neonates. This leads to a higher concentration of lipid-soluble substances in the
central nervous system of newborns (Burt etal. 2001). Accordingly, all these facts
must be considered when recommending breastfeeding in a newborn.
11.4 MS andLactation
11.4.1 Lithium
There is limited data in terms of the effect of continuation of lithium during the
post-partum period and continuation of breastfeeding. Studies have estimated the
serum lithium levels in infants, whose mothers have been taking lithium in the dose
of 600mg to 1500mg/day during breastfeeding and these have reported the levels
among infants to vary from 0% to 30% of the maternal levels (Bogen etal. 2012;
Moretti etal. 2003). However, a recent case report estimated infant serum lithium
levels to be 58% of the maternal levels (Frew 2015). Another study evaluated the
maternal level, levels of lithium in breast milk, and levels in the infants of 10 mothers taking lithium in the dose of 600mg/day to 1200mg/day. The maternal levels
varied from 0.43 to 1.31mmol/liter, the levels in the breast milk were found to be
0.19 to 0.48mmol/liter, and infant levels were found to be 0.08 to 0.25mmol/liter
(Viguera etal. 2007a). A review of literature that included data from 39 motherchild dyads in which the infants were breastfed for a mean duration of 58.9 (83.3)
days was obtained from 13 case reports/series. The mother’s serum lithium dose
was 904 (SD: 293) mg/day with serum lithium levels of 0.73(SD:0.26) mEq/L,
breast milk lithium concentration was 0.84 (SD:0.14) mEq/L, and the mean infant
lithium plasma/serum concentration of 0.23(SD: 0.26) mEq/L.The majority (80%)
of the infants did not experience adverse effects and their serum lithium concentration was ≤0.30mEq/L and a small proportion (20%) had a transient adverse event
(i.e., acute toxicity or thyroid alterations) (Imaz etal. 2019). A recent retrospective
study included data from 25 infant-mother dyads and analyzed the data by dividing
the sample into a high exposure group (HEG, lithium concentrations≥0.6meq/l)
and a low exposure group (LEG, < 0.6meq/l). The median serum lithium level at
birth in the HEG and LEG was 0.90meq/l and 0.40meq/l, respectively. The difference persisted between the two groups at follow-up (0.20meq/l vs 0.06 meq/l,
p<0.05), despite the reduction in maternal dose. The rate of neonatal symptoms in
the HEG was nearly twice that of the LEG group (85.7% vs 41.2; p=0.08) at birth
and was about two and half times (28.6% vs 11.8%; p=0.55) at follow-up at a mean
of 24days. The symptoms at birth included central nervous symptoms (jitteriness,
agitation, lethargy), jaundice, respiratory symptoms (apnea, need for continuous
positive airway pressure and/or ventilation), renal symptoms (increased plasma creatinine levels), and thyroid symptoms (increased levels of thyroxine). There was no
statistically signicant difference between the two groups for symptoms in different
organ systems. In terms of the need for inpatient care, 28.6% of infants in HEG and
only 5.9% in LEG (p= 0.19) required admission. All infants with symptoms at
280
S. Grover et al.
follow-up were either in the HEG or exposed to additional psychotropic medication.
Both in terms of neonatal outcomes and outcomes at follow-up, children of mothers
treated with additional psychotropics experienced more adverse outcomes (Whaites
Heinonen etal. 2023). Another retrospective study evaluated 30 (21 girls and 9
boys) infants exposed to lithium through breastmilk. The median serum lithium
level was 0.10 mmol/L in the second week of life (range < 0.05–0.7 mmol/L),
0.08 in weeks 2–4 (range < 0.05–1.2), 0.06 in the second month of life
(range<0.05–0.2) and 0.07 after 2 months of age (range<0.05–0.2). Unexpectedly
high lithium concentrations were found in two infants in the rst month of life.
Apart from poor weight gain, no adverse effects were noted (Heinonen etal. 2022).
In terms of neonatal side effects, occasional reports have documented adverse
effects like hypothermia, hypotonia, lethargy, and T-wave modications on electrocardiogram (ECG) among neonates whose mothers were taking lithium during the
post-partum period. There is some data to suggest a possible association between
feeding difculties with maternal use of lithium during post-partum, but the evidence for this is inconclusive (Bogen etal. 2012; Imaz etal. 2021a, b). Available
data from small sample size studies suggests a lack of acute growth or developmental delays with exposure to lithium in neonates or infants (Imaz etal. 2021a, b).
Based on the available literature, the British Association for Psychopharmacology
(BAP) recommends that if lithium is continued during pregnancy, serum lithium
levels should be monitored at monthly intervals up to 36weeks and then weekly till
delivery. Lithium should be stopped for 24–48h before a planned cesarean section
or induction of labor. Serum lithium levels should be measured 12h after the last
dose. If serum lithium levels do not exceed the therapeutic range, lithium should be
restarted on day 1 postnatal and the levels should be checked again after 1week
(McAllister-Williams etal. 2017).
11.4.2 Valproate
Available data suggests that valproate is minimally secreted in breast milk. A small
sample size study, which estimated the valproate level in 6 breastfed mother-infant
pairs, reported infants serum valproate levels in the range of 0.9–2.3% of the mother’s serum level (Piontek etal. 2000). Another study, which was limited to 2 infants
whose breast-feeding mothers were taking valproate, reported valproate levels in
the infants to be 1.5 and 6%, respectively (Wisner and Perel 1998). A recent study
that involved 30 nursing mothers suffering from epilepsy showed that with the mean
valproic acid levels of 39 (SD: 16.7) mg/L in the maternal serum, the level of the
same in milk was 1.6 (SD: 3.9mg/L) and mean of 4.3 (SD: 4.3) mg/L in the infant
serum. The ratio of milk/maternal serum levels ranged from <0.03 to 0.25 (mean:
0.03; SD: 0.06), and the infant/maternal serum level ratio ranged from <0.03 to 0.61
(mean: 0.11; SD: 0.13). Overall, about two-thirds of the milk and one-third of the
infant valproate concentrations were below the quantication limit. The authors did
not nd any signicant correlation between maternal serum and milk levels or
between maternal and infant serum levels. Based on their ndings, the authors
11 Mood Stabilizers During Lactation
281
concluded that there is a very small level of transfer of valproate from the mother to
the breastfeeding infant (Ivana Kacirova 2019). Based on all these ndings, it can
be said that valproate/valproic acid use during lactation is safe. American Academy
of Neurology (AAN) and American Academy of Pediatrics (AAP) support breastfeeding if the mother is taking valproate (Harden etal. 2009; Sachs and Drugs
2013). However, it is important to remember that occasional case reports have docu-
mented side effects in the form of anemia, reticulocytosis, and thrombocytopenic
purpura in infants whose mother was treated with valproic acid during the postpartum period. These side effects disappeared when the mother stopped breastfeeding (Stahl etal. 1997).
11.4.3 Carbamazepine
Most of the data on carbamazepine in breastfeeding infants have been based on an
assessment of offspring of mothers who took the drug during pregnancy. The concentration of carbamazepine has been estimated to be 6–65% of maternal levels
among infants (Chaudron and Jefferson 2000). However, it is important to note that
there are occasional case reports of transient hepatic dysfunction (Frey etal. 1990;
Merlob etal. 1992) in infants whose mothers were taking carbamazepine during
breastfeeding (Frey etal. 1990; Merlob etal. 1992). The neonate developed transient cholestasis with pale stools and marked elevations of glutamyltransferase
(322U/L), conjugated bilirubin (3.5mg/dL), and bile acids (78.5μg/mL), raised
transaminases levels (AST 112U/L, ALT 56U/L) with normal coagulation prole
between the third and seventh week of life (Frey etal. 1990).
A recent study that included data from 66 mother-infant dyads assessed the carbamazepine levels in mothers, breast milk, and infant serum. The carbamazepine
levels in maternal serum varied from 1.4 to 10.4mg/L (median 4.5mg/L), varied
from 0.5 to 6.7 mg/L (mean 2.1 mg/L) in breast milk, and varied from 0.5 to
2.6 mg/L (median 0.5 mg/L) in infant serum. The carbamazepine-10,1-epoxide
ranged from 0.3 to 5.4mg/L (median 0.9mg/L), 0.3 to 3.7mg/L (median 0.5mg/L),
and from 0.3 to 0.6mg/L (median 0.3mg/L) in maternal serum, breast milk and
infant serum, respectively, when measured between the 6th and 29th postnatal day
(median 7days). There was a signicant correlation between the maternal serum
and the breast milk carbamazepine and carbamazepine-10,1-epoxide levels. There
was a correlation between breast milk carbamazepine levels and infant serum levels.
There was no signicant correlation between maternal and infant serum levels. In
only 7% of the cases, the milk carbamazepine levels were in the reported therapeutic range, and 65% of the infants had carbamazepine levels that were below the
therapeutic range (Kocirova etal. 2021). Both AAN and AAP support breastfeeding
if the mother is taking carbamazepine (Harden etal. 2009; Sachs and Drugs 2013).