Lithium Placental Passage and Obstetrical Outcome: Implications for Clinical Management During Late Pregnancy

Harvard University, Cambridge, Massachusetts, United States
American Journal of Psychiatry (Impact Factor: 12.3). 12/2005; 162(11):2162-70. DOI: 10.1176/appi.ajp.162.11.2162
Source: PubMed


Lithium has been used during pregnancy for more than four decades, but quantification of fetal lithium exposure and clinical correlations of such exposure are limited. The study objectives were to 1) quantify the rate of lithium placental passage, 2) assess any association between plasma concentration of lithium at delivery and adverse perinatal events, and 3) determine whether lithium concentrations can be reduced by briefly suspending therapy proximate to delivery.
Maternal blood and umbilical cord blood were obtained at delivery for assay of lithium concentrations, and obstetrical outcome data were collected prospectively for 10 participants. These data were combined with results from MEDLINE and PsycINFO searches that identified 32 cases in which maternal lithium was administered throughout delivery. Statistical analysis of the pooled data was conducted.
The ratio of lithium concentrations in umbilical cord blood to maternal blood (mean=1.05, SD=0.13) was uniform across a wide range of maternal concentrations (0.2-2.6 meq/liter). Significantly lower Apgar scores, longer hospital stays, and higher rates of CNS and neuromuscular complications were observed in infants with higher lithium concentrations (>0.64 meq/liter) at delivery. Withholding lithium therapy for 24-48 hours before delivery resulted in a 0.28 meq/liter reduction in maternal lithium concentration.
Lithium completely equilibrates across the placenta. Higher lithium concentrations at delivery are associated with more perinatal complications, and lithium concentrations can be reduced by brief suspension of therapy proximate to delivery. Treatment guidelines are proposed to improve neonatal well-being when lithium use is indicated in late pregnancy.


Available from: D Jeffrey Newport
2162 Am J Psychiatry 162:11, November 2005
Lithium Placental Passage and Obstetrical Outcome:
Implications for Clinical Management
During Late Pregnancy
D. Jeffrey Newport, M.D., M.S.,
Adele C. Viguera, M.D., M.P.H.
Aquila J. Beach, B.A.
James C. Ritchie, Ph.D.
Lee S. Cohen, M.D.
Zachary N. Stowe, M.D.
Objective: Lithium has been used during
pregnancy for more than four decades,
but quantification of fetal lithium expo-
sure and clinical correlations of such expo-
sure are limited. The study objectives were
to 1) quantify the rate of lithium placental
passage, 2) assess any association between
plasma concentration of lithium at deliv-
ery and adverse perinatal events, and 3)
determine whether lithium concentrations
can be reduced by briefly suspending ther-
apy proximate to delivery.
Method: Maternal blood and umbilical
cord blood were obtained at delivery for
assay of lithium concentrations, and ob-
stetrical outcome data were collected pro-
spectively for 10 participants. These data
were combined with results from MEDLINE
and PsycINFO searches that identified 32
cases in which maternal lithium was ad-
ministered throughout delivery. Statistical
analysis of the pooled data was conducted.
Results: The ratio of lithium concentra-
tions in umbilical cord blood to maternal
blood (mean=1.05, SD=0.13) was uniform
across a wide range of maternal concen-
trations (0.2–2.6 meq/liter). Significantly
lower Apgar scores, longer hospital stays,
and higher rates of CNS and neuromuscu-
lar complications were observed in infants
with higher lithium concentrations (>0.64
meq/liter) at delivery. Withholding lithium
therapy for 24–48 hours before delivery re-
sulted in a 0.28 meq/liter reduction in ma-
ternal lithium concentration.
Conclusions: Lithium completely equili-
brates across the placenta. Higher lithium
concentrations at delivery are associated
with more perinatal complications, and
lithium concentrations can be reduced by
brief suspension of therapy proximate to
delivery. Treatment guidelines are pro-
posed to improve neonatal well-being
when lithium use is indicated in late
(Am J Psychiatry 2005; 162:2162–2170)
The management of bipolar disorder during pregnancy
remains one of the most daunting challenges of psychiat-
ric practice. Although the risk for relapse of bipolar disor-
der during gestation is poorly characterized, and evidence
is conflicting as to whether pregnancy alters such risk fa-
vorably or unfavorably (1–13), several studies have indi-
cated that, in the absence of continued pharmacotherapy,
50%–60% of women with bipolar disorder will relapse dur-
ing pregnancy (2, 14, 15). Relapse rates are higher after
abrupt cessation of lithium therapy, and relapse rates have
been poorly evaluated after abrupt discontinuation of
other mood stabilizers (2). Postpartum recurrence of bipo-
lar disorder is especially common (2–4, 12, 16–21), and
postpartum psychosis is more common among women
with bipolar disorder, demonstrating a 100-fold increase
over the background rate of 0.05% (22–24). This vulnera-
bility to perinatal relapse, coupled with evidence that ma-
ternal psychiatric illness carries untoward risks for fetal
development (25–27), underscores the need for effective
clinical management during gestation.
There are, however, numerous reproductive safety con-
cerns regarding the medications used to treat bipolar disor-
der. Psychotropic agents used to manage bipolar disorder
are either known teratogens or have limited reproductive
safety data that preclude sound risk estimates (27). Since
the 1950s, lithium has been the cornerstone of pharmaco-
therapy for bipolar disorder. Its use in pregnancy has gar-
nered considerable attention. Initial retrospective analyses
suggested that lithium exposure was associated with a 400-
fold increase in the rate of Ebsteins anomaly, a tricuspid
valve malformation (28, 29), but subsequent meta-analyses
indicated that the risk ratio for cardiac malformations after
lithium exposure is only 1.2 to 7.7 (30) and the risk for Eb-
steins anomaly rises from 1 in 20,000 to 1 in 1,000 (31). It
has been argued, however, that these revised estimates
could be low as an artifact of study methods, because
Ebsteins anomaly may have been underrecognized in pre-
vious reports as a result of the inconsistent use of fetal echo-
cardiography (32). These revised estimates of lithium ter-
atogenicity are considerably lower than estimates of the
teratogenic risks of valproate and carbamazepine (27). Fur-
thermore, lithium is the only mood stabilizer for which
published neurodevelopmental outcome data show a lack
of adverse effects among prenatally exposed children (33).
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Am J Psychiatry 162:11, November 2005 2163
Early findings from a lamotrigine pregnancy registry are
promising, compared to findings for other anticonvulsants
(34), but additional cases and infant follow-up studies are
Although lithium is not devoid of prenatal safety con-
cerns, and its use during lactation has been widely dis-
couraged (35), it continues to be favored by many clini-
cians for use during pregnancy, given its favorable safety
profile relative to other mood stabilizers. Nevertheless,
lithium use during late pregnancy is associated with par-
ticular clinical concerns that have not been systematically
investigated, and the literature includes numerous reports
of neonatal complications in association with lithium
treatment during late pregnancy, including cardiac dys-
function (36–47), diabetes insipidus (37, 38, 48, 49), hy-
pothyroidism (37, 48, 49), low muscle tone (36–40, 42–44,
46, 48, 50, 51), lethargy (36, 48, 52, 53), hepatic abnormali-
ties (36–39, 42, 45, 46), and respiratory difficulties (36–40,
42–46, 48). Recognizing lithiums low therapeutic index, it
seems plausible that such complications are related to the
level of lithium exposure proximate to delivery, although
some reviewers contend that the occurrence of such ef-
fects is independent of lithium concentration (38, 42).
The objective of the present study was to address this
deficiency in lithiums reproductive safety data by 1) ex-
tending data quantifying the rate of lithium placental pas-
sage, 2) testing for an association between infant lithium
concentration at delivery and the incidence of perinatal
adverse events, and 3) determining whether lithium con-
centrations can be reduced by briefly suspending treat-
ment immediately before delivery.
Participants were recruited from patients who were referred to
the Emory Womens Mental Health Program for the perinatal man-
agement of bipolar disorder and were enrolled in a prospective
observational study of the clinical course of bipolar disorder dur-
ing pregnancy and the postpartum period. Subjects were informed
of the risks associated with fetal and infant exposure to lithium as
well as the risks of untreated maternal bipolar disorder. In addi-
tion, the risks and benefits of alternative treatment options, in-
cluding other mood stabilizers, psychotherapy, and electrocon-
vulsive therapy, were reviewed. In an effort to reduce the potential
for lithium-associated complications at delivery, Womens Mental
Health Program patients are empirically advised to suspend lith-
ium administration 1–2 days before a scheduled delivery or at the
onset of labor in the event of spontaneous delivery. Dose suspen-
sion is a standard of care at the Womens Mental Health Program
clinic that was not randomly assigned or in any respect dictated by
study participation. Data are presented for 10 study participants
who elected to continue lithium therapy during late pregnancy.
Each participant fulfilled the DSM-IV criteria for bipolar I disorder
or bipolar II disorder. The Institutional Review Board of the Emory
University School of Medicine approved the study.
Data Collection
Study data included prospective documentation of prenatal
psychiatric treatment, obstetrical outcome as recorded on the
Womens Mental Health Program Delivery Information Sheet and
the hospital delivery record, and assays of maternal and umbilical
cord blood samples collected during gestation and at delivery.
Blood samples were collected in chilled EDTA-containing tubes,
placed on ice, and centrifuged at 4°C for 10 minutes at 3,000 rpm.
Plasma was coded and stored at –80°C until assay.
Laboratory personnel who were blind to the subjects’ demo-
graphic characteristics and to the source of the blood samples
conducted lithium assays with an ion-selective electrode instru-
ment (Beckman Coulter, Inc., Fullerton, Calif.).
Study data were extended by incorporating findings from previ-
ous reports of fetal and maternal lithium concentrations and ob-
stetrical outcome among women taking lithium at delivery. The
previous reports were identified through a search of the English-
language literature by using MEDLINE and PsycINFO databases.
Data Analysis
A descriptive analysis was performed to characterize the pla-
cental passage of lithium. The ratio of lithium concentration in
infant (umbilical cord) plasma to that in maternal plasma was
calculated for each maternal-infant pair as an index of lithium
placental passage, and a scatterplot was constructed of the calcu-
lated ratios. This analysis was performed by using data for each
dyad from the Womens Mental Health Program participants and
data from previous published studies that reported both infant
and maternal lithium concentrations.
The hypothesis that higher infant lithium concentrations at de-
livery are associated with increased vulnerability to perinatal com-
plications was tested by using data for the infants in the Womens
Mental Health Program group and data from previous studies that
reported both infant lithium concentrations at delivery and ob-
stetrical outcomes. The median neonatal lithium concentration
was calculated, and infants whose lithium concentration at deliv-
ery was greater than the median were assigned to the high lithium
exposure group. The remaining infants were assigned to the low
lithium exposure group. Hypothesis testing to assess group differ-
ences with respect to various complications was performed by us-
ing frequency tests (Fishers exact test) for nominal variables and
one-sample t tests for continuous variables.
Finally, the hypothesis that lithium concentrations at delivery
could be significantly reduced by suspending treatment within 48
hours of anticipated delivery was tested by using a paired t test of
maternal lithium concentrations at delivery and earlier measures
during pregnancy for the participants from the Womens Mental
Health Program. All statistical tests were two-tailed.
At relevant points in the analysis, findings from the Womens
Mental Health Program group were compared to those from pre-
vious reports to assess the validity of the pooled analysis.
The demographic and clinical characteristics of the
Womens Mental Health Program participants are presented
in Table 1. Lithium concentrations were determined for the
10 umbilical cord samples and nine of the 10 maternal sam-
ples (one sample was lost). In addition to the Womens Men-
tal Health Program participants, 32 fetal-maternal pairs ex-
posed to lithium at delivery were identified from published
reports (36–60). Lithium concentrations were reported for
18 of these 32 dyads (38–40, 48, 52, 53, 55–58).
The mean infant-mother lithium ratio at delivery for the
27 pairs was 1.05 (SD=0.13). A scatterplot of the ratios is de-
picted in Figure 1. For these 27 pairs, the mean infant lith-
ium concentration at delivery was 0.72 meq/liter (SD=0.57,
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2164 Am J Psychiatry 162:11, November 2005
TABLE 1. Clinical and Demographic Characteristics of Mothers With Bipolar Disorder (N=10) Who Continued Lithium Therapy
in Late Pregnancy and of Their Infants at Delivery
Plasma Concentration of Lithium
at Delivery (meq/liter) Treatment
Cord Mother Ratio
Maternal Dose of
Lithium (mg/day) Therapy Duration
(years) Race
1 0.20 0.20 1.00 300 Week 0–delivery 30 White Divorced
2 0.26 0.26 1.00 1200 Weeks 0–5, week 26–delivery 28 Asian Married
3 0.33 0.30 1.10 1200 Week 14–delivery 24 White Married
4 0.38 0.33 1.15 1350
Weeks 1–5, week 33–delivery 29 White Married
900 Week 36–delivery 29 White Married
6 0.47 0.63 0.75 900 Week 0–delivery 26 White Married
7 0.47 0.43 1.09 1200 Week 0–delivery 39 White Married
8 0.52 0.65 0.80 600 Week 20–delivery 32 White Married
9 0.72 0.59 1.22 900
Week 0–delivery 36 White Married
10 1.02 1.03 0.99 1800 Week 0–delivery 17 White Single
Mother-infant pairs were recruited from the Emory Women’s Mental Health Program.
Weeks of pregnancy during which the mother received lithium.
Data not available.
Daily dose of a controlled-release preparation.
TABLE 2. Clinical Characteristics of Infants With Low Versus High Lithium Exposure at Delivery
Infants With High Lithium Exposure (N=12) Infants With Low Lithium Exposure (N=12)
N Mean 95% CI N Mean 95% CI
Plasma lithium concentration at delivery
Infant (meq/liter) 12 1.68 1.02–2.34 12 0.40 0.33–0.47
Mother (meq/liter) 8 1.64 0.58–2.70 10 0.42 0.30–0.53
Infant/mother ratio 7 1.07 0.94–1.19 10 1.00 0.90–1.09
Maternal lithium dose (mg/day) 8 1110 654–1566 11 941 737–1145
N % With Complication N % With Complication
Pregnancy complications
Gestational diabetes 10 10 11 18
Polyhydramnios 10 30 11 9
Preeclampsia 10 10 11 0
Any complication 10 60 11 27
Obstetrical outcomes
N Mean 95% CI N Mean 95% CI
Apgar score
1 minute 9 4.3 2.2–6.6 9 7.00 5.9–8.1
5 minutes 7 7.6 5.9–9.3 8 8.50 8.1–9.0
Estimated gestational age (weeks) 12 37.3 35.5–39.2 12 38.9 38.2–39.5
Infant weight (kg) 10 3.08 2.54–3.62 10 3.48 3.15–3.81
Hospital stay (days) 7 10.1 5.0–15.3 8 4.3 1.2–7.3
N % With Complication N % With Complication
Preterm delivery 12 33 12 0
Low birth weight 10 40 10 0
Neonatal complications
Cardiovascular 11 45 11 18
CNS 10 90 11 18
Hepatic 10 30 11 18
Neuromuscular 8 100 12 25
Renal 6 33 10 10
Respiratory 9 67 12 17
Thyroid 10 20 11 0
Any complication 12 100 12 25
Infants were assigned to study groups on the basis of a median split. Infants whose lithium concentration at delivery was greater than the
median (0.64 meq/liter) were assigned to the high lithium exposure group. The remaining infants were assigned to the low lithium exposure
For continuous data, the difference between means and 95% confidence interval are reported. For nominal data, the calculated risk ratio
and 95% confidence interval (CI) are reported. A one-sample t test was used to test group differences in continuous variables. Fisher’s exact
test was used to test group differences in nominal variables.
The risk ratio is not available if either of the group percentages equals 0% or 100%.
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Am J Psychiatry 162:11, November 2005 2165
range=0.20–2.80), and the mean maternal concentration
was 0.71 meq/liter (SD=0.59, range=0.20–2.60). Although
infant (0.49 versus 0.84 meq/liter) and maternal (0.49 ver-
sus 0.82 meq/liter) concentrations were lower in the
Womens Mental Health Program group than in the infant-
mother pairs from previous reports, infant-mother lithium
ratios were remarkably similar (1.01 versus 1.06) between
the two samples. Despite the lower lithium concentrations
at delivery, daily lithium doses in the Womens Mental
Health Program mothers (mean=1050 mg/day, SD=437)
were marginally higher than those in the mothers described
in earlier publications (mean=1013 mg/day, SD=493).
Lithium concentrations and obstetrical outcomes were
available for the 10 infants in the Womens Mental Health
Program group and for 14 of the 32 infants described in
earlier reports (36, 38–40, 42, 44, 48, 49, 51, 52, 53, 56, 57,
59). In the resulting group of 24 infants, 12 with lithium
concentrations below the median of 0.64 meq/liter were
assigned to the low lithium exposure group (range=0.20–
0.58 meq/liter), and 12 with lithium concentrations above
the median were assigned to the high lithium exposure
group (range=0.70 to >4.0 meq/liter). The results of hy-
pothesis testing are presented in Table 2. The mean infant-
mother lithium ratio at delivery was virtually identical be-
tween the low lithium exposure and high lithium exposure
groups, indicating that the degree of placental passage
does not vary with maternal plasma lithium concentration
within the clinical range of concentrations encountered.
Obstetrical Outcomes
Apgar Score
Infant Estimated
Gestational Age at
Delivery (weeks)
8 9 38.9 3.42 None
37.6 3.63 None
8 9 38.9 3.00 None
7 8 38.6 3.29 None
8 9 40.1 3.80 None
7 8 39.6 3.00 None
6 8 37.0 3.20 Hypotonia,
9 9 38.0 3.70 Slight jaundice
2 7 40.9 3.62 Hypotonia,
Difference 95% CI t df p
1.28 0.65–1.90 4.24 22 <0.002
1.22 0.37–2.07 2.71 16 <0.03
0.07 0.07 to 0.21 1.09 15 0.30
169 –243 to 581 0.87 17 0.40
Risk Ratio 95% CI p
0.50 0.04–6.55 0.42
4.29 0.37–50.20 0.23
4.00 0.64–25.02 0.13
Difference 95% CI t p
–2.7 –5.0 to –0.4 –2.44 16 <0.03
–0.9 –2.4 to 0.5 –1.31 13 0.24
–1.5 –3.4 to 0.3 –1.75 22 0.11
–0.40 0.99 to 0.19 –1.43 18 0.18
5.9 0.7–11.1 2.45 13 <0.03
Risk Ratio 95% CI p
3.75 0.54–26.04 0.15
40.50 3.09–530.29 <0.002
1.93 0.25–14.89 0.33
4.50 0.31–65.23 0.27
10.00 1.28–78.12 <0.03
Complications for particular body systems included bradycardia,
cardiomegaly, and systolic murmur (cardiovascular); lethargy
and “depression” (CNS); hepatomegaly and jaundice (hepatic);
hypotonia, “flaccidity,” diminished deep tendon reflexes, and
poor suck or Moro reflexes (neuromuscular); polyuria and diabe-
tes insipidus (renal); apnea, cyanosis, labored breathing, and
need for intubation (respiratory), and goiter (thyroid).
FIGURE 1. Concentrations of Lithium in Plasma Samples
From Mothers With Bipolar Disorder Who Continued Lith-
ium Therapy in Late Pregnancy and From Their Infants at
Data are from mother-infant pairs recruited from the Emory
Women’s Mental Health Program (current study) and from mother-
infant pairs described in the literature (38–40, 48, 52, 53, 55–58).
Maternal Lithium Concentration (meq/liter)
Infant Lithium Concentration (meq/liter)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
Samples from previous studies (N=18)
Regression of all samples
Samples from current study (N=9)
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2166 Am J Psychiatry 162:11, November 2005
The rate of all complications, with the exception of ges-
tational diabetes, was consistently higher in the high lith-
ium exposure group. In particular, the rates of CNS and
neuromuscular complications were significantly higher,
the duration of infant hospital stays was significantly
longer, and 1-minute Apgar scores were significantly lower
in the high lithium exposure group. The rates of preterm
delivery, low birth weight, and infant respiratory compli-
cations were higher in the high lithium exposure group
than in the low lithium exposure group, but the differ-
ences only approached significance. Even when the data
for five infants in the high lithium exposure group who
TABLE 3. Potential Causes of Perinatal Lithium Toxicity and Lithium-Associated Complications
Cause of Toxicity Explanation
Iatrogenic causes
Angiotensin-converting enzyme (ACE)
ACE inhibitors elevate lithium concentration through effects on renal blood flow. Because of
numerous adverse fetal effects associated with ACE inhibitors, they are contraindicated
during pregnancy.
Antiemetics Haloperidol, phenothiazines (promethazine, prochlorperazine), and piperazines (meclizine),
which are used to treat hyperemesis gravidarum, can produce neurotoxic side effects such
as tremor and tardive dyskinesia when coadministered with lithium. They do not, however,
appear to increase the risk for frank lithium toxicity. No untoward interactions have been
reported between ondansetron and lithium.
Calcium channel blockers Calcium channel blockers can be used in pregnancy for tocolysis and to manage
tachyarrhythmias or hypertension. The coadministration of calcium channel blockers with
lithium can produce neurotoxic side effects or bradycardia. Lithium interactions may be
more problematic with verapamil or diltiazem than with nifedipine.
Diuretics Diuretics, usually thiazides, are used in pregnancy to manage hypertension, pulmonary
edema, and peripheral edema. Thiazide diuretics increase lithium concentration by
promoting its reabsorption in the proximal tubule. Loop diuretics (e.g., furosemide), also
used during pregnancy, do not promote lithium reabsorption and thus have less effect on
lithium concentration. Potassium-sparing diuretics increase lithium concentration to a
lesser degree than the thiazides, and osmotic diuretics actually lower lithium concentration
by enhancing its excretion. Because of potential adverse fetal effects associated with
potassium-sparing and osmotic diuretics, these medications should be avoided during
Failure to reduce lithium dose after delivery Because the glomerular filtration rate normally increases during pregnancy, lithium dose
increases can be necessary. However, the glomerular filtration rate quickly reverts to
preconception levels after delivery. Thus, lithium concentration can increase after delivery if
dose adjustments are not made.
Nonsteroidal antiinflammatory drugs
Low-dose aspirin can be used in pregnancy to manage antiphospholipid antibody-associated
pregnancy loss, preeclampsia, or fetal growth retardation. Indomethacin and sulindac have
been used for tocolysis and to manage polyhydramnios. Ibuprofen and naproxen are
infrequently used as analgesics during pregnancy. Because of reports of oligohydramnios
and premature closure of the fetal ductus arteriosus associated with NSAIDs, these
medications are generally discouraged, especially after the 34th week of gestation. NSAIDs
increase lithium concentrations by reducing renal blood flow and perhaps by increasing
tubular reabsorption of lithium. Aspirin and sulindac appear to be less likely to increase
lithium concentrations than other NSAIDs.
Sodium-restricted diet Sodium restriction has been used in pregnancy for the management of preeclampsia and
edema. In response to a sodium-restricted diet, the kidneys attempt to preserve sodium by
increasing its tubular reabsorption. However, because the kidneys do not reliably
discriminate lithium from sodium, lithium reabsorption is also increased, which can lead to
increased lithium concentrations.
Perinatal complications
Fluid loss at delivery Acute loss of blood and amniotic fluid coupled with the insensible loss due to profuse
diaphoresis during labor can lower intravascular volume and thereby theoretically elevate
lithium concentration.
Hyperemesis gravidarum Hyperemesis gravidarum can reduce lithium concentrations by reducing lithium absorption
when emesis occurs shortly after the oral administration of lithium; however, fluid losses
and electrolyte disturbances (e.g., hyponatremia) resulting from profuse vomiting can
increase lithium concentration.
Oligohydramnios Theoretically, lithium-associated fetal renal insufficiency could present as oligohydramnios
secondary to diminished fetal urine production.
Polyhydramnios Polyhydramnios during lithium therapy can be a consequence of fetal diabetes insipidus.
When fetal diabetes insipidus occurs, the lithium concentration in amniotic fluid can be
markedly higher than the serum concentration, but there is no evidence that the high
amniotic fluid concentration causes lithium toxicity. However, fetal diabetes insipidus can
persist for a week or longer after delivery, leading to dehydration and lithium toxicity in the
infant. In addition, some agents used to manage polyhydramnios (NSAIDs) can elevate the
lithium concentration.
Preeclampsia Moderate to severe preeclampsia decreases the glomerular filtration rate through intrarenal
vasospasm. This effect potentially elevates the lithium concentration by reducing the renal
clearance of lithium. In addition, several common management strategies for preeclampsia
(thiazide diuretics, aspirin, sodium restriction) can further elevate lithium concentration.
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Am J Psychiatry 162:11, November 2005 2167
had lithium concentrations at delivery in the “toxic” range
(>1.2 meq/liter) were omitted from the analysis, the rates
of CNS complications (83%) (p<0.04, Fisher’s exact test)
and neuromuscular complications (100%) (p<0.01,
Fishers exact test) remained significantly higher in the
high lithium exposure group, and this group had longer in-
fant hospital stays (mean=10.0 days) than the low lithium
exposure group, although the difference only approached
significance. Because the Womens Mental Health Program
participants had been instructed to suspend lithium treat-
ment before delivery, these participants’ infants are over-
represented in the low lithium exposure group (eight of
12), compared to the high lithium exposure group (two of
12), and had a lower rate of complications than the mother-
infant pairs from previous reports.
Although maternal lithium concentrations at delivery
were subtherapeutic (<0.5 meq/liter) for five of the nine
women in the Womens Mental Health Program group
(mean=0.49 meq/liter, SD=0.26, range=0.20–1.03), they
were in the therapeutic range for all Womens Mental
Health Program participants when sampled at the most
recent prenatal visit (mean=0.79 meq/liter, SD=0.19,
range=0.50–1.10). A paired t test indicated that maternal
lithium concentrations at delivery were significantly
lower than those during pregnancy (mean difference=
0.28 meq/liter, 95% confidence interval [CI]=0.08–0.49; t=
3.38, df=6, p<0.02), with a mean of 20.6 hours (SD=19.2)
having elapsed since the last lithium dose when the deliv-
ery sample was collected. Despite the brief interruption
in lithium therapy, only one of the 10 Womens Mental
Health Program participants was symptomatic in the
perinatal period. That patient experienced a depressive
episode with psychotic features that began 2 weeks before
delivery, prior to any suspension of lithium therapy.
To our knowledge, this study is the first to examine sys-
tematically the clinical relevance of lithium placental pas-
sage at delivery. The study’s findings are as follows:
1. Lithium demonstrates complete placental passage as
evidenced by the mean infant-mother lithium ratio
of 1.05.
2. Lithium ion equilibration across the placental barrier
is remarkably uniform across a wide range of mater-
nal concentrations (0.2–2.6 meq/liter), suggesting
that lithium equilibrates between maternal and fetal
circulation much as it does across the total body wa-
ter space in an individual. This finding is consistent
with the results of preclinical studies demonstrating
minimal transplacental differences in electric poten-
tial after acute lithium administration (60, 61).
3. Adverse perinatal outcomes are more extensive in
the setting of higher lithium concentrations at deliv-
ery as evidenced by the consistently higher rate of
varied complications among infants in the high lith-
ium exposure group.
4. Lithium delivery concentrations can be significantly
reduced at delivery without compromising pharma-
cotherapeutic efficacy by briefly withholding lithium
This constellation of findings bears important implica-
tions for treatment guidelines, now woefully inadequate,
when lithium administration is indicated during late ges-
tation. Conflicting recommendations have been proposed
regarding lithiums use in late pregnancy, with some ex-
perts urging lithium dose reduction or discontinuation
long before delivery to avoid neonatal toxicity (36, 47) and
others advocating the reinstitution of lithium therapy be-
fore delivery to avoid the high risk of postpartum relapse
in patients with bipolar disorder (62). Moreover, despite its
use for more than five decades, no guidelines have been
established for therapeutic monitoring of lithium concen-
trations during pregnancy or potential adverse effects be-
yond surveillance for cardiac teratogenicity (63). Because
poor outcomes in this study were predicted by higher in-
fant lithium concentrations at delivery, and neonate con-
centrations invariably approximated maternal concentra-
tions, infant well-being can be enhanced by monitoring
maternal lithium concentrations as delivery approaches.
Furthermore, the ability to lower maternal concentrations
expeditiously by suspending lithium therapy for 24–48
hours before delivery might improve obstetrical outcome
as neonatal concentrations can be reduced without un-
duly compromising treatment efficacy.
Neonatal effects of lithium exposure are of gravest con-
cern when maternal toxicity arises before delivery. Al-
though lithium toxicity did not complicate the pregnan-
cies of the Womens Mental Health Program participants,
earlier reports indicate that maternal toxicity during late
gestation warrants concern. Of seven reported cases of
prenatal lithium toxicity (39, 44, 46, 50, 52–54), the etiology
is identifiable in only three. In two cases, toxicity arose
iatrogenically after the institution of diuretic therapy and a
sodium-restricted diet to manage edema (44, 54). Toxicity
occurred in another case when a sodium-restricted diet
was initiated to manage preeclampsia (52), a condition
that decreases the glomerular filtration rate (64–66) and,
ostensibly, lithium clearance. The cause of lithium toxicity
in the remaining cases (39, 46, 49, 50) is unclear. Toxicity
may have been a consequence of intentional or accidental
overdose, although this cause was not explicitly stated,
and pregnancy-specific causes, such as abrupt fluid loss
during labor, cannot be eliminated.
From these findings, we propose the following guide-
lines for lithium administration during late pregnancy:
1. Maintain a target lithium concentration at the mini-
mum effective level for the individual. Although lithium
levels of 0.8–1.0 meq/liter are widely cited as the ideal
Page 6
2168 Am J Psychiatry 162:11, November 2005
for maintenance therapy, some individuals can be suc-
cessfully maintained at lower concentrations (67).
2. Periodically monitor lithium concentrations during
pregnancy, particularly during late gestation when
marked changes in glomerular filtration rate can al-
ter lithium clearance (66, 68, 69).
3. Avoid pregnancy treatment modalities that increase
the potential for lithium toxicity (Table 3). However, if
such measures are obstetrically warranted, more fre-
quent lithium monitoring and dose reduction are
4. Lower maternal lithium dose in the event of preg-
nancy complications such as preeclampsia (64–66)
or polyhydramnios (38, 39, 47, 48) (Table 3) that might
predispose the patient or her child to lithium toxicity.
Similarly, any abnormality in amniotic fluid volume,
including oligohydramnios, could be the result of
and/or could increase the likelihood of lithium-asso-
ciated fetal nephrotoxicity.
5. Suspend lithium administration 24–48 hours before a
scheduled Cesarean section or induction, or suspend
lithium administration at the onset of labor in the
event of spontaneous delivery.
6. Check the maternal lithium concentration at the pa-
tients presentation to the hospital for delivery.
7. Administer oral and/or intravenous fluids through-
out the labor and delivery process, and check mater-
nal lithium concentration in the event of clinical
signs of toxicity.
8. Reinstitute lithium therapy as soon as the patient is
medically stabilized after delivery. Use the precon-
ception dose, because the maternal glomerular fil-
tration rate rapidly returns to pregravid levels after
This study is not without shortcomings. The small num-
ber of participants limited the statistical power to eluci-
date fully the association between clinical outcome and
lithium concentration. Another limitation is the demo-
graphic homogeneity of the 10 Womens Mental Health
Program participants, which limits the generalizability of
the study results. It can also be argued that the depend-
ability of the study findings is weakened by the inclusion
of case data from earlier reports that in some instances
were incomplete. Conversely, the consistent character of
the findings when the data are analyzed across so many
reports, despite probable differences in data collection,
serves to reinforce the reliability and potential generaliz-
ability of the findings.
In summary, given the considerable morbidity of un-
treated bipolar disorder and the significant risk of perina-
tal relapse in the absence of continued pharmacotherapy,
prolonged discontinuation of treatment is seldom a viable
option. Despite documented concerns about effects of
lithium in reproduction, this medication remains the pre-
ferred alternative during gestation for many women with
bipolar disorder. When lithium is used during late preg-
nancy, infant and maternal well-being can be maximized
by maintaining maternal concentrations at the minimal
effective level, suspending lithium therapy 24–48 hours
before delivery to reduce neonatal concentrations further,
and avoiding inadvertent or iatrogenic lithium toxicity
during gestation.
Received April 27, 2004; revision received Sept. 5, 2004; accepted
Sept. 10, 2004. From the Departments of Psychiatry and Behavioral
Sciences, Pharmacology, and Gynecology and Obstetrics, Emory Uni-
versity School of Medicine; and the Department of Psychiatry, Har-
vard Medical School, Boston. Address correspondence and reprint
requests to Dr. Newport, Women’s Mental Health Program, Emory
University School of Medicine, 1365 Clifton Rd., N.E., Suite B6100,
Atlanta, GA 30322; (e-mail).
Supported in part by an NIH Patient-Oriented Research Career De-
velopment Award (MH-63507) and an NIH Specialized Center of Re-
search grant (P50 MH-68036).
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  • Source
    • "The main findings of this study have also some support in the indicated mechanisms of lithium toxicity. Lithium, from both therapy and drinking water, crosses freely the placenta (Harari et al., 2012; Newport et al., 2005) and is known to impair the thyroid hormones (Broberg et al., 2011; Grandjean and Aubry, 2009c). Like most of the hormones, the thyroid hormones play a critical role in fetal growth and development (Forhead and Fowden, 2014 ). "
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  • Source
    • "s, neurobehavioral effects in newborns have been repeatedly reported (Kozma, 2005). Our work is, to our knowledge, the first description of persistent symptoms that resemble the neurodevelopmental deficits including hypotonicity and lethargy observed in lithium Floppy baby syndrome affected babies in model organisms days after exposure termination. Newport et al. (2005) showed higher rates of CNS and neuromuscular complications and significantly lower Apgar scores in newborns exposed to higher lithium therapeutic doses during development. Here, animals treated with lithium higher doses showed altered locomotion when compared to controls or the lower potentially neuroprotective dose, traveling shorter d"
    [Show abstract] [Hide abstract] ABSTRACT: Lithium has been the paradigmatic treatment for bipolar disorder since 1950s, offering prophylactic and acute efficacy against maniac and depressive episodes. Its use during early pregnancy and the perinatal period remains controversial due to reports of negative consequences on the newborn including teratogenic and neurobehavioral effects generally referred as Floppy baby syndrome. The mechanisms underlying lithium therapeutic action are still elusive but exacerbation of Wnt signaling pathway due to GSK-3 inhibition is believed to represent its main effect. In this study we evaluated the impact of lithium exposure during zebrafish embryonic and early development including behavioral and molecular characterization of Wnt-β-catenin pathway components. Wild-type zebrafish embryos were individually treated for 72 hpf with LiCl at 0.05, 0.5 and 5mM. No significant teratogenic and embryotoxic effects were observed. At the end of treatment period western blot analysis of selected Wnt-β-catenin system components showed increased β-catenin and decreased N-cadherin protein levels, without significant changes in Wnt3a, supporting GSK-3 inhibition as lithium's main target. At 10 dpf 0.5 and 5mM lithium-treated larvae showed a dose-dependent decrease in locomotion among other exploratory parameters, resembling lithium-induced Floppy baby syndrome neurobehavioral symptoms in humans. At this later period previously altered proteins returned to control levels in treated groups, suggesting that the neurobehavioral effects are a lasting consequence of lithium exposure during early development. qRT-PCR analysis of β-catenin and N-cadherin gene expression showed no effects of lithium at 3 or 10 dpf, suggesting that protein fluctuations were likely due to post-transcriptional events. Other Wnt target genes were evaluated and only discrete alterations were observed. These results suggest that zebrafish may be a valuable model for investigation of early effects of lithium that may be mediated by effects on the Wnt signaling pathway.
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  • Source
    • "In terms of fetal exposure to these drugs, the total concentration of VPA has been shown to be higher in cord serum than in the serum of epileptic mothers prescribed this drug [13], [14]. In comparison, lithium appears to equilibriate across the placenta over a range of maternal concentrations [15]. "
    [Show abstract] [Hide abstract] ABSTRACT: Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.
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