Antipsychotics and mood stabilizers in pregnancy

Objectives:
Background risk of spontaneous congenital anomalies
The impact of mental illness on pregnancy
The impact of pregnancy on mental illness
The impact Antipsychotics and mood stabilizers on pregnancy outcome
Recommendations for prescribing during pregnancy
What to include in discussions with a pregnant women

1. Antipsychotics
and mood
stabilizers in
pregnancy
Mohamed
Ibrahim
Oct 2020

2. The MaudsleyPrescribing Guidelines in Psychiatry –18
May 2018.
RANZCP clinical practice guidelines for the management
of schizophrenia and related disorders, 2016.
RANZCP clinical practice guidelines for mood disorders,
2015.
British Association for Psychopharmacology consensus
guidance on the use of psychotropic medication
preconception, in pregnancy and postpartum 2017

3. Ms. H is a 28-year-old female with a 7-year-history
of bipolar disorder, with history of 4 manic episodes
which required prolonged hospitalizations. Last
admission was 2 years ago. Ms. H was stabilized with
1200mg of lithium carbonate per day with a normal
serum level. Ms. H discovered that she is pregnant,
and attended the clinic today seeking advice
regarding her medication whether to cease or
continue it.
What would be your advice?

4. Background risk of spontaneous congenital anomalies
The impact of mental illness on pregnancy
The impact of pregnancy on mental illness
The impact Antipsychotics and mood stabilizers on
pregnancy outcome
Recommendations for prescribing during pregnancy
What to include in discussions with a pregnant women

5. About 15% of pregnant
women have psychiatric
illness and 10-13% of
fetuses are exposed to a
psychotropic drug.
Marcus SM, Flynn HA, Blow FC, et al. Depressive symptoms among pregnant women screened in
obstetrics settings. J WomensHealth (Larchmt) 2003;12:373-80.
AnderssonL, Sundstrom-PoromaaI, BixoM, et al. Point prevalence of psychiatric disorders during the
second trimester of pregnancy: a population-based study. Am J ObstetGynecol2003;189:148-54.

6. A ‘normal’ outcome to pregnancy can never be guaranteed.
The spontaneous abortion rate in confirmed early
pregnancy is 10–20% and the risk of spontaneous major
malformation is 2–3%.
McElhattonPR. Pregnancy: (2) General principles of drug use in pregnancy. Pharm J
2003; 270:232–234.

7. Untreated or undertreated psychosis is
associated with:
Preterm labor
Poor obstetric and medication adherence
Increased rates of substance use (especially tobacco)
Impulsive acts including suicide
Impaired bonding and attachment with infant
Harm to the foetusor neonate (neglect<-->infanticide).
Risk of mental disorders in the infant.

8. pregnancy does not protect against mental illness and may
even elevate overall risk if medication is stopped.
In late pregnancy and early post partum there is an
increased risk of relapse of mental illness, irrespective of
medication use.

9. Bipolar disorder recurred in 81-85.5% of pregnant women
who discontinued their mood stabilizers compared with
29-37% of those who did not.
About 50% of patients with schizophrenia relapse if they
stop taking their drugs.
VigueraAC, Whitfield T, BaldessariniRJ, et al. Risk of recurrence in women with bipolar
disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J
Psychiatry 2007;164:1817-24; quiz 1923.
Gilbert PL, Harris MJ, McAdams LA, JesteDV: Neuroleptic withdrawal in schizophrenic
patients. A review of the literature. Arch Gen Psychiatry 1995, 52:173–188.

10. The safety of psychotropic drugs in pregnancy cannot be
clearly established because robust, prospective trials are
obviously unethical.
Period of maximum vulnerability for birth defects of the
nervous system is 14 –35 days post conception.

11. Neonatal dyskinesia
Neonatal jaundice (phenothiazines)
Transient extrapyramidal symptoms and withdrawal
symptoms (FGAs in the third trimester )
Collins KO et al. Maternal haloperidol therapy associated with dyskinesia in a newborn.
Am J Health SystPharm 2003; 60:2253–2255.
Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review.
SchizophrBull 2010; 36:518–544.

12. A large American study including over a million women,
showed no meaningful increase in the risk of major
malformations or cardiac malformations in 733 women
prescribed a FGA.
It remains uncertain whether FGAs are entirely without risk
to the foetusor to later development. However, this
continued uncertainty and the wide use of these drugs over
several decades suggest that any risk is small.
HuybrechtsKF et al. Antipsychotic use in pregnancy and the risk for congenital
malformations. JAMA Psychiatry 2016; 73:938–946.
TrixlerM et al. Use of antipsychotics in the management of schizophrenia during
pregnancy. Drugs 2005; 65:1193–1206.

13. First trimester exposure to haloperidol has been reported
to cause limb defects; while cardiac anomalies are
evidenced in the third trimester .
Other malformations that can occur with the use of
haloperidol are micropthalmia, gastroschisis, and renal
dysplasia. However, none of these are found to be
significant when compared to general population.
Iqbal MM, Rahman M (2005) The potential risks of commonly prescribed antipsychotics.
Psychiatry 2: 8.
Diav-CitrinO, ShechtmanS, OrnoyS, ArnonJ, Schaefer C, et al. (2005) Safety of
haloperidol and penfluridolin pregnancy: a multicenter, prospective, controlled study. J
ClinPsychiatry 66: 317-322.

14. Withdrawal and extrapyramidal side effects following third
trimester exposure.
Fetal hypotoniamay occur following a very high-dose
intake.
An increased risk of neonatal jaundice in preterm infants.
Slone D, SiskindV, HeinonenOP, Monson RR, Kaufman DW, et al. (1977) Antenatal
exposure to the phenothiazinesin relation to congenital malformations, perinatal
mortality rate, birth weight, and intelligence quotient score. Am J ObstetGynecol128:
486-488.
ScokelIII PW, Jones NW (1962) Infant jaundice after phenothiazine drugs for labor: an
enigma. ObstetGynecol20: 124-127.

15. First trimester exposure: Congenital cataract,
congenital heart block, tracheomalacia, hypospdiasis,
VSD, undescended testis, pylorostenosis, and ureter
stenosis.

16. Most of the evidence with trifluoperazinesuggests
that it is not associated with an increased risk of
malformations.

17. In a study of 214 women taking a SGA the absolute risk of
major malformation was estimated to be 1.4% compared
with 1.1% in the control group.
In a large American study including over a million women,
no meaningful increase in the risk of major malformations
or cardiac malformations was seen in 9258 women
prescribed an SGA.
Cohen LS et al. Reproductive safety of second‐generation antipsychotics: current data
from the Massachusetts General Hospital National Pregnancy Registry for Atypical
Antipsychotics. Am J Psychiatry 2016; 173:263–270.
HuybrechtsKF et al. Antipsychotic use in pregnancy and the risk for congenital
malformations. JAMA Psychiatry 2016; 73:938 946.

18. Lower mean adaptive behaviourscores in the newborn
Floppy baby syndrome.
Gestational diabetes
Risk of neonatal seizures
Agranulocytosis in the foetus/neonate (theoretical concerns)
Shao P et al. Effects of clozapine and other atypical antipsychotics on infants development who
were exposed to as fetus: a post‐hoc analysis. PLoSOne 2015; 10:e0123373.
Ernst CL et al. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and
broad‐spectrum psychotropics. J ClinPsychiatry 2002; 63 Suppl4:42–55.
Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review.
SchizophrBull 2010; 36:518-544.

19. The use of clozapine appears to present no increased risk of
malformation.
Ideally clozapine should not be initiated in pregnancy.
On the balance of evidence available, clozapine should
usually be continuedif a woman taking clozapine
discovers that she is pregnant.
The MaudsleyPrescribing Guidelines in Psychiatry –18 May 2018.

20. Risk of large-for-gestational age infants
Risk of gestational diabetes / glucose monitoring is
recommended
Olanzapine seems to be relatively safe with respect to
congenital malformations
NewhamJJ et al. Birth weight of infants after maternal exposure to typical and atypical
antipsychotics: prospective comparison study. Br J Psychiatry 2008; 192:333–337
Park Y, Hernandez-Diaz S, Bateman BT, Cohen JM, Desai RJ, PatornoE, et al.
Continuation of atypical antipsychotic medication during early pregnancy and the risk of
gestational diabetes. Am J Psychiatry 2018; 175: 564–74.
Brunner E et al. Olanzapine in pregnancy and breastfeeding: a review of data from global
safety surveillance. BMC PharmacolToxicol2013; 14:38.

21. Quetiapine is one of the SGAs with the most experience in
pregnancy, and it has the lowest placental passage of
23.8%.
Associated with atrial septal defects, cleft lip/palate,
pulmonary atresia, and hydrocephalus in the new born.
Spontaneous abortions were also reported in very few
cases.
Newport DJ, CalamarasMR, DeVaneCL, Donovan J, Beach AJ, et al. (2007) Atypical
antipsychotic administration during late pregnancy: placental passage and obstetrical
outcomes. Am J Psychiatry 164: 1214-1220.
TwaitesBR, Wilton LV, ShakirSA (2007) The safety of quetiapine: results of a post-
marketing surveillance study on 1728 patients in England. J Psychopharmacol21: 392-
399.

22. In a recent review of the safety of SGAs in utero exposure, a
small increased risk was observed with risperidone and
paliperidone.
Third-trimester exposure to risperidone has resulted in
extrapyramidal symptoms in the infant.
DamkierP, VidebechP. The safety of second-generation antipsychotics during
pregnancy: a clinically focused review. CNS Drugs 2018; 32: 351–66.
Coppola D, Russo LJ, KwartaRF Jr, VarugheseR, SchmiderJ. Evaluating the
postmarketingexperience of risperidone use during pregnancy: pregnancy and neonatal
outcomes. Drug Saf2007; 30: 247–64.

23. There is very limited documented evidence of the use of
antipsychotic depots in pregnancy therefore they are best
avoided where possible, given the potential for
accumulation and toxicity in the neonate.
Where a patient is stable and responding well to a depot
antipsychotic and there is a history of non-compliance it
can be continued.
National Institute for Health and Care excellence (NICE). Clinical Guideline CG192:
Antenatal and Postnatal Mental Health. (2014).

24. New and well-designed studies show no associated
increased risk for congenital malformations with most
antipsychotics.
Ennis ZN, DamkierP. Pregnancy exposure to olanzapine, quetiapine, risperidone,
aripiprazole and risk of congenital malformations. A systematic review. Basic Clin
PharmacolToxicol. 2015;116(4):315-320.
GalballyM, Snellen M, Power J. Antipsychotic drugs in pregnancy: A review of their
maternal and fetal effects. TherAdvDrug Saf. 2014;5(2):100-109.
Smith B, DubovskySL. Pharmacotherapy of mood disorders and psychosis in pre-and
post-natal women. Expert OpinPharmacother. 2017;18(16):1703-1719.

25. In two studies (2013/2015): fetal exposure to SGAs was
associated with delays in cognitive, motor, socio-emotional
behaviors at 2 months of age, but these effects were no
longer seen at 12 months.
Peng, M.; Gao, K.; Ding, Y.; Ou, J.; Calabrese, J.R.; Wu, R.; Zhao, J. Effects of prenatal
exposure to atypical antipsychotics on postnatal development and growth of infants: A
case-controlled, prospective study. Psychopharmacology 2013, 228, 577–584.
Shao, P.; Ou, J.; Peng, M.; Zhao, J.; Chen, J.; Wu, R. Effects of Clozapine and other
Atypical Antipsychotics on Infants Development Who Were Exposed to as Fetus: A Post-
Hoc Analysis. PLoSONE 2015, 10, e0123373.

26. Increasing risk of preterm birth with increasing dose of
antipsychotic medication.
Overall safety appears positive, with no appreciable
increase in major congenital malformations reported.
Cessation of antipsychotic medication during pregnancy
was associated with relapse of psychosis, maternal
hospitalisationand the subsequent separation of mother
and baby.
NRAMP: The National Register of Antipsychotic Medication in Pregnancy; established in
2005.
Kulkarni J, WorsleyR, Gilbert H, GavrilidisE, Van RheenenTE, Wang W, et al. A
prospective cohort study of antipsychotic medications in pregnancy: the first 147
pregnancies and 100 one year old babies. PLoSONE 2014; 9: e94788.

27. A recent study in 2017 demonstrated that cardiac
malformations were present in 2.41% of infants exposed to
lithium, 1.39% of infants exposed to lamotrigine, and 1.15%
of nonexposedinfants; indicating a significantly smaller
association than previously suggested.
Lithium has also been associated with perinatal toxicity
including case reports of hypotonia, cyanosis, neonatal
goiter, and diabetes insipidus.
PatornoE, HuybrechtsKF, Bateman BT, Cohen JM, Desai RJ, MogunH, et al. Lithium use
in pregnancy and the risks of cardiac malformations. N EnglJ Med 2017; 376: 2245–54.

28. The RANZCP guidelines suggest that in pregnant women
with severe bipolar disorder, lithium may be the safest
option among available mood stabilisers, providing use is
balanced against the potential risks for the developing
fetus and the risk of relapse during pregnancy if lithium is
discontinued.
MalhiGS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, et al. Royal Australian and
New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust
N Z J Psychiatry 2015; 49: 1–185.

29. Lithium completely equilibrates across the placenta.
Lithium should be avoided in pregnancy if possible.
Monitor plasma levels every 4 weeks until 36 weeks and
weekly thereafter.
Stop lithium during labourand check the plasma level 12
hours after last dose.
Delivery in hospital & monitor fluid balance.
Newport DJ et al. Lithium placental passage and obstetrical outcome: implications for
clinical management during late pregnancy. Am J Psychiatry 2005; 162:2162–2170.
National Institute for Health and Care Excellence. Antenatal and postnatal mental
health: clinical management and service guidance. Clinical Guideline 192, 2014; last
updated August 2017. https://www.nice.org.uk/guidance/cg192.

30. First trimester exposure to valproicacid is associated with a
high rate of malformations (≤10%) including neural tube
defects, effects on cognition and brain volume, craniofacial
anomalies, cardiac defects, cleft palate, and hypospadias.
Exposure to valproicacid has also been recently linked with
autism in two studies.

31. Valproate is by far the most dangerous drug at all stages of
fetal development
Valproate must not be used in girls and women unless
alternative treatments are not suitable and the pregnancy
prevention program is in place.
High dose folate (4 mg/day), theoretically, reduces the risk
of neural tube defects
Second trimester ultrasound to screen for major congenital
anomalies.
Blood levels of valproicacid should be monitored.

32. Risk of malformations at a rate of 2.2-3.3%, primarily of
spina bifida and other neural tube defects, as well as facial
abnormalities, skeletal abnormalities, and hypospadias.
Risk of neonatal hemorrhage. (consider maternal vitamin K).
Consider high dose folate and screening for malformations
Best be avoided in women who are planning a pregnancy,
pregnant or considering breastfeeding.

33. Lamotrigine is safer in pregnancy than carbamazepine or
valproate.
The association between exposure to lamotrigine and oral
clefts: inconclusive.
Lamotrigine levels may decrease over the course of
pregnancy and thus should be monitored and adjusted if
needed.

34. The acute use of lorazepam or
promethazine is unlikely to be
harmful.
Antipsychotics also can be
used.
The mother should not be
secluded or left alone after
rapid tranquillisation.
Adapt restraint procedures to
avoid possible harm to the
foetus(restraint on a bean
bag).

35. Always discuss the possibility of pregnancy –half of all
pregnancies are unplanned.
Avoid using drugs that are contraindicated during
pregnancy (especially valproate and carbamazepine /
Consider prescribing folate).

36. Try to avoid all drugs in the first trimester unless necessary.
The most safety data are available for quetiapine,
olanzapine, risperidone and haloperidol, with more limited
data for clozapine, aripiprazole and ziprasidone.
Avoiding depot preparations and anticholinergic drugs.
No mood stabiliseris clearly safe (consider antipsychotics).
In acute mania use an antipsychotic; if ineffective→ECT.
In bipolar depression use CBT for moderate depression
and an SSRI for more severe depression. Lamotrigine is also
an option.

37. If the woman is well and at low risk of relapse: gradually
discontinue treatment .
In case of severe mental illness or high risk of relapse :
continue treatment or switch to a low risk drug (switching
drugs may increase the risk of relapse !!!).
Drug‐induced hyperprolactinaemiamay prevent
pregnancy.
Valproate should be gradually ceased before pregnancy. If it
is the only option, continue with a signed informed
consent.

38. Abrupt discontinuation of treatment post conception for
women with severe mental illness and at a high risk of
relapse is unwise; relapse may ultimately be more harmful
to the mother and child than continued, effective drug
therapy.
Consider remaining with current (effective) medication
rather than switching, to minimisethe risk of relapse and
hence the number of drugs to which the foetusis exposed.

39. Always encourage
switching to nicotine
replacement therapy –
smoking has numerous
adverse outcomes,
nicotine replacement
therapy does not.
Royal College of Physicians. Nicotine without smoke: tobacco harm reduction. A report by the
Tobacco Advisory Group of the Royal College of Physicians. 2016.

40. Involved woman/family as possible in all decisions.
Aim for: Monotherapy / Lowest effective dose / Lowest
known risk.
Adjust doses as pregnancy progresses and be aware of
potential problems with individual drugs peripartum.
Referral to specialist perinatal services / Ensure adequate
foetalscreening.
Inform the obstetric team of psychotropic use and possible
complications.
Monitor the neonate for withdrawal effects after birth.
Document all decisions.

41. The impact of an untreated mental disorder on the foetus.
The background risk of spontaneous foetalmalformations.
The risk associated with drug treatments during pregnancy.
The risks from stopping medication abruptly.
Severity of previous episodes, response to treatment and the
woman’s preference.
Stopping a drug with known teratogenic risk after pregnancy is
confirmed may not remove the risk of malformations.
Advise about diet and monitor for excessive weight gain.
Breastfeeding.

42. Pregnancy does not protect against mental illness and may
even elevate overall risk if medication is stopped.
The impact of untreated mental illness on the mother and
foetusmay be higher than the potential complications of
the medication used to treat that mental illness.
The teratogenic risk of antipsychotics and lithium is lower
than previously thought.
Always seek the latest recommendations and guidelines
when treating a mental illness during pregnancy