Download FDA Use-in-Pregnancy Ratings A Adequate, well

Dora Wang, MD, MA
Clinical Associate Professor
Historian of the UNM School of Medicine
A Brief History of the Ovary and
Uterus
Circa 300 B.C.
 Herophilus of Alexandria discovers the ovaries
 “The ovaries of sows are excised with the view of
quenching in them sexual appetites and of stimulating
fatness”—Aristotle
Hysteria
From the Greek for uterus, hystera
Hippocrates thought madness was due to the uterus
becoming too light, and wandering upward to
compress the heart, lungs, and diaphragm
The wandering uterus explanation for mental illness
persisted for about 2000 years
Dictionnaire encyclopedique des sciences medicales, late
1800’s: hysteria in women is entirely of ovarian and
not of uterine origin
Female reproductive organs were associated with mental
illness for 2000 years.
 1808 Percival Pott, a British surgeon, removed the
ovaries of a female with bilateral ovarian herniation
into her inguinal sacs , “Her breasts, which were large,
are gone; nor has she menstruated since the
operation, which is now some years.”
 1843 Theodor von Bischoff speculated that ovaries
govern the female reproductive cycle based on travel
writings of Dr. G. Roberts who observed that
“castrated” females in India had undeveloped breasts
and no menstruation.
 1870’s Surgeons Robert Battey (American) and Alfred
Hegar (German) popularize ovariectomies as a cure
for: hysteria, excessive sexual desires, and aches and
pains of unknown etiology
 Thousands of ovariectomies performed
1878 Alfred Hegar shows that the removal of ovaries in
pigs, results in atrophy of the uterus. Discovers that
ovaries govern menstruation.
 Misconceptions of women and mental
illness have been the rule, rather than the
exception for most of history
Teratogen
 An agent, as a chemical, disease, etc., that causes
malformation of a fetus.
--Webster’s Dictionary
 Risk of organ or limb malformation
 Risk of neonatal toxicity or withdrawal syndromes
 Risk of long-term neurobehavioral sequelae
American Journal of Obstetrics &
Gynecology, 1957
DES
 Diethylstilbestrol, the first synthetic estrogen, FDA
approved in 1941 for menopausal symptoms
 1948-1949, Harvard professors George and Olive Smith
published papers in the American Journal of Obstetrics
and Gynecology:
 advocated using DES to prevent miscarriages, make
babies healthier and more robust
 Prescribed widely, like a vitamin to 5-10 million
women, mostly pregnant between 1941-1971, even if by
1953, studies refuted that DES prevented miscarriages
 April 15, 1971, NEJM, rare cervical adenocarcinoma in 8
girls, ages 14-22. Seven were born to mothers who took
DES in first trimester of pregnancy.
DES and Numbers
 5-million to 10-million women exposed
 30 years, 1941-1971
 Teratogenesis was exposed with 7 cases of cervical
adenocarcinoma
DES teratogenic effects
 DES daughters: increased risk of cervical
adenocarcinoma, cervical dysplasia, infertility, breast
cancer
 DES sons: hypospadia, infertility, lower sperm count
FDA Use-in-Pregnancy Ratings
 A
Adequate, well-controlled studies in pregnant women have not shown an
increased risk of fetal abnormalities to the fetus in any trimester of
pregnancy.
 B
Animal studies have revealed no evidence of harm to the fetus, however,
there are no adequate and well-controlled studies in pregnant women. OR
Animal studies have shown an adverse effect, but adequate and well-controlled
studies in pregnant women have failed to demonstrate a risk to the fetus in any
trimester.
 C
Animal studies have shown an adverse effect and there are no adequate
and well-controlled studies in pregnant women. OR No animal studies have been
conducted and there are no adequate and well-controlled studies in pregnant
women.
 D
Adequate well-controlled or observational studies in pregnant women have
demonstrated a risk to the fetus. However, the benefits of therapy may outweigh
the potential risk. For example, the drug may be acceptable if needed in a lifethreatening situation or serious disease for which safer drugs cannot be used or
are ineffective.

X
Adequate well-controlled or observational studies in animals or pregnant
women have demonstrated positive evidence of fetal abnormalities or risks. The
use of the product is contraindicated in women who are or may become pregnant.
 Category A psychotropic meds: NONE!
 No controlled studies exist for psychotropic
medications in pregnancy
 FDA ban prohibited women of reproductive age in
clinical trials following the thalidomide incident in
1950’s and DES incident in 1970’s
 Information gleaned from: case studies, pregnancy
registries, teratogen reporting centers, a few
prospective studies
Because of limited information and
no controlled trials of psychotropic
meds in pregnancy, the psychiatric
treatment of women during
pregnancy is a prime example of
the importance of the doctorpatient relationship
Special Considerations
 Psychiatric Disorders in women usually have onset in
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


childbearing years
All psychotropic medications cross the placenta
Uteroplacental circulation forms at about 2 weeks
post-conception
All medications are secreted in breast milk
All women of childbearing age can potentially expose a
fetus to medications, as 50% of pregnancies are
unplanned, and pregnancies are often not detected for
several weeks
For Any Woman of Childbearing
Age
 Discuss the possibility of pregnancy before prescribing
medications.
 Discuss contraception and the importance a planned
pregnancy, in order to minimize exposure/risk to a
fetus
Treatment of Psychiatric Disorders
in Pregnancy--Guidelines
 A different goal--not maximum reduction of
symptoms, but minimizing risk of harm to mother and
fetus
 Weigh the risk of an untreated psychiatric disorder vs.
possible teratogenic effects of medication
 Maximize non-pharmacologic treatments such as
cognitive behavioral therapy
 Organs and limbs are formed in the first trimester
Most Importantly
 Involve the patient in all treatment decisions with
careful risk-benefit discussions.
 The patient’s values and attitudes are important in the
decision-making
 Document the discussion
Mood Disorders
•Mood Disorders--21.4 % percent of the US, lifetime
prevalance (National Comorbidity Study Replication, 2002)
• 16.9%
• 4.4
• 2.5
Major Depression
Bipolar I and Bipolar II
Dysthymia
Major Depression
 The incidence of Major Depression in pregnant women
appears equal to the incidence in women in general
 Effects of maternal depression: decreased prenatal care,
decreased maternal-infant bonding
 Premature delivery, decreased breastfeeding (Grigoriadis,
2013)
 Cognitive-Behavioral Therapy and Interpersonal Therapy
are as effective as meds in most cases, long lasting, and not
teratogenic
 Supportive, couples, interpersonal and psychodynamic
psychotherapy should also be considered
 ECT is a safe and quickly effective option
 TMS appears safe and effective in limited studies (Felipe,
2016)
SSRI’s
 Fluoxetine, the first SSRI, approved in 1987.
 Limited data about long-term effects
 1996: Among 228 pregnant women taking fluoxetine
and 254 not taking it, fluoxetine was associated with
15.5% of minor anomalies compared to 6.5%. Third
trimester fluoxetine associated with: premature
delivery, respiratory difficulty, jitteriness, cyanosis, low
birth weight (Chambers 1996)
 2001 APA Concise Guide to Women’s Mental Health: “No
evidence of major congenital anomalies” for fluoxetine,
sertraline, paroxetine, fluvoxamine, citalopram
 2005: FDA issues warning that paroxetine in first trimester
may cause 1.5- to 2-fold increased risk for cardiac
malformations including atrial and ventricular septal
defects
 Increased risk for cardiovascular malformations, RR=1.36,
95% CI, 1.08-1.71, P=.008 (Grigoriadis, 2013)
 2006: FDA issues warning of 6-fold increased risk of
Neonatal Persistent Pulmonary Hypertension for all SSRI
exposure after 20 weeks of gestation
 2.9-3.5 per 1000 exposed infants (Grigoriadis, 2014)
SSRI-Related Neonatal Syndrome
 FDA Alert, Dec., 2005: “Neonates exposed to Paxil and
other SSRIs or serotonin and norepinephrine reuptake
inhibitors (SNRIs), late in the third trimester have
developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding.
Such complications can arise immediately upon
delivery”
 About 30% of neonates will experience this syndrome.
Self-limiting
 “Poor Neonatal Adaptation Syndrome” or “PNAS”,
respiratory distress (OR 2.20), tremors (OR 7.89)—
Grigoriadis, 2013
SSRI's Animal Studies
 "Overall, however, it is clear that early FLX exposure in
non-human animals can alter the development of the
brain in ways that are relevant to behaviour in
adulthood, decreasing exploration and social
interaction, and in some cases altering anxiety- and
depression-like behaviours."
--Kiryanova, McAllister, Dyck
(Dev Neuroscience, 2013)
Tricyclic antidepressants
 Over 1,100 cases of all TCA’s combined
 50+ years of use
 Not associated with major congenital defects or
miscarriage.
 Associated with low birth weight, pre-term delivery
 Anticholinergic effects in neonates including
constipation, tachycardia, urinary retention. Use
nortriptyline or desipramine (least anticholinergic)
 Monitor blood levels. Dose may need to change thru
pregnancy.
 MAOI’s--contraindicated because of clear increased risk of
birth defects in animals
 Bupropion—Little published data. Drug company
registry of 300 cases—no evidence of increased risk of
birth defects. Should not be used first-line.
 Mitrazipine—Djulus, 2006
 104 women each, on mitrazipine, SSRI’s, and nonteratogenic
meds
 Mitrazipine group: 77 live births, 20 spontaneous abortions,
6 tABs, 1 stillbirth, 2 major malformations
 Spontaneous abortions: mitrazipine 19%, other AD’s 17%,
nonteratogens 11%
 Preterm births: mitrazipine 10%, other AD’s 7%,
nonteratogens 2%
Case Study 1
 30 yo married graduate student has just learned she is
pregnant
 Husband has announced he’s seeking a divorce and
moving in with his new girlfriend
 Your patient exhibits symptoms of depression—crying
spells, hypersomnia, hyperphagia, depressed mood,
suicidal thoughts
 WHAT DO YOU DO?
Case Study 1
 The patient is diagnosed with an adjustment disorder
 Counseled about continuing pregnancy or not.
 Decides to continue pregnancy, given her age in the
early 30’s.
 Depression remits with counseling and support.
 Gives birth to healthy baby.
Case Study 2
 26yo married dentist, lifelong dysthmia and h/o
recurrent Major Depression,
 5 months pregnant with second child, and reports lack
of bonding feelings.
 Never bonded with first child, who is 4 years old,
developmentally delayed and didn’t speak until age 2.
Psychologists speculate neglect has contributed to his
developmental delay.
 WHAT DO YOU DO?
Case Study 2
 Fluoxetine 20mg QD instituted.
 Mood improves. Mother more interactive with 4yo
child, and feels bonded to fetus.
 Baby born without obvious sequelae.
 Happy ending
Bipolar Disorder
 Women with bipolar disorder may have improvement
of symptoms during pregnancy (Altshuler 1998)
 Take a careful history including:
 typical manic episode and worst manic episode
 typical depressive episode and worst depressive episode
 history of suicidal or dangerous behavior
 frequency of cycling
 Consider maintaining patient off medications,
especially during first trimester.
 Frequent visits with good doctor-patient access, so
medications can be instituted if needed.
Bipolar Disorder
Non-pharmacologic interventions
 Sleep hygiene
 Decrease stress
 Cognitive-Behavioral and Interpersonal Therapies
Lithium
 Lithium is the mood stabilizer of choice (Burt,
Hendrick, 2001). The initial reports of Ebstein’s
anomaly are exaggerated. First trimester risk is now
believed to be .1%. 5-year study of children with in
utero exposure—no behavioral abnormalities (Schou).
Use long-acting forms with divided dosages to
minimize peak concentrations.
 Floppy Baby Syndrome—cyanosis, hypotonicity
Lithium—practical guidelines
 Monitor levels closely
 May require increased dosage—maternal fluid
increase, vomiting
 Consider decreasing dosage prior to delivery to prevent
toxicity, anticipating rapid post-partum fluid shifts
 Keep in mind that post-partum period is a time of
highest risk for psychiatric disorders, especially mood
disorders
Anticonvulsants
 Valproic Acid: 1-5% risk of spina bifida with first
trimester exposure. Other possible effects are similar
to those of Carbamazepine
 Carbamazepine: 0.5-1% risk of spina bifida with first
trimester exposure. Also associated with craniofacial
defects, developmental delay and fingernail
hypoplasia
 Lamotrigine: 2006 FDA alert—possible association
with cleft lip/palate with first trimester exposure.
Consider risk of Stephens-Johnson Syndrome
Other Options
 ECT is safe and quickly effective
 Haldol—not associated with fetal anomalies (Hanson
1975, Van Woes 1969, Altshuler 1996)
Case Study
 40 year old MWF executive with BPAD I and 3 prior
psychiatric hospitalizations for mania with psychotic
features. Hospitalized for 2 weeks following birth of
first child. Maintained on lithium with occasional use
of Seroquel. Now learns she’s 2 weeks pregnant.
 Previous manias have occurred in early fall, and
January. It’s April.
 After a careful discussion, pt and I decide together to
minimize risk of lithium upon the fetus. We
discontinue lithium. Pt as usual has my cellphone
number to call for symptoms.
Case Study
 Sleep hygiene emphasized
 CBT focused on decreasing stress—relaxation techniques.



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Re-calibrated goals at work in order to decrease risk of
mania.
In September, in 6th month of pregnancy, pt. began have
mild hypomania. Called me on a Saturday, c/o insomnia
for 2 nights. Pressured speech, euphoria.
Started Haldol 1-2mg QHS for 3 days. Hypomania
subsided. Pt. took prn Haldol for remainder of pregnancy
Delivered healthy baby girl.
Restarted on Lithium and prn Seroquel
Anxiety Disorders
 The most prevalent of all psychiatric disorders
 31.2% of the U.S. population (NCS-R, 2002)
•
•
•
•
•
12.5%
12.1%
6.8%
4.8%
2.3%
Specific Phobia
Social Phobia
PTSD
Panic Disorder
OCD
Anxiety Disorders
 Symptoms of Panic Disorder may decrease while OCD
symptoms may increase
 Cognitive-Behavior Therapy is the treatment of
choice
 SSRI’s, as above
 Benzodiazepines are associated with cleft palate
malformations
Schizophrenia
 No change in incidence among pregnant women
 Age of onset coincides with reproductive years
 Schizophrenia itself may be associated with higher
incidence of birth defects.
 Poor prenatal care and diet
Atypical Antipsychotics
 The most widely prescribed of all medication, a $70-
billion/year industry
 Risk of tardive dyskinesia (0.5% yearly), cumulative
with exposure
 Petersen, 2016—review of all UK EHRs, 1995-2012,
primary care, for women taking antipsychotics,
lithium or anticonvulsant mood stabilizers
 No association between atypical antipsychotics and
birth defects
 Association found for valproate
Atypical Antipsychotics
 Coppola, 2007—Risperidone Worldwide database
 713 pregnancies
 3.8% organ malformations
 16.9 spontaneous abortions
 21 cases of behavioural or motor disorders
 Conclusion—does not appear to increase risk of
teratogenesis or miscarriage.
 EPS, self-limiting in neonates if exposed in 3rd trimester
Atypical antipsychotics
 Limited data
 Olanzapine—129 cases, 4 malformations, 1 delayed
motor development
 Risperidone—61 cases, no malformations
 Quetiapine—39 cases, no malformations
 Clozapine—19 cases, 2 neonatal seizures, 1 premature
with severe anomalies, 5 pregnancies with gestational
diabetes and/or hypertension
Atypical Antipsychotics
 No clear association with major birth defects
 Longterm neurobehavioral effects unknown
 Associated with EPS in neonate
 Should be used if benefits outweigh risks
Phenothiazines
 Associated with nonspecific congenital anomalies and
neonatal jaundice. In a meta-analysis of studies
encompassing 74,337 pregnant women, babies born to
mothers on phenothiazines had 2.4% incidence of
congenital anomalies, whereas those born to control
mothers had 2.0% incidence. Suggests that
phenothiazines may cause a slightly increased risk of
congenital anomalies, of 0.4% (Altshuler, 1996). These
were studies of phenothiazines used for hyperemesis
gravidum, not psychosis.
 Perinatal syndrome: respiratory depression, floppy infant,
hypertonicity, EPS, agitation—self-limiting
Haldol
 Not associated with fetal abnormalities in multiple
reports, including one of 100 patients.
 A series of 199 patients—10.3% with nonspecific
abnormalities, 2 case reports of limb deformities with
first trimester use.
 Benadryl is the side-effect medicine of choice with
no proven teratogenesis, but watch for anticholinergic
withdrawal in the infant
 Propranolol also appears safe, but watch for neonatal
bradycardia
 Cogentin and Artane are associated with minor
congenital anomalies
 Amantadine is associated with cardiovascular
malformation
A Brief History of Medicine and
Women
 Misunderstandings prevalent throughout medical history
 1990 U.S. Government Accounting Office shows that
13.5% of NIH budget goes to research diseases unique to
women
 1991 PHS Office of Women’s Health created
 1992 The first Deputy Assistant Secretary for Women’s
Health is appointed. Susan Blumenthal, M.D., “What is
known about the causes, treatment and prevention of
illness—whether schizophrenia, heart disease, or cancer—
comes from studies conducted primarily with men.”