1. Psychiatric Treatment During Pregnancy
Dora Wang, MD, MA
Clinical Associate Professor
Historian of the UNM School of Medicine

2. 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

3. 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.

4. 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

5. 1878 Alfred Hegar shows that the removal of ovaries in pigs, results in atrophy of the uterus. Discovers that ovaries govern menstruation.

6. Misconceptions of women and mental illness have been the rule, rather than the exception for most of history

7. 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

8. American Journal of Obstetrics & Gynecology, 1957

9. DES
Diethylstilbestrol, the first synthetic estrogen, FDA approved in 1941 for menopausal symptoms
, 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 , even if by 1953, studies refuted that DES prevented miscarriages
April 15, 1971, NEJM, rare cervical adenocarcinoma in 8 girls, ages Seven were born to mothers who took DES in first trimester of pregnancy.

10. DES and Numbers 5-million to 10-million women exposed
30 years,
Teratogenesis was exposed with 7 cases of cervical adenocarcinoma

11. DES teratogenic effects
DES daughters: increased risk of cervical adenocarcinoma, cervical dysplasia, infertility, breast cancer
DES sons: hypospadia, infertility, lower sperm count

13. 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 life-threatening 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.

14. 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

15. 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 doctor-patient relationship

16. Special Considerations
Psychiatric Disorders in women usually have onset in 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

17. 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

18. 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

19. 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

20. Mood Disorders
Mood Disorders % percent of the US, lifetime prevalance (National Comorbidity Study Replication, 2002)
16.9% Major Depression
4.4 Bipolar I and Bipolar II
2.5 Dysthymia

21. 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)

22. 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)

23. 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, , 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
per 1000 exposed infants (Grigoriadis, 2014)

24. 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

25. 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)

26. 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.

27. 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%

28. 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?

29. 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.

30. 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?

31. 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

32. 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.

33. Bipolar Disorder Non-pharmacologic interventions
Sleep hygiene
Decrease stress
Cognitive-Behavioral and Interpersonal Therapies

34. 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

35. 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

36. Anticonvulsants
Valproic Acid: 1-5% risk of spina bifida with first trimester exposure. Other possible effects are similar to those of Carbamazepine
Carbamazepine: % risk of spina bifida with first trimester exposure. Also associated with craniofacial defects, developmental delay and fingernail hypoplasia
Lamotrigine: FDA alert—possible association with cleft lip/palate with first trimester exposure. Consider risk of Stephens-Johnson Syndrome

37. Other Options ECT is safe and quickly effective
Haldol—not associated with fetal anomalies (Hanson 1975, Van Woes 1969, Altshuler 1996)

38. 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.

39. Case Study Sleep hygiene emphasized
CBT focused on decreasing stress—relaxation techniques. 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

40. Anxiety Disorders The most prevalent of all psychiatric disorders
31.2% of the U.S. population (NCS-R, 2002)
12.5% Specific Phobia
12.1% Social Phobia
6.8% PTSD
4.8% Panic Disorder
2.3% OCD

41. 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

42. 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

43. 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, , primary care, for women taking antipsychotics, lithium or anticonvulsant mood stabilizers
No association between atypical antipsychotics and birth defects
Association found for valproate

44. 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

45. 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

47. 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

48. 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

49. 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.

50. 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

51. A Brief History of Medicine and Women
Misunderstandings prevalent throughout medical history
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.”