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James J. Nocon, M.D., J.D.
[email protected]
 Addiction
is a disease of the Brain.
 Review the effects of drugs on the fetus.
 Understanding that treatment works!
 What are the effects of drugs on
breastfeeding?
 Assess the risk of drugs among breast-fed
infants.
 Currently,
less than 10% of substance
users are detected in pregnancy.
 Identifying the drug using woman is the
critical factor in successful treatment and
successful breast-feeding.
 Alcohol
and Tobacco
cause more fetal harm
than all the other
drugs combined
 Including
environmental
pollutants and
medications
 Among
Women using BOTH Alcohol and
Nicotine in the pregnancy
• 20.4% used Marijuana
• 9.5% used Cocaine
 Women
NOT using Alcohol or Nicotine
• 0.2% used Marijuana
• 0.1% used Cocaine
Alcohol and Nicotine use is a marker for
other drug use.

What drugs and various pleasurable behaviors, have
in common is the release of various psychoactive
chemicals in the brain:
• Dopamine – creates the buzz
• Serotonin – sense of well being
• Endorphins – euphoria
• GABA (gamma amino butyric acid) – satiety and
somnolence (sleepy after a big meal or sex)
• Do men make more GABA?



Most psychoactive drugs and many behaviors trigger the
dopamine response in the nucleus accumbens.
As repeated use of the drug or behavior depletes the
dopamine, more activity is required to get the same
effect.
This phenomenon is called “tolerance.”

There comes a point when the affected person becomes
an addict, as if a switch in the brain is flipped, and the
person no longer has the ability to make free choices
about the continued use of the drug.

Leshner AI. Addiction is a brain disease, and it matters. Science 1997;278:45-47
Addiction is a double
whammy.
Tolerance - The brain needs
more and more of the drug in
order to get the same effect.
And in this process, the brain
cells are actually altered.
It’s as if the brain is hijacked,
along with the mind and the will.
 Is
the fetal brain altered by maternal
substance use?
 Where are the changes?
 Are such changes permanent?
 Are structural changes associated with
specific behaviors?
 Do such changes lead to addiction?

Neurotox Teratol 2006;28:386-402



Grey matter increase
adjacent to the corpus
callosum as a function of
severity of cocaine usage.
This cohort (21) had
deficits in attention,
visual-motor, cognitive
and language skills
compared to non exposed
children (14).
Singer, et al. Neurotoxicology and Teratology
2006;28:386-402

Credit: Courtesy Christopher Watson and
Michael Rivkin, MD, Children's Hospital
Boston



The brain image at left is from a
subject exposed to alcohol,
cigarettes, cocaine and marijuana
in utero,
The image at right is from a sameage, same-sex control with none of
these exposures.
Note that the cortical gray matter
appears thinner in the exposed
brain than in the control (black
arrowheads).
In addition, the subcortical gray
matter appears fuller and more
robust in the control brain (see
arrows near top of image) than in
the exposed brain.
 Does
it make the gray matter thicker?
 Or Thinner?
 And what if there are no differences in
behavior at 7 months?
 Changes
due to alcohol are permanent
 Do Changes in the Brain result in physical
changes in the body?
 Do the changes in the brain affect later
behavior?
 Are such changes specific to the drug?
 Does the maternal substance beget substance
users? or
 Do “Drunks beget Drunks”
• Plutarch (46-120 AD)
 Binge
drinking in the preconception period
leads to an increased risk of unintended
pregnancy.
 Duh!
 Ethno-cultural effect: this occurs almost
exclusively in white college-aged women.
 Alcohol
is a known teratogen
• There is NO known safe level of drinking in pregnancy
• Alcohol use in pregnancy is the leading
preventable cause of mental retardation in the
United States
 Alcohol
easily crosses the placenta but is
eliminated at ½ the rate in the maternal blood
 Amniotic fluid alcohol level elevated even after
mom’s level is zero.
 Perinatal
and/or postnatal growth retardation
 Central Nervous System involvement
 Characteristic facial features
 History of maternal alcohol use during pregnancy
*Consensus Case Definition by Research Study of Alcoholism, Fetal Alcohol
Study Group
Flattened Midface
Elongated, flat
philtrum
Shortened Palpebral
fissures
 Fetal
Alcohol Syndrome; FAS
 Fetal Alcohol Spectrum Disorders: FASD
• Neonates and children who exhibit fewer of the
characteristics than deemed necessary for the full
diagnosis
• Alcohol-related birth defects
• Alcohol-related neurodevelopment disorder
 Low
IQ – average is 67
 For
children with FASD, ADHD more likely to be
earlier onset inattention subtype
 Appear to have a disturbance in brain structure
(in the corpus callosum)
 Response to standard psycho stimulant
medication can be very unpredictable.

O’Malley and Nanson. Can J Psychiatry 2002;47;349–
354
 Cigarette
smoke contains carbon monoxide,
cyanide and aromatic hydrocarbons which bind
more strongly to hemoglobin than oxygen.
 Thus, oxygen is reduced both to the mother and
fetus.
 Nicotine (vasoconstrictor) reduces placental flow
compounding the effect of the smoke.
 Cigarette smoking is the leading preventable
cause of low birth weight babies.
 Low
birth weight
 Preterm delivery
 SIDS
 Congenital defects (cleft lip and palate)
 Linked to Attention Deficit Disorder
 Asthma and other respiratory disorders.
 Second Hand smoke: asthma; SIDS; ear
infections; pneumonia; hyperactivity.
 If
smoking cessation achieved before 16 weeks,
most or all of the adverse effects are avoided,
specifically:
• 20% of all low birth weight babies
• 8% of all preterm deliveries
• 5% of all perinatal deaths
 Nicotine
Replacement Therapy (patches or gum)
alone has little harmful effect on fetus and
minimally excreted in breast milk.
• Benefits greatly outweigh risk.
• Dempsy and Benowitz. Risks and benefits of nicotine to aid smoking cessation in
pregnancy. Drug Saf 2001;24:277-322.
 Crosses placenta easily
• Fetal circulation lacks plasma esterases to metabolize
• Remains in fetus for prolonged time – 12-14 weeks
• 99% of cocaine use at Wishard is “Crack.”
 Potent vasoconstrictor
• Acute hypoxic insult may occur with vasoconstriction
• Decrease in oxygen and nutrient exchange
• Growth restriction
• Abruption
• Teratogenicity? Secondary to lower blood flow during
morphogenesis
Meconium Testing in 40 Term Newborns of
Mothers Treated 2002-2007







All 40 tested positive for cocaine at first prenatal visit
27 negative: mean wt/gm: 3253.55; s.d. 473.99
13 positive. mean wt/gm: 2775.85: s.d. 466.68
Difference of the means: 477.7 gm.
It takes 12-14 weeks for the meconium to clear after
cessation of cocaine use - mechanism is unclear.
Thus, the negative newborns had to be drug free well
before the third trimester.
Wishard Prenatal Recovery Program.
 No
consistent negative association between
prenatal cocaine exposure and physical growth,
developmental test scores or receptive or
expressive language
 Less optimal motor scores found up to 7 months
but not thereafter.
 The “Crack Baby Syndrome” was a myth.

JAMA 2001;285:1613-25

THC binds to CNS receptors (CB1) in human fetus
• Limbic structures – impulse control – blind munchies
• Amygdala – social functions – we’re all friends
• Hippocampus – amnesia – short term memory loss

Underappreciated toxicity
•
•
•
•

Growth restriction
Reduced limb length noted
Increased startles and tremors in first year of life
Schwartz: Pediatrics 2002;109:284-289
Grossly underreported use – national survey 2.9%
pregnant women admit to using marijuana whereas urine
drug screens at first prenatal visit reveal 30-40% positive
for THC in Indiana.




24 OB patients from a IUMG clinic – June 2005 Through
April 2006
All between ages of 17-22
All had 1st prenatal visit in first trimester
10 (41.6%) tested Positive for THC at 1st prenatal visit
• All stated they used THC for nausea
• All tested negative by 20 weeks


No special treatment other than routine urine testing for
drugs in this group.
Results of another hospital in Southwestern Indiana
where all patients tested at first prenatal visit revealed
30% positive for THC (White, insured)



Prenatal alcohol and tobacco exposure have direct
consequences on development.
BUT large multi-center studies failed to show that
prenatal cocaine and heroin exposure causes
devastating child consequences when environmental
variables are controlled, especially chronic poverty.
Jones. Current Directions in Psychological Science
2006;15:126-30.
 The
nation’s number one prenatal public health
problem
• Various studies: 40-70% abstinent at 6 months
• Less than 25% of addicts receive treatment
 The
major problem is underutilization of proven
treatment options:
• Failure to identify the addict
• Failure to continue treatment after delivery
 US
Dept Justice Fact Sheet 2001 May #17.
 Drug
concentration in breast milk.
 Drug clearance.
 Therapeutic dose – clinical effect on infant.
 Levels of exposure - the exposure index
 Effects of drugs on production of breast milk.
 Effects of drugs on the breast-feeding patient

Ito S. Drug therapy for breast-feeding women. NEJM 2000;343:118127
 Transcellular
diffusion
• Small molecules, ethanol
• Rapid transfer
 Intercellular
diffusion
• Occurs during colostrum phase
• Alveolar cells spaced wide apart
 Passive
diffusion
• Most drugs
 Lipid
Solubility - benzodiaepines
 Protein binding – free and unbound
 Half-Life – fluoxetine prolonged
 Molecular size - ethanol
 Infant Factors
• Gastric pH; transit time
• Less plasma proteins = more unbound drugs
 Milk
to plasma ratio.
 Varies over time.
 When the amount of drug ingested from
the milk, per unit of time, is less than the
therapeutic dose (clinical effect),
 Then the level of exposure is low.
 Regardless of the milk to plasma ratio.
 If
the rate of drug clearance is high,
 Then even a high milk-to-plasma level will
not result in a clinical effect.
 However, long acting drugs like fluoxetine
may accumulate over time and create a
clinical effect.
 Exposure
index
 Amount of drug in breast milk is expressed
as a percentage of the therapeutic dose
(clinical effect) for the infant.
 Arbitrary “safe value” is 10% of the
therapeutic dose.
 If the exposure index is less than 10, then
the effect is not clinically important.
 Most
tricyclic antidepressants and SSRI’s have
an exposure index less than 10.
 Exceptions: Use with caution:
• Fluoxetine – long acting; may accumulate; colic
• Doxepin - sedation
• Lithium – hypothermia, hypotonia; contraindicated

Lester BM, et al. Possible association between fluoxetine
hydrochloride and colic in an infant. J Am Acad Child Adolesc
Psychiatry 1993;32:1253-1255.
 Sertraline
– no adverse effects noted.

Level of alcohol dehydrogenase in first year is 50% of
that in adults: rapid absorption into infant’s bloodstream.
• May impair neurologic development.
• Decreases time spent in active sleep
• Beer drinking may reduce milk intake by 20%




Dose-response effect – takes about 2 hours for one drink
to be eliminated from mother
If breast feeding every 2-3 hours, then should not
consume more than one drink between feedings.
Or, instruct patient to drink just AFTER breastfeeding.
Or, “Pump and dump.”

A Standard Drink is defined as
12 ounces of beer,
5 ounces of wine, and
1.5 ounces of 80 proof distilled spirits

In a study of pregnant drinkers, the median patientdefined “drink” size was:
22 ounces of malt liquor, or
8 ounces of fortified (up to 20%) wine, or
2 ounces of 100 proof spirits
A
bit o’ brandy before breastfeeding can help
let-down – NOT!
 Evidence does not support that alcohol has any
benefit to any aspect of breastfeeding.
 If a woman cannot stop or limit her drinking to
one drink a day after breastfeeding, than one
may correctly assume she has a problem.
 In this case, AA may be more important than
breastfeeding.



Depends on the amount she smokes.
60-90 minutes to eliminate 50% of nicotine
Nicotine induced toxicity reported in breast-fed infants.
• Decreased Milk volume
• Early weaning from breast-feeding
• Decreased weight gain in infant - controversial
• Vio, Salazar, Infante. Smoking during pregnancy and lactation and its effects on
breast milk volume. Am J Cnin Nutr 1991;54:1011-1016

Secondhand smoke may be far more dangerous.
• SIDS
• Asthma
 Women
who breastfeed and continue to
smoke have infants with lower incidence of
acute respiratory illness compared with
bottle-fed infants of women who smoke.
 If
she can’t stop smoking, there is still a
benefit to breastfeeding.
– milk/plasma ratio high
 Half-life about 24 hours
 Nicotine levels in patch patient about 1/3 of
the 1 pack a day smoker (substance users
often smoke more than 1ppd)
 Safer than smoking because dose to infant
is lower
 Unless mom smokes and uses patch
 Prolonged-release
 Not
Contraindicated
 BUT, large amounts of caffeine (7-8 cups) may
cause irritability in the infant.
• Ryu JE. Effect of maternal caffeine consumption on heart rate and sleep
time in breast-fed infants, Dev Pharmaco Ther 1985;8:355-363.
 Rate
of caffeine clearance 10% of that in adults
so there may be a wide range of exposure.
 2-3 cups per day appear to have no effect.
 Cocaine
induced toxicity:
• Tremulousness
• Irritability
• Vomiting and diarrhea.
be more acute with “crack” cocaine.
 Contraindicated.
 May

Chasnoff IJ, Lewis DE, Squires L. Cocaine intoxication in a breastfed infant. Pediatrics 1987;80:836-838.
 Same
effects as cocaine
 Passes readily into breast milk
 Same for methamphetamine
 MDMA = MethyleneDioxyMethAmphetamine;
invented by Merk in 1013 as an appetite
suppressant – “Ecstasy”
 These are difficult addictions to treat and
patients are poor candidates for breastfeeding.
 Potent
hallucinogen at low doses
 Low molecular weight – would pass rapidly
into milk
 Infant hallucination – dilated pupils,
salivation, nausea
 Contraindicated.

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Sparse literature.
May decrease prolactin production
May forget where she put the baby.
Second hand smoke effects same as tobacco.
Blind munchies – chocolate (theobromine) may cause
irritability or increased bowel activity in excess amounts.
May affect neurologic development.
Astley SJ, Little RE. Maternal marijuana use during lactation and
infant development at one year. Neurotoxicol Teratol 1990;12:161168.
 Long
half life
 BUT, transfer to milk is minimal.
 Maternal dose of 80 mg. per day (typical) yields
infant dose about 2.8% of maternal.
 Some studies indicate concentrations in breast
milk unrelated to maternal methadone dose
 Appears to have mitigating effect on NAS –
shorter LOS of breast-fed infants.

Phillip BL, Merewood A, O’Brien S. Methadone and breastfeeding;
new horizons. Pediatrics 2003;111:1429-1430.
 Reduced
acuity (95%),
 Nystagmus (70%),
 Delayed visual maturation (50%),
 Strabismus (30%),
 Refractive errors (30%), and
 Cerebral visual impairment (25%).

Hamilton; Ophthalmic, clinical and visual electrophysiological findings
in children born to mothers prescribed substitute methadone in
pregnancy. Br J Ophthalmol doi:10.1136/bjo.2009.169284
 Suboxone:
buprenorphine and naloxone.
 Oral Rx for opiate dependent maintenance.
 Substantially reduced NAS.
 Minimal to no effect on breastfeeding.
 Most recent literature indicates using
buprenorphine to treat NAS in newborn:
improved efficacy and shortened LOS
• Kraft WK, et al. Sublingual buprenorphine for treatment of neonatal
abstinence syndrome: a randomized trial. Pediatrics; published online
August 11, 2008.
 Hydrocodone,
oxycodone and fentanyl.
 Usual doses for pain relief appear to have
minimal to no effect on infant.
 However, many of these patients also use pain
moderators which may depress infant:
• Benzodiazapines: Xanax; Klonopin
• Gabapentin: Neurontin
• Amytripilene: Elavil (generally safe)
• Cyclobenzaprine: Flexoril
 High
rate of tobacco use.



National Birth Defects Prevention Study, case-control study for
infants born October 1, 1997, through December 31, 2005, in 10
states
Therapeutic opioid use was reported by 2.6% of 17,449 case
mothers and 2.0% of 6701 control mothers.
Treatment was statistically significantly associated with:
• conoventricular septal defects (OR, 2.7; 95% CI, 1.1–6.3
• atrioventricular septal defects (OR, 2.0; 95% CI, 1.2–3.6),
• hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4–4.1),
• spina bifida (OR, 2.0; 95% CI, 1.3–3.2), or
• gastroschisis (OR, 1.8; 95% CI, 1.1–2.9) in infants
http://www.ajog.org/article/S0002-9378(10)02524-X/abstract
 Readily
pass into breast milk
 May cause lethargy in infant
 Common prescribed for
• Anxiety - Alprazolam; Clonazepam
• Sleep – Flunitrazepam (Rohypnol)
• Muscle relaxant
 Commonly
mixed with alcohol or opiates
and very frequently found in fatal
overdoses.
 Gamma-Hydroxy-Butyrate
• “Club drug;” Raves; heightens sexual pleasue
• The other date rape drug
• Rapidly concentrated in milk and then excreted –
withdrawal in infant
 PCP
– phencyclidine
• Sense of Power; anesthetic
• Can be detected in breast milk several weeks after
use
 Women
using these drugs not good candidates
for breastfeeding.
 Most
common are butane gas lighters and
aerosol sprays
 Small molecules, and highly lipid soluble
 Rapidly concentrate in breast milk
 Short half life.
 Breastfeed, then sniff!
 Pump and dump.
 About
30% of substance users.
 Most common drug combinations:
• Hydrocodone or oxycodone
• Benzodiazepine
• Cocaine
• THC
 Very
difficult to treat
 Most involved with CPS intervention.
 Poor candidates for breastfeeding.
 Be
aware of HIV and hepatitis in
substance users.
 Poor nutritional status
 Domestic violence and sexual abuse 5070%
 Homeless
 Tobacco use 65-70%
 Does
breastfeeding enhance or detract from
ongoing recovery in the postpartum patient?
 The most common cause of relapse is stress,
and it don’t take much.
 If breastfeeding is not going well and the patient
is experiencing significant stress, she is ripe for
relapse.
• Plays into low self esteem - “I’m a failure”
• Baby always crying – “I need some peace and quiet.”
• Despair – using drugs to “numb out.”
 Alcohol
and tobacco cause more fetal
damage than all the other drugs combined.
 Detection of the substance user is 85% of
the battle.
 Breastfeeding is to be encouraged in
substance use patients with rare
exception.