James J. Nocon, M.D., J.D.

jnocon@me.com

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 same-age, 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 *Consensus Case Definition by Research Study of Alcoholism, Fetal Alcohol Study GroupStudy 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;343:118-

127

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 patient-defined “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.

Prolonged-release – 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

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.

May be more acute with “crack” cocaine. Contraindicated.

Chasnoff IJ, Lewis DE, Squires L. Cocaine intoxication in a breast-fed 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.

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;12:161-168.

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 50-

70% 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.