Pregnancy and Lactation

How were pregnancy risks previously categorized?

• until 2015, as A, B, C, D, or X by FDA

What did category A mean?

• adequate and well-controlled human studies

• failed to demonstrate risk to fetus in first trimester

What did category B mean?

• animal reproductive studies failed to demonstrate risk to fetus

• no adequate and well-controlled studies in women

or

• animal studies showed an adverse effect

• adequate and well-controlled studies failed to demonstrate risk

What did category C mean?

• animal studies showed adverse effect

• adequate and well-controlled studies in humans

• potential benefit may warrant use despite risks

What did category D mean?

• positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience in humans

• potential benefits may warrant use despite risks

What did category X mean?

• studies in animals or humans demonstrated fetal abnormalities

and/or

• positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience

and

• risks involved outweigh potential benefits

Can drugs have different categories for different indications?

Yes, drugs can be categorized differently based on their indications, meaning a drug might be assigned a different pregnancy category for various uses. (e.g. Valproic acid → D for bipolar, and X for all other indications)

How are drug risks in pregnancy and lactation now represented?

• enacted Pregnancy and Lactation Labeling Rule → labeling use in specific populations

  • pregnancy → risk summary, clinical considerations, data of case reports of congenital malformations

  • lactation → risk summary, clinical considerations, data such as amount of drug found in breast milk

  • females and males reproductive potential → need for pregnancy testing, contraceptive recommendations, information about infertility as it relates to the drug

What PKs can impact drug levels in pregnancy?

• increase in total body water, ECF and plasma volume → due to estrogen-mediated effects on RAAS pathway

  • increases Vd for hydrophilic drugs

• increase in body fat stores

  • increases Vd for lipophilic drugs

• increase renal clearance (30-50%) → due to increased renal blood flow and GFR

  • decreases conc renally cleared drugs

• decrease albumin and glycoprotein

  • higher % of free drug, may need to lower

• decrease intestinal motility → progesterone mediated delay gastric emptying

  • impact not well understood

How can CYP enzymes change during pregnancy?

• increased efficacy (need higher doses)

  • 2B6

  • 2C9

  • 2D6 - UM/EM

  • 3A4

  • UGT

• decreased efficacy (need lower doses)

  • 1A2

  • 2C19

  • 2D6 - PM

How is risk determined in breastfeeding?

• milk plasma ratio → determines if accumulation in breast milk

  • little clinical value on its own

• exposure index (aka relative infant dose)→ theoretical infant dose/maternal dose

  • theoretical infant dose → Cmaternal x MP x Vd_infant

  • if EI <10% considered clinically unimportant

  • if EI < 15% may be considered safe if weigh risk/benefit

• Upper area under the curve ratio → simulated pediatric AUC using comp modeling to determine EI

  • not readily available

Besides risk to pass to infant, what else needs to be considered for risk during breastfeeding?

• decreased milk production

  • amphetamines

  • pseudoephedrine

  • estrogen

  • antihistamines (at high doses, and 1st gen)

  • DA agonists

  • diuretics (high doses)

• reduces ejections

  • chronic alcohol and opioids

  • antihistamines (1st gen)

  • anticholinergics

  • labetalol → inhibits oxytocin release/production

• phenotypes

  • UM/PM of parent and baby

    • e.g. 2D6 and codeine

    • e.g. G6PD and nitrofurantoin

What is the risk of untreated chronic heroin addiction?

• lack prenatal care

• increased risk of fetal growth restriction

• placental abruption

• fetal death

• preterm labour

• intrauterine passage of meconium (meconium aspiration syndrome)

• increased activity in high risk activities (sex for drug, criminal activity)

• comorbid mental health conditions (depression, PTSD, anxiety)

• increased concurrent substance use (tobacco, cannabis, cocaine)

• poor nutrition

• disrupted support symptoms

*a lot of psychosocial factors that increase risk of poor fetal outcomes

For OUD is there a preferred agent in pregnancy?

• current guidelines do not recommend one over another

• most studies tend to favour buprenorphine

  • data not obust enough to drive one recommendation however

What is the evidence for buprenorphine vs methadone in fetal/maternal outcomes?

• in almost all cases (except C-section) buprenorphine was favourable vs methadone for fetal outcomes

• no difference in severe maternal complications

What is the one important thing to ensure when treating OUD in pregnancy?

• avoid withdrawal completely

  • is known to increase risk of poor outcomes like preterm labour, fetal distress and miscarriage

• rules out buprenorphine standard induction and macrodosing

  • may consider if actively presenting in withdrawal

What else needs to be considered when treating OUD in pregnancy?

• immediate connection to OBGYN

  • need close monitoring

  • risks to newborn so prepare to this (addiction, HIV, Hep C)

• dosing may need to be adjusted between trimesters

  • both agents metabolized via 3A4, which increases in activity during pregnancy

What is the major risk concerned for in infants born with in utero exposure to opioids?

• Neonatal opioid withdrawal syndrome (NOWS) - aka neonatal abstinence syndrome (NAS)

  • diagnosed if history of exposure and signs of opioid withdrawal

  • may do toxicology testing in urine, meconium or umbilical cord tissue (but testing rarely changes management)

What signs and symptoms are you looking for in opioid withdrawal in infants?

WITHDRAWALS

• wakefulness

• irritability (unable to console)

• tremors, temp increase, tachypnea

• hyperactivity (high pitch cry), hiccups

• diaphoresis, diarrhea, disturbed sleep/feeding

• respiratory distress, runny nose, regurgitation

• apnea

• weight loss (more than typically expected)

• alkalosis

• lethargy and lacrimation

• sniffles, sneezing, seizures

How long is infant monitored for with diagnosed with NOWS and what is the standard assessment tools used?

• observes 3-7d depending on opioid exposure

• assess with

  • modified Finnegan score

  • MOTHER neonatal abstinence measure

  • Eat, sleep, console

How is NOWS managed?

• non-pharm → for all infants

  • keep mom and baby together

  • provide quiet and non-stimulating environment

  • encourage breastfeeding if possible

• medication (opioids) → if severe withdrawal

  • morphine

  • buprenorphine

  • methadone

When is a baby ready for discharge?

• no significant signs of withdrawal for 24-48h

• parents counseled on:

  • signs of withdrawal

  • safe sleep practices

  • usual newborn discharge counseling

• follow-up appt in 24-48h

What is the risk of AUD in pregnancy?

• can lead to physical impairments and neurodevelopmental changes

  • Fetal Alcohol Spectrum Disorders (FASD)

What are the characteristics of FASD?

• neurodevelopmental impairments (occurs in first trimester)

  • impulse control

  • social skills

  • coordination

  • learning

• physical impairments

  • facial deformities (occurs in later trimesters)

  • growth deficiencies

  • microcephaly

  • organ malformations (occurs in first trimester)

What are the facial deformities that can occur with FASD?

• small head

• epicanthal folds

• flat midface

• smooth philtrum

• low nasal bridge

• small eye openings

• short nose thin upper lip

What are the screening tools to assess for potential risk to fetus?

• T-ACE

  • Tolerance (more drinks to get euphoria)

  • Annoyance

  • Cut Down

  • Eye-Opener

What are the risks of alcohol withdrawal to fetus?

• withdrawal may present several risks to the fetus (data hard to find b/c ethical issues)

  • physiological and psychological stress → preterm birth and low birth weight

  • increased release cortisol → increases corticotropin-releasing hormone in placenta which elevation < 20w can lead to preterm labour

  • HTN may impact placental perfusion

What is the evidence for using benzos to manage alcohol withdrawal in pregnancy?

• systematic review showed no conclusive evidence of risk for major malformations with:

  • alprazolam, clonazepam, chlordiazepoxide or diazepam in first trimester

• small increase of anal atresia with lorazepam

  • absolute risk VERY small 0.002%

  • can be fixed with surgery if occurs, so benefits outweigh risks

What is the evidence for naltrexone in pregnancy for AUD management?

*evidence comes from use in OUD

• increased length of hospital stay, premature births and urogenital birth defects

• small studied without comparator or compared to methadone/burprenorphine

• hard to know what actual risk is versus not treating AUD

What is the evidence for acamprosate in pregnancy for AUD management?

• scarcity of data; mixed

• one study (54 ppl) found no difference in fetal outcome compared to general population

What is the current management recommendation of AUD in pregnancy?

• recommend use of non-pharms for low-moderate consumption during pregnancy

  • Norwegian study found pregnancy is high motivator (85% altered consumption)

• intensive behavioural therapy preferred over medications

How to manage pregnant AUD patients where behavioural therapy is not enough?

• balance risk of continued alcohol use and risk of medications

  • needs to be discussed with the patient