508: Lecture 5 - Pregnancy and Lactation 1

Learning Objectives for this lecture:

• Understand the variations during pregnancy trimesters, and how this may impact effect of drug exposure

• Explain the factors influencing teratogenicity of a drug

• Summarize which pts require preconception planning and why this is important

• Evaluate general epidemiological and medical needs for management of pregnancy termination/loss

• Given a patient case, evaluate medical management of pregnancy loss/induced termination

• Understand the changes in ADME that occur in pregnant patients and how these changes may impact drug pharmacokinetics

• Review the current and new FDA pregnancy risk categories and 5 lactation categories and be able to apply this information for justifying drug therapy in patient cases

• Given drug information and characteristics, evaluate a medication for use during acute/chronic illness in pregnancy

• Given a patient case, be able assess, select and recommend, and educate on the appropriate pharmacologic, and non-pharmacologic treatments for common acute/chronic conditions during pregnancy

Briefly describe the pathophysiology of pregnancy:

Fertilization

• Day 1-2: usually occurs in the fallopian tube

• Day 3: the fertilized egg reaches the uterus.

  • Cell division continues for another 2 to 3 days in the uterine cavity before implantation.

Implantation – occurs by day 10 post fertilization

How is pregnancy diagnosed? Which hormone is used?

• hCG (human chorionic gonadotropin)

  • Produced by the placenta (usually by D6 post fertilization)

  • hCG concentration doubles every 2-3 days and peaks at 8-12 weeks

  • Comprised of two subunits: α and β

    • α subunit has cross-reactivity with LH, TSH, FSH and may produce false positive results

    • β subunit unique to hCG; what pregnancy tests are evaluating

  
  

What about using home pregnancy tests (HPT)?

Detects urine hCG

97+% accurate, most false negatives are the result of patients testing too soon

• only 25% are false negatives

• False positives are incredibly rare

What is the general duration of pregnancy?

• 267 days from conception

• 280 days from the first day of the last menstrual period (LMP)

What’s the gestational age? At what point during pregnancy is the risk of drug exposure greatest?

Number of completed weeks of pregnancy since the first day of the last menstrual period (LMP)

• Embryo is < 8 weeks of gestational age (wga)

• Fetus is >8 wga

1st Trimester has the greatest drug exposure risk.

What is gravidity? What is parity? What is the acronym TPAL?

• Gravidity (G) = the total number of pregnancies a patient has experienced, including active pregnancies

• Parity (P) = number of deliveries

  • Term (T) = any deliveries after 37 wga

  • Prepterm (P) = any delivery of live infant 20-37 week gestational age

  • Aborted/ectopic (A)

  • Living children

What physiologic changes occur during pregnancy? What are the effects of this?

Metabolic changes: hepatic metabolism can be increased or decreased →

• Leads to increased/decreased drug metabolism →

  • Increased/decreased drug concentrations

Placental changes: thinning of fetal-maternal blood barrier →

• Leads to increased drug distribution →

  • Increased fetal drug concentrations

  • Decreased maternal concentrations

Renal changes: Increased renal blood flow →

• Increased GFR and drug elimination →

  • Decreased drug concentrations for the mother

Volume of distribution changes: normal blood volume, decreased albumin, increased body fat →

• Leads to Increased drug distribution, increased distribution for lipophilic medications, Decreased protein binding →

  • Decreased concentration of lipophilic drugs,

  • Increased concentrations of free drug

GI changes: Decreased motility and increased intestinal blood flow →

• Increased drug absorption →

  • Increased drug concentration

When thinking of the placental-fetal compartment, what should we consider?

Considerations:

• Amount of drug crossing placenta

• Placental metabolism

• Fetal distribution

Placental drug transfer (simple diffusion is most common):

• Molecular weight of drug (400-600 Daltons cross easily)

• Lipid solubility

• Ionization

• Protein binding

• Exchange area

• Blood flow

What is teratogenicity?

• Teratogenicity – capability to produce congenital abnormalities; can be major or minor

  • Major – incompatible with life / requiring corrective surgery

  • Minor – most are cosmetic (extra digits / skin tags)

  • Normal rate of birth defects: 3-6%

• <10% of FDA approved drugs have information regarding use in pregnancy

What are preconception risk factors to counsel/discuss?

• Use of teratogenic drugs

• Uncontrolled chronic conditions

  • HTN, DM, Asthma, mood disorders

• Lifestyle modifications

  • Etoh

  • Tobacco use

  • Illicit drug use

  • Nutritional supplementation

What are some examples of teratogenic drugs and how do we manage?

• Antiepileptic Drugs (carbamazepine / valproic acid) • Lowest dose to control condition vs transitioning to alternative agent

• Isotretinoin

  • REMS program for use requires 2 methods of pregnancy prevention

  • Known severe teratogen: CNS, craniofacial, cardiac

• Warfarin ➔ change to alternative anticoagulant (LMWH preferred)

How do we manage chronic disease states in pregnancy?

• Objective control of primary disease state

  • Achieve BP or DM goals

  • Seizure free periods

  • Prevent asthma exacerbations

• Transition to low-risk regimen for pregnancy

How do we manage alcohol and recreational drug use in pregnancy?

• Discontinue use as soon as possible; consider entrance into treatment program if assistance needed.

• Etoh: no amount considered safe

  • Increased risk for FAS (fetal alcohol syndrome)

• Tobacco: offer cessation counseling and pharmacotherapy if needed

  • Increased risk for LBW, SAB (spontaneous abortion), PTB, premature placental detachment, SIDS, and fetal deformities

  • NRT or bupropion preferred

  • Best if before 16 wga

• Marijuana

  • low birth weight (LBW) and preterm delivery (PTD)

• Cocaine

  • intrauterine growth restriction (IUGR), PTD, LBW, malformations, functional/behavioral deficits, fetal/neonatal death

• Amphetamines

  • IURG, LBW, PTD, fetal/neonatal death

• Heroin

  • IURG, LBW, PTD, cardiac malformations (1st trimester), neonatal abstinence syndrome (NAS), fetal/neonatal death

What supplementation is recommended for preconception?

• Iron supplementation: required for maternal/fetal erythropoiesis

  • 2nd + 3rd trimesters require ~30mg of iron daily

• Folate supplementation: reduces incidence of neural tube defects

  • Most critically during 1 month prior to conception and 1st trimester

  • For all childbearing pts → 0.4 - 0.8mg (400-800mcg) daily

    • If history of neural tube defects or epilepsy meds → 4mg/daily

• Calcium supplementation: benefits maternal and fetal bone development

  • 1000-1200 mg/day

What is the epidemiology of spontaneous abortion?

• Early pregnancy loss occurs in approximately 10% of clinically recognized pregnancies, with 80% of losses occurring in the 1st trimester

  • Most occur due to fetal chromosomal abnormalities

  • Risk Factors: advancing maternal age (>35yo) and previous early pregnancy losses

• Spontaneous abortion is the most common adverse pregnancy outcome worldwide

What are the three different kinds of management of early pregnancy loss (spontaneous abortion)?

1) Expectant Management - Limited to 1st trimester losses, results in pregnancy evacuation in about 80% of cases

2) Medical Management

3) Surgical Management

What does medical management of early pregnancy loss include?

Medication used to induce evacuation of pregnancy tissue; Recommended for those up to 10 wga

• Misoprostol regimen: 800mcg inserted vaginally, may repeat within the 7 days if no response after 1st dose

• Mifepristone/misoprostol regimens can be used if available

What does surgical management of early pregnancy involve?

• Indicated for patients not good candidates for expectant/medical management (i.e hemodynamic instability, bleeding disorders, signs of infection)

• Provides an immediate resolution for patients for those desiring/requiring this and an intervention with less follow-up

What are our medical abortion agents?

Mifepristone

• Norethindrone derivative

• Causes progesterone blockade; Binds with more affinity to progesterone receptors & therefore acts as a antagonist

• Starts the detachment process of products of conception

Misoprostol

• Prostaglandin E1 analogue

• Causes uterine cramping and expulsion

What is the dosing protocol for Mifepristone/Misoprostol?

• Mifepristone: 200mg orally (in office or home)

• Misoprostol: 800mcg buccally (4 tablets) 24-48 hours after Mifepristone

• Follow up 7-14 after mifepristone

What is the maximum gestational age to take mifepristone/misoprostol?

70 days since last menstrual period

What are adverse effects of Mifepristone?

Nausea, weakness, fever/chills, vomiting, headache, diarrhea, dizziness

What drugs interactions dose Mifepristone have?

CYP3A4 inducers/inhibitors

What adverse effects does Misoprostol have?

• >10%: diarrhea, abdominal pain

• <10%: headache, constipation, dyspepsia, flatulence, nausea, vomiting

What drug interactions does Misoprostol have?

Antacids may enhance diarrhea, enhnces carbetocin and oxytocin

What do we us manage acute pain in pregnancy?

• Non-Pharmacologic management preferred, however, can use us pharmacological agents

• Pharmacologic Agents:

  • Acetaminophen (APAP) is drug of choice

  • Fioricet

  • Narcotics + APAP (short term use)

  
  

• NSAIDs, Aspirin, Fiorinal → trimester implications

• Triptans (for migraines) – use in pregnancy is limited

What is the time course for N/V in pregnancy? What are our concerns?

• Time course: 1st trimester most common

  • Starts weeks 4 and 6 of gestation and usually resolves by weeks 16 to 20

  • Peak symptoms occur between weeks 8 and 12

• Concerns: severe n/v (hyperemesis gravidarum) ➔ dehydration

• Symptom severity will guide therapy

How do we manage mild N/V in pregnancy?

• Pyridoxine [vitamin B6] (A)

• Doxylamine (A)

Or Diclegis (A) – (which is a combo of doxylamine/pyridoxine) $$$

How do we manage moderate N/V in pregnancy?

• Metoclopramide (B)

  • Use >12 weeks leads to inc risk of tardative dyskinesia

• Promethazine (C)

  • Suppository available

• Prochlorperazine (C)

  • Suppository available

How do we manage severe N/V in pregnancy?

Ondansetron

**only use in 2nd & 3rd trimester because of cardiac risk/oral clefts**

What are non-pharm ways to manage N/V?

• Light snack 15-20 minutes before getting out of bed

• Small, dry, more frequent meals

• Avoid spicy or fatty foods and strong odors

• High protein and high carbohydrate intake

• Ginger

• Colder foods

• Acupressure

What is the time course for GERD in pregnancy? What are non-pharm ways to manage GERD?

• Time course: occurs in 2nd half of pregnancy

  • Caused by relaxation of esophageal sphincter and increased abdominal pressure from the uterus

• Non-pharmacological:

  • Trigger avoidance

  • Avoid caffeine and nicotine

  • Elevate head of bed if nighttime sx

  • Avoid tight clothing

  • Smaller, more frequent meals

What meds do we use for GERD in pregnancy?

• 1st line – Al/Mg/Ca antacids (B)

  • Caution with Mg in late pregnancy

• 2nd line – H2RA: famotidine and ranitidine (B) or metoclopramide (B)

• 3rd line – PPI (most are B; omeprazole is C)

  • Large trials have demonstrated efficacy

What should we AVOID using to treat GERD in pregnancy?

Sodium bicarb antacids → Increased risk of fluid/electrolyte imbalance in other + fetus

What are non-pharmacologic ways to manage constipation/diarrhea in pregnancy?

Constipation

• High fiber foods

• Increase fluid intake

• Decrease caffeine

• Moderate exercise as allowed

Diarrhea

• Keep patient hydrated

• Correct electrolyte issues

What agents do we use for constipation in pregnancy? What should we AVOID?

• 1st line (C)

  • Bulk forming laxatives:

    • Polyethylene glycol (PEG)

    • Docusate

• 2nd line (C)

  • Senna

  • Bisacodyl

  • Lactulose

• Avoid: castor oil; mineral oil

What agents do we use for diarrhea in pregnancy? What should we AVOID?

1st Line:

• Bulk forming laxatives (C)

• Loperamide (B)

AVOID: bismuth subsalicylate, diphenoxylate/atropine

What agents do we use to manage cough/cold/allergy in pregnancy?

Cough

• 1st line – guaifenesin +/- dextromethorphan (C)

Decongestant

• 1st line – saline nasal spray or topical decongestant

  • Topical products with limited date but also limited bioavailability

• Not recommended – pseudoephedrine or phenylephrine***

Allergy

• 1st line – topical nasal steroids (B budesonide; C others); oral 2nd generation antihistamine (B)

• 2nd line – diphenhydramine (B); fexofenadine (C)