Women’s Health

Ibrahim Sales, Pharm.D. Associate Professor of Clinical Pharmacy

King Saud University College of Pharmacyisales@ksu.edu.sa

Lecture OutlinePregnancy & Lactation

DevelopmentalTeratogenicityVitamin supplementation

Gestational complicationsNausea, Vomiting; Constipation & Heartburn

Maternal HealthGestational diabetes, thyroidHypertension (pre-eclampsia), VTE

Contraception

Menopause

Pregnancy40 weeks (280 days or 9 months)

Gestational age First day of the last menstruation2 weeks prior to fertilization

Week 2-8 = Embryonic periodBody structures

Week 9-40 = Fetal periodGrowth and maturity

Congenital Anomalies Minor 10-25% Major 3%

DefinitionsTeratogen – Drug or environmental agent with

the potential to cause abnormal fetal growth and development (thalidomide)

Teratogenicity – Capability of producing congenital abnormalities, major or minor malformations

Causes of Birth Defects

Genetics64%

Medica-tions25%

Unknown11%

Cause of Defect

Influencing FactorsGenotypes of mother and fetus

Embryonic stage at exposure

Medication dose

Simultaneous exposure to other drugs that may increase or decrease

Influencing FactorsTiming of exposure

One month before conception: ≥ Folic acid 0.4mgPrevent neural tube defects

Around time of conception and implantationFirst 12-15 days postconception

If one cell is damaged another can assume its functionFirst 3 months

Physical malformationsThroughout pregnancy: Functional and behavioral

defectsBrain development occurs throughout pregnancy

Vitamin Supplementation

Folic acid 0.4 – 1 mg daily Neural tube defectsNeural tube closure occurs during the first month

of pregnancyMost common major congenital abnormalities

Cleft palate and lipCardiac anomalies

4 mg if on Carbamazepine, Valproic Acid etc

Iron27% anemic in 3rd trimester

Influencing FactorsFactors for placental transport

Molecular weight of drug less than 400–600 Daltons crosses placentaMost drugs weigh 250–400 Da

Degree of protein bindingPlasma albumin decreases in mother and increases in

fetus; higher concentrations of protein-bound drugs in the fetus

Maternal and fetal blood flow usually equivalent

Pregnancy Risk Categories

Risk Category

Definition

A Controlled studies in women fail to show risk

B Animal studies indicate no risk

C No available studies of women or animals

D Positive evidence of fetal risk

X Definite fetal risk in animals or women

Factors to ConsiderRisk-benefit ratio

Is the drug necessary?

Most effective with least risk

Lowest effective dose for shortest possible duration

Health of mother without drug

Gestational Complications

ConstipationPrevalence ranges from 25 to 40%

Nonpharmacologic therapy initially Light physical exercise Increased intake of dietary fiber and fluid

Pharmacologic therapy Osmotic laxatives (polyethylene glycol, lactulose,

sorbiol, and magnesium and sodium salts) Senna and bisacodyl Avoid castor oil and mineral oil

The irritating effects of mineral oil in the bowel also tend to irritate the uterus, which is in close proximity

Gastroesophageal Reflux Disease

Prevalence of up to 80%

Lifestyle and dietary modifications

Antacids (aluminum, calcium, or magnesium preparations) or sucralfate

H-2 receptor antagonists

Metoclopramide

Avoid sodium biocarbonate and magnesium trisilicate 1960 study found an increase in major and minor congenital

malformations in infants; but currently no such association

Reserve PPI for complicated or intractable GERD

Nausea and VomitingPrevalence of up to 90%

Begins around week 5 and continues through the first trimester

Dietary modificationsEating frequent, small, bland meals and avoiding

fatty foods

Nausea and VomitingPharmacologic

MultivitaminsPyridoxine (vitamin B6)AntihistaminesPhenothiazines

(Promethazine and prochlorperazine)MetoclopramideOndansetron Ginger

Gestational DiabetesPrevalance ranges from 1 to 14%

Glucose testing recommended at first prenatal visit if risk factors:ObesityHistory of diabetesGlycosuriaStrong family history

Repeat at weeks 24 and 28 if normal

Test women at weeks 24 and 28 with average risk

Gestational DiabetesLow risk patients are not in need of testing

Low risk patients must fulfill all of the following:Younger than 25 y/oNormal body weightNo known diabetes in first-degree relativesNo history of abnormal glucose toleranceNo history of adverse obstetric outcomesNot a member of an ethnic group with a high

prevalence of GDM (African Americans, Native Americans, Asian Americans, Hispanic Americans, Pacific Islanders)

Gestational DiabetesDietary modification is first-line therapy

Self-monitoring of blood glucose is required

Insulin therapy when on dietary therapy and:Preprandial glucose ≤ 105mg/dL (5.3mmol/L)One hour PPG ≤ 140mg/dL (7.8mmol/L)Two hour PPG ≤ 120mg/dL (6.7mmol/L)

Diabetes Care 2014; 37(1): S14-S80

Women With Pre-existing Diabetes

Optimal glycemic goals

Premeal, bedtime and overnight glucose: 60-99mg/dL (3.3-5.4mmoL/L)

Peak postprandial glucose: 100 – 129mg/dL (5.4-7.1mmol/L)

A1C < 6.0%

Diabetes Care 2014; 37(1): S14-S80

Gestational DiabetesPregnancy Category B Pregnancy Category C

DetemirNPHInsulin lisproInsulin aspart

GlargineInsulin glulisine

Gestational DiabetesOral agents for women who cannot or will not use insulin

GlyburideMetformin

Hypertension Prevalence of 10%

Four categories in pregnancy Chronic hypertension (preexisting) Gestational hypertension (w/o proteinuria) Preclampsia (w/ proteinuria) Preclampsia superimposed on chronic HTN

Mild-to-moderate hypertension Treatment of HTN (140-159/90-109) reduces the risk of severe

HTN by 50%, but doesn’t substantially affect fetal outcomes

Severe hypertension Can cause maternal complications, hospital admission and

potential premature delivery

HypertensionPharmacologic therapy

MethyldopaLabetalolNifedipine (extended-release)

No evidence supports selection of one agent as first-line-therapy

Avoid ACE inhibitors, ARBs, diuretics, magnesium sulfate, high-dose diazoxide, nimopidine, and chlorpromazine

PreeclampsiaWhen a pregnant woman develops high blood pressure

> 140/90 AND protein in the urine after the 20th week (late 2nd or 3rd trimester) of pregnancy

Severe if target organ damage

Treatment IV Labatolol Hydralazine - more hypotension Nifedipine PO 30 mg then 10-20 mg Q4-6 hrs NOT ACE-I, DON’T reduce too quickly

Eclamptic seizures Magnesium 6 g / 15 minute then 1-3 g / hr

Hypothyroidism Occurs in up to 2.5% of pregnancies

Second most common endocrine d/o after DM

50 to 85% will require a dosage adjustment

Treatment of choice: levothyroxine

Empiric treatment Increase levothyroxine dose as soon as a menstrual cycle is missed One method is to take two extra doses per week (i.e., increase

from seven doses to nine doses per week).

Preexisting history or untreated subclinical hypothyroidism TSH should be monitored every four weeks during the first 20

weeks of pregnancy (i.e., first half of pregnancy), and then at least once between 26 weeks and 32 weeks of gestation

Reference TSH RangesTrimester Range (mIU/L)

First 0.1 – 2.5

Second 0.2 – 3.0

Third 0.3 – 3.0

Nonpregnant 0.4 – 4.0

HyperthyroidIncrease in thyroxine binding globulin leads to

increased T3, T4

Propylthiouracil drug of choice

ThromboembolismOccurs in 0.06 to 0.13% of women

5 to 10-fold increase in risk over nonpregnant women

Preferred agent is a LMWH

Alternative is unfractionated heparin

Treatment durationThroughout pregnancy and for 6 weeks postpartum

for acute and prior VTELong-term vitamin K antagonist (VKA)

Adjusted dose or 75% of therapeutic dose of LMWH; restart VKA postpartum

Epilepsy No seizure frequency change in 54 to 80% of women

Risk of untreated epilepsy Drug withdrawal should be planned at least 6 months before

planning to conceive

Polytherapy associated with greater rate of malformation

Carbamazepine and lamotrigine Appear to be safest

Valproic acid 6.2 to 10.7% major malformations

Folic acid supplementation All women taking AEDs should receive FA suppl. 4 to 5 mg daily

before pregnancy and through at least the first trimester

Human ImmunodeficiencyVirus (HIV) Infection

Newly diagnosed women should receive HAART (Highly active antiretroviral therapy) 2 NRTIs (Nucleoside Reverse Transcriptase Inhibitors) plus either a

NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitors) or a protease inhibitor

Women currently receiving therapy should continue

Delay prophylaxis until after the first trimester

Zidovudine and lamivudine Recommended for use during pregnancy, labor, delivery, and the

postpartum period

Nevirapine or lopinavir/ritonavir

Efavirenz Avoid during the 1st trimester and the entire pregnancy if possible

Mental Health Conditions

Nonpharmacologic therapies

Monotherapy is preferred

SSRIs

Benzodiazepines Use in 3rd trimester associated with infant sedation and

withdrawal symptoms

Mood stabilizers Refer to seizure medication section (lithium: cardiovascular

malformations)

Typical and Atypical antipsychotics Typical agents studied more than atypical although atypical are

first line in general population treatment

Medication Effects upon Lactation

Decrease Milk Supply Increase Milk Production

SympathomimeticsNicotineLevodopaBromocriptineErgot alkaloidsPyridoxineMonoamine oxidase inhibitors (MAOIs)EstrogenAndrogens

AntipsychoticsCimetidineMetoclopramideReserpineAmoxapineMethyldopa

Strategies to Minimize Effects

Short-term drug: Mother can pump and discard milk

Choose drugs with short half-lives

Administer drug immediately after a feeding or before a long sleep period

Consider whether the drug is given to neonates

Drugs Contraindicated in Breastfeeding

Contraindicated in Breastfeeding

Amphetamines Bromocriptine

Cocaine Ergotamine

Lithium Nicotine

Antineoplastics Drugs of abuse

Safe Agents During Lactation

Relatively Safe During Lactation

Alcohol (in moderation) Caffeine (in moderation [1 or 2 cups/day])

Analgesics Laxatives

Anticonvulsants Insulin

Antibiotics (penicillins, cephalosporins, erythromycins)

Percentage of FailureTypical Use Perfect Use

No Method 85% 85%

Sponge/Spermicide

16-32%, 29% 9-20%, 18%

Condom 15% 2%

Oral Contraceptives

8% 0.3%

IUD 0.8% 0.6%

Implant 0.05% 0.05%

Sterilization F 0.5%M 0.15%

F 0.5%M 0.5%

Oral ContraceptivesSuppress ovulation, change cervical mucus &

alter endometrium

Synthetic estrogens and progestinsEstrogens:

Ethinyl estradiol 20 – 50 mcg/day (35 mcg usually)Mestranol (prodrug)

Progestins: manyNorethindroneNorgestimate, Desogestrel, Gestodene, DrospirenoneLevonorgestrel (more androgenic – not good)

Female Reproductive System

Ovarian cycle and the menstrual cycleEndocrine system produces hormones that control

these cyclesAverage cycle lasts 28 days

Ovarian cycle Follicular phase and the luteal phase Follicular phase Day 1 to 14

FSH (follicle stimulating hormone)Follicle that contains the egg begins to matureOnce mature, egg is released from ovary into the

fallopian tube and begins the luteal phase

Female Reproductive System

Luteal phaseLH (lutenizing hormone) increasesAllows the corpus luteum to develop from the

follicleNeeded in pregnancy to provide progesterone until

the fourth monthThe ovum (egg) itself does not reach the uterus

until 72 to 96 hours after release

Female Reproductive System

Menstrual cycle

Occurs 14 days after ovulation in non-pregnant females

Four phases: Menstrual, Proliferative, Secretory, and Ischemic phases Menstrual

Days 1 to 6 Estrogen levels are low and the endometrium (inner layer of the uterus) is

shed Proliferative

Days 7 to 14 Endometrial glands in the uterus enlarge due to an increase in estrogen

levels Blood supply to the endometrium is increased and the thickness of the

endometrial layer increases 6 to 8 times Cervical mucus begins to thin to allow sperm easier passage

Female Reproductive System

Menstrual cycle continued… Secretory

Preparation for a fertilized ovum begins Vascularization increases, glycogen stores for nourishment

increase, endometrium continues to thicken Ischemic

Occurs in the absence of fertilization Estrogen and progesterone levels fall, small blood vessels rupture,

blood flow to the endometrium decreases

Fertilization Limited time period

Egg is only fertile for 12 to 24 hours after ovulation Sperm is fertile for only 48 to 72 hours after it enters the female

reproductive tract

Oral ContaceptivesOral formulations differ with regard to the dose, as well as

combination, of progestin and estrogen they contain

Newer formulations of oral contraceptives contain less estrogen and progestin compared to older preparations Reports of increased risk of ischemic stroke, myocardial

infarction, and pulmonary embolism with high-dose estrogen Contraceptive efficacy has not diminished with lower-dose

formulations

Ethinyl estradiol doses: 50 mcg (high-dose) to 20 mcg (ultra-low-dose) Average doses: 30 to 35 mcg

Mestranol: 50 mcg (~35 mcg of ethinyl estradiol)

Oral Contaceptives Current products more closely mimic a woman's natural

menstrual cycle Vary the dose of estrogen, progestin, or both throughout the cycle

Biphasic, triphasic, or quadriphasic Monophasic preparations contain a consistent amount of estrogen and

progestin

Yasmin (ethinyl estradiol/drospirenone) is a combination, monophasic oral contraceptive that is unique in that its progestin is structurally similar to spironolactone 30 mcg of ethinyl estradiol and 3 mg of drospirenone (~25 mg of

spironolactone) Weak potassium-sparing diuretic effect may be preferred by women

who experience water retention associated with their menstrual cycle

Patients should be monitored for hyperkalemia

Oral Contaceptives Progestin-only pill (POP) also known as the mini pill

Oral alternative for lactating women Progestins have not been shown to decrease milk production

Women with contraindications or intolerance to estrogen-containing contraceptives or who would like to become pregnant in the near future (progestin-only pills do not stop ovulation)

Strict adherence to timing of daily dosing is necessary with progestin-only pills Decreased effect of the progestin on the cervical mucosa 22 hours

after the dose is taken A dose that is three hours late is considered missed and should be

taken as soon as it is remembered Recommended to use an alternative means of contraception for two

days following late or missed doses

Oral ContaceptivesProgestin-only pill (POP) continued

Slightly less effective than combination oral contraceptives 99.5% vs. 99.9% for combination products

Associated with a greater degree of irregular bleeding 35% to 45% of women on POPs experience spotting and

breakthrough bleeding throughout the first three months of use; in comparison, 5% to 20% of women using combination oral contraceptives experience these adverse effects

Other common side effects include headache, breast tenderness, nausea, and dizziness

MonophasicContain the same amount of estrogen and progestin in

each active tablet Less likely to cause side effects that may stem from

fluctuating hormones

Classified by their estrogen level: Low dose tablets have the least amount of estrogen (20 mcg) Regular dose pills contain 30–35 mcg estrogen High dose pills have about 50 mcg of estrogen

Work as well as the phasic options

Low estrogen, monophasic pills may cause less bloating or breast tenderness, but may result in more spotting

Biphasic Alter the level of hormones once during the menstrual cycle

Deliver the same amount of estrogen each day, but the level of progestin is increased about halfway through the cycle

Although the estrogen level remains the same, during the first half of the cycle, the progestin/estrogen ratio is lower to allow the endometrium to thicken as it normally does

During the second half of the cycle, the progestin/estrogen ratio is higher to allow for the normal shedding of the lining of the uterus

The first 7 to 10 days are one strength (and usually one color), and the next 11 to 14 tablets are another strength (and another color). The last 7 tablets (if included) are placebo pills and contain no hormones

Triphasic Contain 3 different doses of hormones in the 3 weeks of active

tablets

The hormone combination changes approximately every 7 days throughout the tablet pack

The amount of estrogen may change as well as the amount of progestin May have a gradual estrogen increase and/or some pills may also

increase the dose of progestin 3 different strength combinations in each pack The first third of tablets consist of one strength (and one color) The next 5, 7 or 9 tablets are another strength (and another color) The final phase of tablets are a different color The last 7 tablets (if included) are placebo pills and contain no

hormones

QuadriphasicFor the first 2 days, the tablets consist of one

strength (the first phase)

The next 3 to 7 days, a second strength (the second phase)

Days 8 to 24, a third strength (the third phase)

For days 25 and 26, a fourth strength

Two days of inactive tablets

Other Hormonal Contraceptives

Injectable Q 3 months; 6-12 month infertilityMedroxyprogesterone (Depo-Provera)

Implant Q 3 yearsEtonogestrel

Intrauterine Device (IUD)Copper or levonorgestrel

Emergency Oral Contraceptionwithin 72 hours

Contraindication & Risks

Absolute Previous VTE or Stroke Estrogen-dependent tumor Active liver disease Pregnancy Undiagnosed abnormal

uterine bleeding Hypertriglycerides Age > 35 years and

smokes > 15 cigarettes/day

Relative Hypertension Anticonvulsants

Increased MI (smokers > 35 years Hypertension (RR = 1.8) VTE (RR = 4) Stroke if also htn Cervical CA (RR = 2-4)

Decreased Ovarian CA (50% less) Endometrial CA (40% less)

Benefits Regulate menses Reduce ectopic pregnancy,

benign breast disease. Improve hirsutism & acne

Pill Early Danger Signs (ACHES)

Signals Possible Problem

Abdominal pain (severe) Gall bladder disease, hepatic adenoma, blood clot, pancreatitis

Chest pain (severe), shortness of breath or coughing up blood

Blood clot in lungs or myocardial Infarction

Headache (severe) Stroke, hypertension or migraine headache

Eye problems: blurred vision, flashing lights or blindness

Stroke, hypertension or temporary vascular problem

Severe leg pain (calf or thigh)

Blood clot in legs

Practical Issues – Patient Education

Start taking pills by following manufacturers recommendations

Use back up method for first week at least when starting

Take at same time every day

If you miss one dose, take two pills the next day

If you miss more than one dose, follow package insert including using backup method for at least one week

Practical IssuesDrug Interactions leading to spotting,

breakthrough bleeding or pregnancyAny antibiotic via altering intestinal bacterial floraDrugs (including antibiotics) that alter

enterohepatic circulationEnzyme inducers (rifampin, phenytoin etc)

Unlikely, but safest to use alternative method

MenopauseLoss of ovarian follicular activity

Stop making estradiol, progeteroneStarts making androgens (testosterone)Not all at once, rather in phases

Symptoms 4 years before menses stopIrregular cycles, Vasomotor, Mood, Sexual

Hormonal clues10 – 15 x increase in FSH4-5 increase in LH90% decrease in estradiol

TreatmentWhy treat?

Short term for symptoms (70 – 80% reduction) Long term for osteoporosis prevention (HR 0.66)

20 – 50 % decreased risk of fracture

Risks of therapy? Endometrial CA if not given with progestin (HR 3-6) Women’s Health Initiative 16,608

Thrombosis (HR 2.13)Cardiovascular disease (HR 1.29)Stroke HR (1.41)Breast Cancer HR (1.26)Gall bladder disease (110% increase risk)

Estrogen for SymptomsSystemic

Oral EstrogensConjugated equine estrogens (Premarin 0.625 mg)Give with progestin if patient has uterus

Medroxyprogesterone acetate Protect against endometrial cancer

Otherwise (i.e after hysterectomy) estrogen aloneLess effective: Antidepressants, gabapentin,

clonidine, vitamin E phytoestrogens

Topical for local (genitourinary) symptoms

Estrogen for Osteoporosis

Safer alternatives now availableCalcium & vitamin DBisphosphonatesSelective Estrogen Receptor Modulators

Estrogen agonist on bone, antagonist at other tissues Tamoxifen Raloxifene

Women’s HealthIbrahim Sales, Pharm.D.

Associate Professor of Clinical PharmacyKing Saud University College of Pharmacy

isales@ksu.edu.sa

Oral Estrogen Products

Vaginal Estrogen Products

Transdermal Estrogen Products

Combination Products

Progestogen Products

Category X Medications HMG CoA Reductase Inhibitors (Statins)

Cholesterol synthesis important in fetal development

Oral Contraceptives Controversial

Ergotamines Convulsions, vomiting, diarrhea, gangrene

Ethanol Fetal Alcohol Syndrome

Isotretinoin Abnormalities, spontaneous abortion

Methotrexate Immune system dysfunction

Raloxifene Spontaneous abortion

Category D MedicationsACE Inhibitors

2nd and 3rd trimester Renal defects

Benzodiazepines Neonatal withdrawal, respiratory problems

ASA Doses > 81mg/day Closure of the ductus arteriosus, inhibit labor

Atenolol Intrauterine growth retardation

Category D Medications Carbamazepine

Neural tube defect

Divalproex Neural tube defect, facial abnormalities

Doxycycline 2nd and 3rd trimester Tooth abnormalities

Angiotensin Receptor Blockers 2nd and 3rd trimester Renal abnormalities

Lithium Cardiovascular dysfunction

Category D Medications NSAIDS

Use near term may cause premature closure of the ductus arteriosus, inhibits labor

SSRIs Congenital malfromations, neonatal behavior syndrome,

persistent pulmonary hypertension

Phenobarbital Sedation, withdrawal, blood dyscrasias

Phenytoin Fetal Hydantoin Syndrome

Warfarin Facial abnormalities, fetal hemorrhage