Lecture



Drugs in Pregnancy – November 14, 2002

By: Joanne C.Y. Chan

Introduction

• Limited # of drugs that can negatively affect a patient’s pregnancy

• 30% of pregnancies go on to have spontaneous abortions/miscarriages before women knows she is pregnant

• 15% go on to have miscarriages after women has missed a period

• 3% of all pregnancies have major congenital anomaly no matter what

o Material exposure to drugs or environmental chemicals are responsible to 4-6% of abnormalities of the 3%

Teratogenic Drugs

• If any meds given after vulnerable period (after fetus is formed) won’t cause structural abnormalities

• there is a fixed amount of time to be concerned about structural abnormalities due to a drug

Hormonal Medications

1) Oral Contraceptives

• no relationship with 1st trimester OCP use and congenital abnormalities ( can reassure the patient 100% that no harm will be done to baby

2) Danazol/Androgenic Meds

• If taken during pregnancy, can cause clitoral enlargement in fetus if you take it < 13 weeks

3) DES (Diethyl ?)

• associated with clear cell cancer of vagina and cervix

• Uterine abnormality in daughter’s who’s mothers took DES while pregnant

• Abnormality in male children (cryptorchism – problems with testes)

Drugs that should NEVER be given to a Pregnant Women

1) Warfarin

• In Canada this is NEVER used in pregnant women

• In Europe, they still use it b/c they think its “safe”

• 25% of fetuses develop a congenital abnormality if mom takes it in 1st trimester

• Critical time period = 6 – 9 weeks

• Fetal Warfarin Syndrome Symptoms

o Hypoplastic nose

o Epiphyseal stipling

o Optic atrophy

o Small head

o Intrauterine growth retardation

o Neurologic abnormality (mental retardation)

Exam Hint: She said that the FWSS would be a good exam question

Alternative to Warfarin

• If mom is on W b/c of a clotting abnormality, can switch to heparin or LMWH, which are both safe in pregnancy

2) Anti-Convulsants

• Significant (ed risk of neural tube defects

|Carbomezipine |1% risk above baseline risk |

|Valproic Acid |2% risk above baseline risk |

|Phenytoin |10% risk of above baseline risk |

• Carbomezipine is the DOC for a pregnant women at risk of seizures b/c it is associated with the lowest risk

• You would never use Phenytoin (high risk)

• Fetal Hydratoin Syndrome

o Cradle, facial and limb deformities

o Mental deficiencies

|Folic acid supplementation|4 mg/day in pregnancy |Needed for all epileptics |

| | |Needed to prevent neural tube defects |

|Vitamin K supplementation |20 mg/d for 2 weeks before estimated |Needed for patients on Carbomezipine, otherwise Fetal |

| |delivery date |Coagulopathy |

Aside

• Benzodiazepines are safe

• In pregnancy, you always have to consider that there are 2 patients ( must consider BOTH the mother’s and the fetus’s well-being

• Often need to weigh risk/benefit ratio of both of

3) Lithium

• 0.5% risk of Ebstein’s anomaly (serious cardiac anomaly)

• if you take it in late pregnancy, can get:

o transient lithium toxicity in fetus

4) Isotretinioin

• Retinoids

o Vitamin A

▪ No (ed risk associated with it

▪ OK to use

• Tretinoin

• Most potent drug that we know about

• 35-50% exposed (taken anytime in pregnancy) will have abnormalities including:

o (ed risk of marriage

o risk of heart disease

o deafness

o cleft lip/palate

o small ears and eyes

• if a female is trying to get pregnant, don’t take it

• Topical tretinoin is safe in pregnancy

In general,

• most drugs will cause a problem early on in pregnancy, therefore, the first 12 weeks of pregnancy is CRUCIAL time NOT to take these medications

5) Thalidomide

• If the fetus is exposed to this, there is a 20-25% risk of the following:

o Severe limb abnormalities

o General heart disease

o Kidney problems

o Stomach problems (e.g duodenal atresia)

o Hearing problems

o Hernias

• Once exposed, the risk of limb defects is 80%

• NEVER take it anytime during pregnancy

6) Misoprostol (Cytotec ®)

• 1 – 2 % above baseline risk of Moebius seqius (sp?)

• congenital cardiac abnormalitiy and facial abnormalities - very rare defect

• used as an abortefacient (e.g. used to abort fetus in 1st trimester if fetus has a genetic abnormality or if personal has had a miscarriage)

• has prostaglandin ( makes uterus contract, induces “labor”

• Varying doses (400-800 ug) ( can give vaginally or P.O.

o 800 ug PV – give 12 hours apart for 2 doses

o very effective

• In Canada, trials underway about inducing labor term

• Used for cervical softening before procedures such as: D & C, hystroscopy

o Softens it up by making uterus contract

o Decreases risk of perforating

o Giving it vaginally

• Experiments underway for using this in post-partum hemorrhage

o Makes uterus contract

• Term studies use lower doses (50 ug)

Giving Misoprostol after Miscarriage

• except pain/cramps (putting them in “labor”)– Rx Tylenol #3 (analgesia)

• after taking Misoprostol, the following occurs:

o development of menstrual cramps (get more intense)

o short period with extreme bleeding

o abnormal dead fetus is “passed”

▪ If this occurs < 10 wks – can’t tell that it is a baby, as it appears like grayish tissue among a blood clot

o a women will continue to bleed after passing the dead fetus, but her bleeding and cramps will (

• If she still has a heavy period (“heavy” = you have to change your pad every hour) – send them to ER

• Variable time effect – a few hours, some have to repeat dose to get effect

• if pass fetus and bleeding stops – don’t need to take the 2nd dose

7) Alcohol

• Fetal Alcohol Syndrome

o Microencephaly

o Heart defects

o Facial abnormalities

o Mental retardation

• You need to intake > 3 oz/day of alcohol every day of your pregnancy to get this (you have to be a severe alcoholic)

• In pregnancy, you can take most things in moderation, and it will be ok.

• 1 glass of wine is safe

8) Tobacco

• Tobacco is now illegal to sell in the pharmacy, you can only buy them in the grocery store

• Associated with:

o Miscarriage

o Low birth weight

o Placenta abruption (placenta separates from the uterus prematurely and cuts off circulation to the baby)

• If a women stops smoking in the last 4 months of her pregnancy, the risk of having a low birth weight baby is the same as people who have been non-smokers for life

• Can smoke up to 20 weeks with no problem

9) Marijuana

• Has been shown to be teratogenic in animals only, no human studies

Other Drugs to Avoid

1) ACE-Inhibitors

• cause fetal damage

2) Tetracycline

• can cause bone abnormalities and yellow teeth

3) NSAIDS

• can cause:

o premature closure of the ductus arteriosis (doesn’t allow oxygenated blood to the fetus)

o fetal kidney problems

• care with long term NSAID use

• safe to take 1 – 2 tablets, but better options available, that are safe:

o Tylenol (100% safe)

o Codeine

• In general, there are often better options available

4) Sulfonamides

• avoid when near term

5) Methotrexate

• avoid at all costs

• MTX is used to abort pregnancy

• For Etopic Pregnancy

o for patients that are stable and don’t want surgery, they use MTX to kill etopi

• Some people are experimenting with this for abortion rather than surgical abortion

o They use MTX first, and then use Misoprostol

Infections that are Dangerous in Pregnancy

1) Varicella (Chicken Pox)

• < 13th week of pregnancy, there is a 1% risk of congenital varicella if exposed

• > 13th week of pregnancy, this increases to a 2% risk if exposed

• this is very severe syndrome, as it can cause:

o mental retardation

o limb and eye abnormalities

• no documented cases of congenital varciella syndrome with herpes zoster

Cases

• If women is exposed to chicken pox and..

o 1) HAD it before = she’s ok, don’t need to do anything

o 2) NEVER had it before:

▪ She needs to go see MD/walk-in clinic and get tests to see if she is sero-positive (+) or sero-negative (-)

• If sero-positive (+) = she is ok, she is not at risk

• If sero-negative (-) = give immunoglobin BC?

2) Rubella

• Part of the routine prenatal screening is for rubella

• Screening is performed in the form of a blood test

• Want to know if you are immune to it, if not, need to get vaccinated

• If this is transmitted in:

|First 10 weeks of pregnancy |100% that baby Is infected – can get heart defect, deafness, mental retardation|

|13 – 16th weeks of pregnancy |only deafness has been reported |

|> 20th week of pregnancy |no abnormalities |

Exam hint = she mentioned this would be a good exam question

Uterus Size Changes in Pregnancy

• different weeks in pregnancy correspond with different uterus sizes

|Normal Uterus |About the size of a fist, or a small plum |

|At 10-12 weeks |Uterus comes out of the pelvis, can feel it abdominally |

| |About the size of an orange |

|At 20 weeks |Uterus is felt at the belly button |

|At 36 weeks |Uterus is up to the rib cage |

Right after delivery, the uterus goes back to the belly button, and after 10 days, should be back at the pelvis and you shouldn’t be able to feel it.

Pre-Natal Vitamins

• can use ANY pre-natal vitamin, doesn’t have to be Materna

• these do NOT replace a well-balanced diet

• still need a well-balanced, Canada Food Guide diet

• “eating for 2” is a myth – you are only eating for ONE

Iron (Fe)

• need 30 mg elemental Fe/day in pregnancy

• nausea/vomiting in first 3-4 months in pregnancy which is aggravated by Fe

o Option 1 = It is ok to NOT take Fe during the first 12 weeks

o Option 2 = take Fe at BEDTIME (so nausea occurs while you sleep)

Vitamin C

• need 20% increase during pregnancy – use 70 mg/d

Folic Acid

• ( neural tube defects

o Spina epifida = failure to close neural tube at 26-28 days of gestation – occurs very early on, therefore it is important to take this BEFORE you get pregnant

• often found in multi-vitamin

• it is very important to take this medication right before due date

• should recommend to anyone in child-bearing age who may want to get pregnant

|For general population |0.4 mg/d X 1 month prior to conception |

|For high risk (i.e. previous infant w/ spina epifida, or mother|4 mg/d X 3 months prior to conception |

|has epilepsy) | |

Random Questions

• Lower C-section (go transversely in the lower part of the uterus)

o CAN potentially have vaginal delivery afterwards (not dangerous)

o 2% risk of rupturing uterus (mom and baby can die from this) if you had a lower –C section

• Classically C-section (go up and down uterus) or previous surgery involving cavity (removal of fibroid)

o Not eligible for a eligible for a vaginal delivery

o Don’t want to belabor that scar b/c the risk of rupture increases a lot (4-8%)

• Cold C-Section

o Had a C-section b/c you had breached baby, twins, patient wasn’t allowed to go into labor

o Chances to have a successful vaginal delivery is the same as someone who has NEVER had a C-section

• If you had a C-section b/c you previous tried labor (e.g. for 18 hours), would’nt recommend you do vaginal delivery.

• 75% of V-backs (vaginal birth after C-section) will have vaginal delivery

How long do you bleed?

• It is variable, could be 5-7 days you have heavy bright red bleeding, then similar to a regular period, then brownish, old blood, then a yellow discharge – ends in 6 weeks

• heavy bleeding stops in a 1-2 weeks

Intercourse safe in pregnancy?

• perfectly safe to have sex during pregnancy (encourage right before pregnancy)

Detecting twins

• at regular MD visits, they should be measuring the size of the abdomen, which should correlate to the number of weeks into pregnancy

• So between 20-36 weeks, size of abdomen should ( 1 cm/week (e.g. at 23 wk, should measure roughly 23 cm)

o E.g. at 31 weeks, if you measure 39 cm, may be indicative of twins

• Usually ultrasound is used

Weight gain

• Usually patients gain 25-35 lbs during pregnancy

• Obese patients gain less weight, thinner patients tend to gain more weight

• Don’t try to lose weight during pregnancy

• Generally lose around 11 lbs after pregnancy, and you have to lose the right of the weight by exercise

• Metabolic changes that occur during pregnancy

• Those who aren’t breastfeeding – takes a lot longer to lose weight

Common Complaints in Pregnancy

1) Nausea/Vomiting

• most serious between 6-13 weeks (majority will get better after this time)

• 1st line treatment:

o a) Adjust diet – smaller more frequent meals,

▪ dry bland foods

▪ separate solids from liquids

▪ if this method doesn’t work by itself, go to b)

o b) Gravol – safe, very effective, can take P.O. or rectally

▪ no RCTs, but long term evidence that show there are no contraindications.

▪ Safe all the way through pregnancy, but we don’t give it all the way through b/c it makes them feel tired.

▪ Good for needed it the “odd” time

o c) Dicleptin – longer term Tx’s, can be used for entire pregnancy

▪ give according to patient Sx

▪ max 4/day – typical dosing regimen – 1 @ AM, 1 @ Noon, 2 @ Bedtime

▪ can stop at 14 weeks and see how they feel

2) Constipation

• During pregnancy, you get a lot of smooth muscle relaxation – uterus grows and compresses bowels

• exacerbated by Fe and vitamins taken during pregnancy

Options:

o 1) ( Fiber

o 2) Metamucil/Protium or Stool softeners (want stools soft, to prevent hemorrhoids)

3) Hemorrhoids

• uterus obstructs venous return in all veins – including rectal vein

• thus you get hemorrhoids b/c of the increased pressure

• they get worse as pregnancy progresses

Options

o 1) Stool softeners – can give any

o 2) For Sx relief - use Anusol HC or Anusol Cream – safe in pregnancy

• generally, hemorrhoids improve after pregnancy (go away spontaneously)

• Cortisone and steroids are safe in pregnancy (e.g. inhaled steroids, oral steroids, often used for rash)

4) Heartburn

• uterus pushes up the stomach and esophagus and compresses it

• smooth muscle relaxation causes lower esophageal sphincter to not close properly

Options

o 1) Change diet – avoid spicy foods or things that aggravate it, avoid lying down after eating. This doesn’t work very well

o 2) Antacid (Maalox, Zantac, or Tums (has Ca+)) – for patients with bad heartburn, liquid formulation may be more effective than tablet

• don’t recommend Pepto-Bismol b/c better options are available

5) Yeast Infection

• 30-40% occurrence in pregnant women

• no danger to fetus when you have yeast infection

• toward end of term (week 35) – avoid putting creams/tablets inside the vagina, but put it around on the outside (worry that if you rupture membrane, you would have the cream/tablets lingering around)

• before end of term, can use cream/tablet inside vagina

• can’t use Diflucan, is contraindicated

Option

o only use topical azoles

o 1 day Tx – don’t use this as patients will relapse – recommend 3 or 7 day Tx

6) Headaches

Options

o DOC = Tylenol – safe in pregnancy

o Codeine – safe in pregnancy

o Morphine/demoral – for severe pain – safe

▪ Don’t give close to delivery b/c it may ( fetus respiration

• AVOID ASA/NSAIDS b/c they can cause:

o Premature closure of ductus arteriosis

o Kidney problems

o Bleeding problems at end of pregnancy

• Exceptions

o 1) Sometimes women on 81 mg/d ASA b/c of hypercoagulable state (thrombophila) that may predispose them to clotting, but never had documented clot so not on heparin

o 2) Infertility patients on low dose ASA to prevent miscarriage or pre-term labor

▪ advise patients to STOP low-dose ASA @ 36 weeks

7) Cough and Cold

• OTC meds are generally safe AFTER 1st trimester (12 weeks)

• Tell patients to use drowsy formulations b/c there are more studies done on them

• Try to avoid preps with ASA and NSAID in them

Options

o Vicks vapor rub

o Lozenges

o Pseudoephedrine – avoid if you can, probably ok after 1st trimester

o B2-agonist and steroids - use if you have prolonged cough or refractory asthma can use

• If unsure about anything – call Mother Risk – have lots of EP info

Antibiotics

• most are safe

• stay away from tetracycline, sulfa, quinolones (avoid in breastfeeding)

• quinolones = controversial topic, animal studies showed grey matter problems, therefore don’t use 1st line

Choice of Antibiotic

UTI

• asymptomatic bacteruria (2-7% occurrence in pregnant women)

• 25% of patients with asymptomatic bacteruria go on to develop symptoms

• big concern of UTI is that it puts you at risk of preterm labor

o 1st line – Nitrofurantoin

o Amoxicillin-Clavulin

o Macrobid ®

• 30% will fail on any Tx regimen

• Duration = 5-7 days (as opposed to 3-days)

Cardiac Prophylaxis

• American Heart Association - Tx all intermediate - high risk groups during high risk procedures (i.e. labor delivery)

• ACOG – said to use prophylaxis all women with any cardiac problems

• E.g. Patients with mitral valve prolapse with NO regurgitation – considered LOW RISK

o Prophylaxis is given only during labor delivery (ampilcillin and gentamicin)

• High risk = any women with cardiac problems

• Prevents 90% of infections

• Mostly for vaginal deliveries (infection during passage through vagina)

• Prophylaxis given only during labor

Group B Streptococcus

• 15-20% of women carry this vagina or rectum

• part of your normal flora

• Guidelines regarding Tx are always changing

• 1) Base Tx on risk factors

o Risk factors:

▪ preterm labor before 37 completed weeks of pregnancy

▪ ruptured membranes over 18 hours (break water but don’t go into labor)

▪ a previous infant who has been affect by Group B Strep

▪ temperature

o therefore, Tx if ANY RF are present

• 2) Screen everyone by obtaining a culture

o If culture is (-) – ruptured X 24 hours ( Don’t Tx

o If culture is (+) – Treat

• Give Penicillin G + Ampicillin IV

o Use clindamycin if allergic

• Risk is to newborn, not to mother

• Two types of infection

o 1) Early onset disease immediately after birth, usually 6-12 hours

▪ 25% mortality rate

o 2) Late onset disease occurs > 1 wk after birth

▪ usually manifests as meningitis

Drugs during Induction of Labor

• before labor, want to ripen their cervix (gets cervix ready for labor and delivery)

• typically, your cervix is usually 3-4 cm long and hard as a rock

• you need it to be shortened, and dilated

1) PGE2 – various formulations

• gel that you put in vagina (1-2 mg)

• gel that you put in cervix (0.5 mg)

• New insert called Servedil -10 mg that is CR (0.3 mg/hr)

o It has a long string attached to it for easy removal if big long uterus contraction is cutting off circulation to the baby.

• Side Effect – uterine hyperstimulation (5%) – remove as much of PG as possible (try to flush out gel – not easy or effective), or can give Salbutomol or Terbutaline (stops contraction)

2) Oxytocin

• uterine response to this depends on gestational age (( myometrial receptors as you age)

• t ½ = 5 minutes, response within 3-5 minutes

• Goal is to have 3-5 contractions every 10 minutes, and you don’t want them to last more than 1 minute

• Dosing

o Usually 10-20 U of oxytocin in a liter of normal saline

o Start at 1-2 milli units/ minute, and increase by 1-2 milli units every 20-30 minutes until good contractions

• SE = uterine hyperstimulation seen as:

o > 5 contractions in 10 minutes,

o or contractions < 2 minutes apart

o or contractions that last for > 1 minute

o Risk of this is Fetal Distress - uterus squeezes down and the baby is not getting O2

• At higher doses (45 milliunits/minute) – can get Anti-diuretic effect and water intoxification

Hypertension in Pregnancy

• Pre- Eclampsia = transient pregnancy-induced hypertension

o These are patients who have never had high BP before 20 weeks of pregnancy, and they develop it after 20 weeks and it is not associated with other Sx

o associated with proteinuria

• Essential or Chronic Hypertension = developed it > 20 weeks

• can get pre-eclampsia superimposed onto chronic HTN

o very common that people with underlying HTN will develop Sx consistent with pre-clampsia such as proteinuria, headache, visual disturbances and gastric pain.

Treatment

• Doesn’t affect maternal outcome

• Benefits fetus

• Low dose ASA – low dose prevents preeclapmsia

• DOC = methyldopa

• Labetolol (blocks ( and (), recent RCT shows that it may be better than methyldopa,

• Hydralazine 5 mg IV for emergency use (relaxes smooth muscle)

• MgSO4 – give IV, bolus 4g, then run 1-2 g/hr

o Give to ( seizure threshold

o Pre-eclampsia can go onto eclampsia, which is a full-blown seizure

• In emergency situation = don’t want to ( blood flow too quickly, b/c the first place it will cut circulation is the placenta

Avoid:

• Calcium Channel Blockers in 1st trimester (only animal study shown teratogenic) – 2nd /3rd line

• Diuretics

• ACE-inhibitors (contra-indicated)

Post Partum Depression

• Up to 15% occurrence

• very big concern

• refer to see psychiatrist

• can use almost any anti-depressant during pregnancy and breastfeeding (SSRI)

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