Medicines in Pregnancy

Dr Treasure McGuire
Mater CPD Womens Health Conference 2010

Fact 1: Pregnant women use drugs

100 80 60

%
40 20 0
re sp ira to ry an al ge si cs ga st ro in te st in al an tim ic ro bi al s N S ca rd io va sc ul ar en ts em C

95% of women take 4 or more drugs at some stage of pregnancy

(based on data collected for 82,525 mother child pairs)

su pp l

Week 0-2 2

Developemental Stages
Conception Blastogenesis Implantation
Nutrients / Drugs are transferred into luminal secretions of fallopian tube & uterine cavity through which ovum then blastocyst must pass. Drugs can kill but cannot cause congenital malformations

2-8

Embryogenesis
have a direct connection between maternal & fetal circulation period of organ formation eg. Heart days 18 - 40 Brain days 18 - 60 Eyes days 25 - 40 Limbs days 25 - 38 Genitalia days 40 - 60 to delivery) also complete closure of palate differentiation of external genitalia -> pseudohermaphrodism histogenesis of CNS ---> postnatally -> behavioural / mental changes

8 - >22 Fetogenesis / fetal Toxicity (especially in the last 10 weeks prior

-

Tuchmann-Duplessis H. Drug effects on the fetus. New York: ADIS Press; 1977.

To be a Proven Teratogen a Drug must:

1.

Produce deformities in > 2-3% of mothers exposed

Approx. 2-3% of all babies not exposed to drug therapy have congenital anomalies Incidence of minor abnormalities such as birth marks, skin tags is around 7%

2.

produce a consistent pattern of deformities

Difficulties need large numbers of patients need to exclude other possibilities To Produce a Malformation, the drug must not only be given (1) In Sufficient Dosage (dose related effect) BUT (2) Embryo must be Sensitive (species specific) (3) Drug must be given at the Precise Moment the Target Organ is Forming ie the susceptible stage of development (4) Maternal pathophysiology also plays a role

ADEC Pregnancy Categories

A: taken by a large number of pregnant women without ANY PROVEN increase in the frequency of malformations or other direct harmful effects on fetus. B: Taken by only limited numbers of pregnancy women, without an increase in frequency of malformation etc AND WRT ANIMAL STUDIES: B1 Show no evidence of fetal damage B2 Inadequate but avail. Data show no evidence of fetal damage B3 Have shown evidence of increased occurrence of fetal damage, but human significance uncertain. C: Suspected of causing harmful effects BUT NOT MALFORMATIONS in HUMAN FETUS; may be REVERSIBLE. D: Suspected or expected to cause an increased incidence of HUMAN FETAL MALFORMATIONS or IRREVERSIBLE DAMAGE.
Cat.D drugs not absolutely contraindicated (e.g. anticonvulsants); In some cases assigned on basis of `suspicion'. Due to legal considerations, sponsors have, in some cases, applied a more restrictive category than can be justified on available data.

X: High risk of permanent damage in the fetus

Pregnancy assoc condition

e.g. Morning sickness
occurs in 70% of pregnancies (1:1 mild: severe) us. appears wks 4-8 & disappears by wks 14-16; aetiology unknown
?linked with inc. HCG levels ?neural &/or endocrine changes ?Progesterone-induced relaxation of stomachs smooth muscle & gut stasis

Tx/Px
Prevent dehydration!
fluid/electrolyte replacement (po/ IV)
Carbonated drinks can help

Pyridoxine (Vitamin B6)

up to 3 times a day can help some women.

Antiemetics
Metoclopramide, prochlorperazine, promethazine, chlorpromazine, (doxycycline), considered safe in 1st trimester

In hyperemesis gravidarum:
metabolic acidosis; disturbances; wt loss

recommendation for further exploration of ginger root in both nausea and vomiting (Jewell and Young, 2003)

Constipation
Safe to take
Bulk forming laxatives
eg Metamucil

Surfactants
E.g. Coloxyl

Osmotic laxatives
Lactulose, sorbitol, Mg SO4

AVOID
Stimulant laxatives uterine & gut both contain smooth muslce, if stimulate may stimulate the other!

PIH/ pre-eclampsia
occurs in 3-8% of pregnancies; after approx 20 wks gestation sl. inc. incidence in primagravida incidence 2-3 times higher in diabetics & pts with pre-existing renal disease.

Presentation:
generalised vasoconstriction; assoc with :
coagulation changes (TXA2 released during platelet aggregation & occlusive-thrombotic lesions may develop in renal &/or utero-placental circulation; inc BP (systolic inc of >30 mmHg) (diastolic inc.of >15mmHg) proteinuria oedema

PIH/ Pre-eclampsia
variant = HELLP syndrome
ie. haemolysis, elevated liver enzymes low platelet count although minimal inc in BP & renal dysfunction; the liver disease, coagulation & platelet changes are life threatening.

Selective beta blockers

atenolol 50-200mg/day metoprolol 50-200mg/day oxprenolol 40-480mg/day widely used as gradual onset & lack of postural hypotension monitor of IUGR, fetal bradycardia, respiratory distress

Non-selective beta blockers

eg propranolol more likely to to induce uterine contractions, bronchospasm, inc. sensitivity to insulin than selective agents.

Tx of hypertension
Methyldopa
most extensively used (normal physical & mental fetal development with 10 year follow-up) 0.5-4g/day

Labetalol
combined alpha & beta blocker theoretically preferred as dec. peripheral resistance without changing CO or producing tachycardia Prazosin (limited use)

Tx of Pre-eclampsia
1. Lower BP
hydralazine
(5-10mg iv bolus then infusion);

diazoxide
(30mg iv bolus q 5 mins) to prevent excessive hypotension;

3. Px/Tx convulsions magnesium sulphate (iv)

peripherally has a curare like effect on NMJ, dec. Ach release, dec. contraction of vascular smooth muscle; also central action also tocolytic (can delay labour)

nifedipine
(po/sl) as a uterine muscle relaxant

2. Maintain urine output

>0.5ml/kg/hr add IV fluid if reqd

phenobarbitone

Drugs to avoid in Tx of PIH

Diuretics
cause plasma volume contraction

ACE Inhibitors
can cause fetal hypotension; IUGR; oligohydramnios; oliguria; renal failure; stillbirths. effects reported with use in 2nd & 3rd trimesters not in 1st trimester.

Thromboembolic disorders
inc. risk of thromboembolic disorders in pregnancy:
dec. venous return from lower limbs; inc. concs. of clotting factors trauma assoc with delivery.

Most common thrombotic disorder is superficial thrombophlebitis

vs

life threatening thromboembolism.

Thromboembolic disorders Px/Tx

Heparin
recc for high risk pts eg Hx of clotting disorders; dose 5000 - 10,000 iu bd-tds safe as cant cross placenta monitor for HITTs

LMW heparin
less experience than with heparin considered relatively safe in pregnancy

Warfarin
not recommended crosses the placenta & assoc with birth defects from 1st trimester use; 2nd & 3rd trimester assoc with eye defects, inc. risk of fetal haemorrhage

Common Psychiatric drug families

DRUG BIRTH DEFECTS TOXICITY / WITHDRAWAL Sx

BENZODIAZEPINES e.g. diazepam (Valium) ( C ) TCAs (C) Most SSRIs

e.g. sertraline (Zoloft)

No (? McBride) No (No)

Yes (hypotonia) Yes Yes

(C) (+/-) Heart defects No (C) No Yes Yes

PAROXETINE (an SSRI) (D) PHENOTHIAZINES

e.g. trifluoperazine (Stelazine)

Yes

ATYPICAL ANTIPSYCHOTICS e.g. olanzapine (Zyprexa) (B3) LITHIUM (D) CARBAMAZEPINE (Tegretol)

Yes Heart defects (+/- ) is used No

+/changes in TFTs Yes

VENLAFAXINE (Efexor) (B2)

OTHER

Yes

No

Yes

Mirtazapine (B3); Moclobemide (B3 Mianserin (B2)

Sertraline in Pregnancy
Animal data
decreased growth at 20 times the human mg/kg dose

Clinical data:
Prospective study of 147 women followed after contacting a CMIS wrt their use of sertraline. Incidence of malformations comparable to unexposed control subjects. Offspring of 112 women who used sertraline (all trimesters) found not to have an increase in birth defects c.f. a control population.
Transition difficulties at birth and admission to a special care nursery were associated with late pregnancy exposure to the medication. (Cat

C!) Case report

symptoms of sertraline withdrawal in infant whose mother ingested drug through gestation & 1st 3 wks postpartum. 1 day after drug cessation:
Sx of agitation, poor feeding, constant crying & insomnia. (intense for 48 h and subsequently subsided). authors suggested that withdrawal Sx had been offset by residual levels of sertraline or active metabolites in breast milk.

Paroxetine FDA alert (Dec 05)

Category changed from C to D
Based on preliminary epidemiological data
Study using Swedish national registry data Women receiving paroxetine early ion pregnancy had a 2-fold increased risk for cardiac defect cf entire national registry population (2% vs 1%) US Insurance claims database cardiac defects (1.5% paroxetine vs 1% other antidepressants).

Most were atrial or ventricular septal defects

Where wall between R & L sides of heart not completely developed Also a common non-drug related malformation Severity ranged from asymptomatic & may resolve on own to symptomatic requiring surgery

Fetal Toxicity (1 3rd Trimester)

Most Psychiatric drugs are associated with fetal toxicity e.g Tricyclic Antidepressants
possible long or difficult labour as fetus may be sedated (due to drug accumulation) Neonatal withdrawal symptoms likely
irritability, tachycardia, muscle spasms, convulsions, urinary retention in neonate.