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Christina Nurmahi

Women & Newborn Lead Pharmacist

University Hospital Southampton

Why does it matter?

The Problem Manufacturers unlikely to do clinical trials in

pregnancy so we are dependent on post marketing surveillance.

Most studies are in animals - do not necessarily extrapolate to humans.

The harm may not be immediately apparent.

Other factors also contribute to fetal harm

Aims

RISK vs BENEFIT

By end of session:

be better equipped to make an informed decision

ObjectivesGain understanding of the:

The stages of fetal development and some of the risks associated with drug exposure in pregnancy

Factors that influence drug handling in pregnancy including impact of physiological changes in pregnancy

General principles of prescribing in pregnancy and how to reduce risk

Morbidity and mortality in pregnancy and the management of some of the high risk groups identified

TeratogenDefinition – a drug or other substance capable of

interfering with development of the fetus

Congenital malformation (structural or functional)

Failure of implantation of the conceptus

Miscarriage

Abnormal mental development

Development of Intra-uterine growth retardation

(IUGR)

Fetal death

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Background Statistics 2-3% of all pregnancies in UK and Europe affected by

major congenital abnormality

65% of these uncertain aetiology

25% linked to variety of genetic problems

10% associated with environmental factors including medicinal products (1% of all abnormalities)

A 2011 study using U.S. data from 1976-2008 reported:

90% of women take at least one medication during pregnancy

70% take at least one prescription medication.

MedicinePercentage of

Women taking

Paracetamol 65%

Ibuprofen 18%

Pseudoephedrine 15%

Antidepressants 4.5%

Factors that influence fetal development

Genetic factors

Environmental factors (maternal exposure to environmental toxins, medication, alcohol, tobacco, psychoactive drugs and radiation during pregnancy)

Nutrition (eg folic acid, iron, iodine, vitamin C & D)

Infection (e.g. rubella, syphilis, varicella zoster, Zikavirus)

Socioeconomic & demographic factors (low income, age >40yrs or <20yrs)

Embryonic and Fetal Development

• “all or nothing effect”

Pre-embryonic Phase (days 1-17)

• Period of maximal teratogenicpotential

Embryonic phase (days 18-55)

• Cerebral cortex, gastrointestinal tract and renal glomeruli still susceptible

Fetal Phase (days 56 – term)

Close to term - predictable pharmacological effects may be seen

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High risk medication associated with congenital abnormalities

CNS – Neural tube defects

(e.g. spina bifida, anencephaly)

Sodium valproate, hydantoins, rifampacin

CNS – Other structural defects Retinoids, warfarin, carbamazepine, sodium valproate

CNS – Mental impairment Anti-epileptics, alcohol

Cardiac Lithium, thalidomide, retinoids, paroxetine, valproate

Renal – Oliguria, renal failure NSAIDs, ACE inhibitors, COX-2 inhibitors

GI tract – Necrotising enterocolitis Co-amoxiclav, NSAIDs

GI tract - Gastroschisis Cannabis, recreational drugs

Facial – Cleft lip and palate Rifampacin, retinoids, steroids, sodium valproate, benzodiazepines

Facial – Abnormal facial features Alcohol

Skeletal Thalidomide, cocaine, tetracyclines

Growth restriction Beta blockers, alcohol, valproate, amphetamines

Placental abruption Aspirin, warfarin, crack cocaine

Fetal effects Medication Drug Characteristics and Fetal Exposure

99% of drugs cross the placenta by simple diffusion.

This is influenced by:

Polarisation – non-ionised drugs cross more easily

Lipid solubility – lipophilic drugs cross more easily than hydrophilic drugs e.g. labetalol cf atenolol

Molecular weight – high MW tend not to cross placenta e.g. insulin, heparin

Protein binding – unbound drug cross more easily

Drug Characteristics and Fetal Exposure

Degree of exposure determined by

Drug does not need to cross placenta to cause fetal toxicity.

Half - Life

Plasma

Concentration

Volume of

Distribution

Physiological changes in Pregnancy

• Reduced blood pressure

• Increased blood volumeCardiovascular

• Increased renal blood flow and GFR

• Fluid and sodium retentionRenal

• Haemodilutional Anaemia

• Increased clotting and reduced fibrinolysisHaematological

• Reduced albumin levels

• Altered enzyme activity (CYP450 and UGT)Hepatic

• Reduced oesophageal sphincter muscle pressure

• Reduced gastric motilityGastrointestinal

• Insulin resistance

• Fetal macrosomiaDiabetes

Pharmacokinetic/PharmacodynamicImpact on drugs

• Reduced GI motility

• Increased gastric pH

• HyperemesisgravidarumAbsorption

• Increased Vd

• Decreased albuminDistribution

• Altered hepatic metabolism

• ? Increased liver blood flowMetabolism

• Increased GFR (peaking in 2nd trimester)Excretion

No known drugs affected

Sodium valproate (↓)

Metoprolol, lamotrigine, phenytoin, morphine(↓); Caffeine (↑)

Beta-lactams, LMWH, amino-glycosides , lithium, digoxin (↓)

General Principles for Drug Prescribing in Pregnancy

Consider non-drug treatment and only prescribe drugs if essential

(risk vs benefit)

Consider period of gestation; if possible avoid all drugs in 1st trimester

Avoid known human teratogens

Avoid new drugs with no long term data

Avoid polypharmacy

Use lowest effective dose for shortest period possible

Consider need for dosing change and therapeutic monitoring

Remember patient experience and need for shared decision making

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Dddd indirect causes

direct causes

d

2016 Report (data from 2012-14)8.54 deaths per 100,000 maternities

Thrombosis & thromboembolismis the leading cause of direct maternal death during pregnancy

Cardiac disease is the leading cause of indirect maternal deaths accounting for ¼ of all maternal deaths

Suicide is the leading cause of deaths during and up to 1 yearafter pregnancy

Death by Direct Cause

Death by Indirect Cause

Haemorrhage

Cardiac disease

Epilepsy

Stroke

Sepsis–pneumonia/ other

Cancer

60%40%

Sepsis

Thrombosis

Pre-eclampsia& eclampsia

AFE

Early pregnancy deaths

Psychiatric-suicide

Psychiatric-drug/alcohol

Sepsis - influenza

Haemorrhage

Royal College of Physicians and Surgeons of Glasgow and Royal College of Obstetrics & Gynaecologists, in collaboration with other organisations, have produced new video and poster to raise awareness of indirect causes of maternal deaths:

https://rcpsg.ac.uk/college/influencing-healthcare/policy/maternal-health

New Measures to Prevent Maternal Death

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Cardiac DiseaseKey messages – how can we help as pharmacists?

Pre-pregnancy counselling, including dietary, smoking and contraceptive advice for women with pre-existing conditions

Lower threshold for referral and investigation of cardiac and respiratory symptoms, and chest/arm/back pain

Importance of continuing medication; restarting medicines postnatally if indicated e.g. ACE inhibitors, warfarin

Good interdisciplinary working and communication

Venous Thromboembolism 2009-2013 – 48 deaths from VTE

50% VTEs antenatally (though some died postnatally)

50% VTEs postnatally (up to 6 weeks postpartum)

83% of these women had risk factors for VTE

VTE risk assessment should be done for all women at booking, admission to hospital (up to 6 weeks postpartum), with any change in clinical situation, immediately post delivery (within 6 hours) and on discharge from hospital.

Venous ThromboembolismRoyal College of Obsteticians and Gynaecologists (RCOG)

Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium

Green-top Guideline No. 37a April 2015

Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management

Green-top Guideline No. 37b April 2015

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Venous ThromboembolismProphylactic Dose of Low molecular weight heparin

*Can give BD if high prophylaxis dose required

Weight Enoxaparin dose Dalteparin dose Tinzaparin dose

<50kg 20mg OD 2500 units OD 3500 units OD

50-90kg* 40mg OD 5000 units OD 4500 units OD

91-130kg 60mg OD 7500 units OD 7000 units OD

131-170kg 80mg OD 10000 units OD 9000 units OD

>170kg 0.6mg/kg/day 75 units/kg/day 75 units/kg/day

Contraindications LMWH allergy Acute stroke within previous 4 weeks

Increased risk of major haemorrhage Active bleeding Uncontrolled BP (>200/120)

Planned delivery within 12hrs Bleeding disorder Severe liver disease with raised INR

Recent spinal anaesthesia or epidural catheter removal < 4hrs

Platelets<75 x 109/lRenal failure (Cr> 125 and rising; or eGFR<30mL/min/1.73m2)

Venous ThromboembolismTreatment dose of low molecular weight heparin

Enoxaparin 1mg/kg BD / Dalteparin 100units/kg BD *

*Insufficient evidence to recommend whether dose be given once daily or in two divided doses (RCOG 2015)

Doses titrated against woman’s booking or early pregnancy weight. Unfractionated heparin preferred for initial treatment of pulmonary embolism Treat during remainder of pregnancy and for at least 6 weeks postnatally and

until at least 3 months of treatment has been given in total.

Weight Enoxaparin dose Dalteparin dose

<50kg 40mg BD or 60mg OD 5000 units BD or 10000 units OD

50-69kg 60mg BD or 90mg OD 6000 units BD or 12000 units OD

70-89kg 80mg BD or 120mg OD 8000 units BD or 16000 units OD

90-109kg 100mg BD or 150mg OD 10000 units BD or 20000 units OD

110-125kg 120mg BD or 180mg OD 12000 units BD or 24000 units OD

>125kg Discuss with haematologist Discuss with haematologist

Venous Thromboembolism Warfarin – TERATOGEN

Avoid weeks 6-12 & week 36 onwards – give LMWH BD

Postpartum, can recommence day 5 post delivery

INR range aim for 2-3

Give vitamin K 10mg (phytomenadione) from 36 weeks till delivery once warfarin stopped

Aspirin 75mg given if Antiphospholipid syndrome (APL) + fixed dose LMWH

(give 1mg/kg OD if APL syndrome plus previous thrombosis)

NOACs Avoid in pregnancy and if breastfeeding

SepsisWomen who are pregnant, have given birth or had a termination of pregnancy or miscarriage in the last 6 weeks, are in a high risk group for sepsis. In particular, women who:

have impaired immune system because of illness or drugs

have gestational diabetes or diabetes

needed invasive procedures (for example, caesarean section, forceps delivery, removal of retained products of conception)

had prolonged rupture of membranes

have been in close contact with people with group A streptococcal infection e.g. scarlet fever

have continued vaginal bleeding or offensive vaginal discharge.(NICE Sepsis Guidelines July 2016)

SEPSISKey actions for Doctors, Midwives and Allied Health Professionals for diagnosis and management of sepsis are:

Timely recognition and early diagnosis –‘THINK SEPSIS’

Rapid antibiotics – within 1 hr of suspected diagnosis

Review by senior doctors and midwives

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Sepsis – Antibiotic safety in pregnancy and breastfeeding

Safety in pregnancy:

Penicillins, cephalosporins, macrolides – generally safe; co-amoxiclavincreased risk of necrotising enterocolitis in neonate

Clindamycin – safe

Metronidazole – most likely safe; significant amounts in breastmilk but considered safe - unusual taste

Gentamicin – safe at therapeutic levels; monitor levels.

< 20 weeks – 1.5mg/kg tds > 20 weeks – 3-5mg/kg stat

Ciprofloxacin - moderately safe nevertheless use with caution; one report of pseudomembranous colitis in breastfed infant

Generally all compatible with breastfeeding

HypertensionChronic Hypertension – present at booking or during pregnancy before 20 weeks.

If pre-pregnancy hypertension, review early and ensure safer drugs used: methyldopa, nifedipine MR,labetalol; avoid ACEi, A2RAs (ARBs), diuretics and atenolol.

Aim to keep BP < 150/100

Aspirin 75mg od commenced from 12 weeks until birth if high risk of pre-eclampsia.

Check BP and urinalysis for protein at each antenatal visit (key message from MBBRACE 2016)

HypertensionGestational Hypertension – presents after 20 weeks

Degree of hypertension

Mild >140/90mmHg

Moderate >150/100mmHg

Severe >160/110mmHg

Admit No No Yes

Treat No Yes(commence labetalol)

Yes(commence labetalol)

Monitor BP Weekly (twice weekly if < 32 weeks or high risk of

pre-eclampsia)

Twice Weekly QDS initially then twice weekly

Check for protein At each antenatal visit

At each antenatal visit

Daily

Hypertension Postnatal

Consider reducing dose if <140/90mmHg

Reduce or stop anti-hypertensives if BP < 130/80mmHg

If chronic hypertension, continue with antenatal anti-hypertensivesand review long term treatment at 2 weeks (NICE 2010)

If on methyldopa for chronic hypertension, stop postpartum and restart pre-pregnancy drug if compatible with breastfeeding

6-8 week follow up with GP

Breastfeeding

Beta blockers – labetalol; atenolol; metoprolol

Calcium channel blockers – nifedipine; amlodipine??

ACEi – captopril; enalapril; ramipril??

A2RAs – insufficient information

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Hypertension Pre-eclampsia = Hypertension + Proteinuria

May progress to eclampsia – convulsions

Associated with high morbidity and mortality if severe

Admit and monitor (mild hypertension, only need to admit if symptomatic or abnormal bloods)

If delivery likely between 24-34 weeks, treat with single course of corticosteroids (beta/dexamethasone) 12mg x 2 12hrs apart

Fluid restrict – 80ml/hr

Treat with magnesium sulphate injection 20% if severe

Depression

Tokophobia

OCD Panic disorder

Anxiety

PTSD Psychosis

Uncertainty about the benefits, risks and harms of pharmacological treatments for mental health problems in pregnancy and the postnatal period

Mental Health in Pregnancy

Mental Health in Pregnancy NICE 2014 (CG192) – Antenatal and Postnatal Mental Health

UHS perinatal mental health team commonly prescribe:

TCAs – amitriptyline, imipramine

SSRIs – sertraline, citalopram, fluoxetine

SNRIs – venlafaxine

Do not offer benzodiazepines to women in pregnancy and the postnatal period except for the short-term treatment of severe anxiety and agitation.

Mental Health in PregnancyKey recommendations from NICE 2014 – CG192 cont.

Lithium

CarbamazepineValproate Lamotrigine

Olanzapine

Haloperidol Quetiapine

Risperidone

Fluoxetine

Analgesia in Pregnancy

NSAIDS Delay or prolong labour Bleeding risk Premature closure of

ductus arteriosus Persistent pulmonary hypertension

Impairs implantation Spontaneous abortions Congenital malformations Fetal renal dysfunction OligohydramniosAVOID

Opioids

CAUTION

Congenital disorders

Respiratory depression

NAS

NOT KNOWN TO CAUSE HARM

Paracetamol

Further data needed

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Anti-emetics Nausea and vomiting common in early pregnancy;

severe N&V can progress to hyperemesis gravidarum

Management consists of correction of fluid & electrolyte imbalances and treatment with anti-emetics

Antihistamines (promethazine, cyclizine)

Phenothiazines (prochlorperazine)

Dopamine antagonists (metoclopramide, domperidone)

Serotonin antagonists (ondansetron)

If uncontrolled hyperemesis, consider corticosteroids

If risk of Wernicke’s encephalopathy, consider thiamine

Useful ResourcesReference sources: Drugs in Pregnancy and Lactation – G. Briggs, R. Freeman, S. Yaffe

Drugs during Pregnancy and Lactation – C. Schaefer, P. Peters, R. Miller

Therapeutics in Pregnancy and Lactation – A. Lee, S. Inch, D. Finnigan

British National Formulary and BNF for children

Summary of Product Characteristics (www.emc.medicines.org.uk)

UKMI Q&A (www.ukmi.nhs.uk/activities/medicinesQAs/)

UK Teratology Service (UKTIS) (www.uktis.org or 0344-8920909)

Uktis BUMPS - http://www.medicinesinpregnancy.org/

NHS Choices - https://www.nhs.uk/Conditions/pregnancy-and-baby/Pages/medicines-in-pregnancy.aspx

http://www.motherisk.org/women/index.jsp

https://www.cdc.gov/pregnancy/meds/treatingfortwo/