Week 5 - G - Prescribing in Pregnancy - Thalidomide, Diethylstilbesterol, Teratogenic Drugs, Hypertension, VTE&Diabetes

Question 1

Just a fun question, any memory of the supposed ‘wonder drug’ for morning sickness given to mothers from 1958-1961 worldwide? Throughout the world, about 10,000 cases were reported of infants with phocomelia (malformation of the limbs) due to the drug

Answer 1

This drug was thalidomide ‘One of the biggest medical tragedies of all time’

3,500 deaths in first year of life

>10,000 children in 46 countries born with deformities

Question 2

Why are there very few randomised clinical drug trials carried out in pregnancy?

Answer 2

There are few randomised clinical drug trials carried out because it is deemed unethical to carry these trials out on women as it can have serious effects on the baby

Question 3

Most drugs are not licensed for use in pregnancy Usually prescribe outwith the licence When is this done in hypertension in pregnancy?

Answer 3

Labetalol is the only licensed drug for treating hypertension in pregnancy But methyldopa, nifedipine And hydralazine 3rd line are also prescribed by doctors

Question 4

* Most women are reluctant to take drugs during pregnancy * Most doctors are reluctant to prescribe drugs to pregnant women * Balance of risk to mother and foetus of not treating illness vs risks of drug to foetus * Older drugs with better safety records * Lowest effective dose for shortest period Even through all the reluctancy, what percentage of women take drugs during pregnancy?

Answer 4

>90% of women actually take drugs during pregnancy

Question 5

>90% of women take drugs in pregnancy Painkillers ~12% Antibiotics ~11% Antacids ~8% (Also folic acid and iron) What is the dose of folic acid that should be taken during pregnnacy? What dose should be taken by epileptics and diabetics?

Answer 5

Folic acid dose * 400 micrograms folic acid daily whilst they are trying to conceive and up to 12 weeks gestation * In diabetes - 5mg folic acid daily for 3 months prior to conception and up to 12 weeks gestation * IN epilespy - take 5mg folic acid daily for 3 months prior to conception and up to 12 weeks gestation - should continue throughout pregnancy to reduce risk of folate deficiency anemia

Question 6

What are some self medicating drugs taken in pregnancy? What is a specific herbal remedy that may be taken to treat depression during pregnancy?

Answer 6

Self medicating drugs taken in pregnancy - this can be NSAIDs Herbal remedies Eg St Johns Wort - used to treat depression although shown not to have any better effect than placebo in moderate to severe depression

Question 7

Most drugs cross the placenta in pregnancy, apart from what? Which minerals can only cross form mother to placenta despite the osmotic gradient?

Answer 7

Large molecular weight heparin This would be calcium and iron

Question 8

Pharmacokinetics - the branch of pharmacology concerned with the movement of a drug within the body (what the body does to the drug) What are the four aspects of pharmacokinetics?

Answer 8

This would be Absorption Distribution Metabolism Elimination

Question 9

How may the pharmacokinetics be affected by pregnancy?

Answer 9

* Absorption - morning sickness can decrease the absorption of the drugs * Distribution - there is more free drugs circulating due to decreased protein binding * Metabolism - the liver metabolism of some drugs is increased * Elimination - the renal clearance of drugs (ie the drugs going through the renal tubules) increases in pregnancy due to the increased GFR

Question 10

May need to check concentrations and alter dose during pregnancy and after delivery Lithium, digoxin The pharmacodynamics of the drugs (what the drug does to the body) is not really effected during pregnancy apart from sometimes in anti-hypertensives WHat can anti-hypertensives cause during the 2nd trimester?

Answer 10

During the 2nd trimester, hypotension is associated with the antihypertensives

Question 11

Any woman of childbearing age * Are they pregnant? * Are they planning a pregnancy? * Could they become pregnant? * Folic acid 400mcg daily for 3 months prior and first 3 months of pregnancy * Counselling re chronic conditions * Epilepsy, diabetes, hypertension * Optimise therapy to choose safest drugs What are women at risk of in 1st trimester?

Answer 11

They are at risk of an early miscarriage

Question 12

What period in the 1st trimester is there the greatest risk of miscarriage? Avoid drugs if at all possible unless maternal benefit outweighs risk to foetus What stages of feotal development occur after implantation of the egg into the endometrium in the 1st trimester? When is the 1st trimester?

Answer 12

* It is from the 4th-11th week of gestation where the foetus is at the greatest teratogenic risk * This would be Gastrulation and Organogenesis * Organogenesis is the stage in the 1st trimester over which the greatest teratogenic risk occurs The first trimester of pregnancy is week 1 through week 12, or about 3 months. The second trimester is week 13 to week 27. And the third trimester of pregnancy spans from week 28 to the birth.

Question 13

There are a lot of teratogenic drugs What can ACEi/ARBs do if used during the 1st trimester? What can anti-epileptics cause? What can lithium cause? What can methotrexate cause? What can warfarin cause?

Answer 13

* ACEinhibitors/ARBs - can cause renal hypoplasia - this can lead to oligohydramnios and POTTER syndrome * Anti-epileptics - can cause cardiac, facial, lim and neural tube defects * Lithium - cardiovacular defects * Methotrexate - skeletal defects * Warfarin - limb and facial defects

Question 14

What effects can drugs have on the foetal pregnancy during the 2nd and 3rd trimesters?

Answer 14

Due to growth and functional development of the foetus - Can cause intellectual impairment and behavioural abnormalities in the foetus Also can cause toxicity to foetal tissues as well as causing withdrawal

Question 15

What can the use of labour cause to the baby if given around the third trimester?

Answer 15

This can causes respiratory depression in the baby

Question 16

What was the drug given to pregnant women in the mistaken belief it would reduce the risk of pregnancy complications and losses between 1940-1971?

Answer 16

This would be diethylstilbestro (DES) It was found to not actually be effective in reducing miscarriage rates as well as causing cancers in young girls

Question 17

What was the cancer caused by diethylstilbestrol? When did this cancer present? What was the drug given between 1958-1961 gain that caused malformation of the limbs? What is malformation of the limbs known as?

Answer 17

Diethylstilbestrol caused vaginal adenocarcinoma (clear cell adenocarcinoma) in young girls aged 15-20 year whose mothers were exposed to the drug during pregnancy Thalidomide was the drug given between 1958-1961 - malformation of the limbs known as phocomelia

Question 18

Chronic conditions and pregnancy Need to discuss risk/benefit balance with patient * Ideally pre-conception Compliance with medication may be poor * Many women avoid taking their asthma inhalers in pregnancy * Up to 20% of women discontinue antiepileptic medication in pregnancy What drug should be avoided in patients with asthma?

Answer 18

Avoid labetalol in patients with asthma

Question 19

Incidence of congenital malformations higher in untreated women with epilepsy than women without epilepsy If a women has a first time seizure (de novo) in pregnancy what does this make you think?

Answer 19

This makes you think eclampsia Epilespy de-novo in pregnancy is very rare

Question 20

Women having how many monthly seizures are shown to only have more seizures during pregnancy?

Answer 20

Women greater than 1 seizure per month prior to pregnancy shown to have worsening seizure rates during pregnancy

Question 21

There are a lot of teratogenic drugs What can ACEi/ARBs do if used during the 1st trimester? What can anti-epileptics cause? What can lithium cause? What can methotrexate cause? What can warfarin cause?

Answer 21

Acei/ARBs - can cause renal hypoplasia Anti-epileptics - cardiac, limb, facial and neural tube defects Lithium - cardiovascular defects Methotrexate - skeletal defects Warfarin - limb and facial defects

Question 22

What are the risks of foetal seizures during pregnancy?

Answer 22

Decrease in foetal IQ, hypoxia, bradycardia, foetal death, maternal death

Question 23

Increased seizures in 10% of women * Non-compliance Changes in plasma concentrations of drugs * Persistent vomiting * Increased clearance What may be the anti-epileptic drug of choice during pregnancy?

Answer 23

Carbamezapine may be the drug of choice during pregnancy

Question 24

There is a much higher assoicated risk of congenital malformations the more anti-epileptics the mother is on and therefore monotherpay is preferred What anti-epileptics are avoided? What should be taken as a supplement?

Answer 24

Avoid sodium valproate and phenytoin Take 5mg folic acid 3months prior to conception and throughout pregnancy Up to 12 weeks to try avoid neural tube defects, throughout pregnancy to avoid folate deficiency anaemia

Question 25

96% of babies born to women taking antiepileptics will not have major congenital malformations Benefits of treatment outweigh risks in most cases Which antiepileptics are associated with Neural tube defects? Orofacial Cleft? Cardiac defects?

Answer 25

Neural tube defects - sodium valproate mainly and carbamezapine Orofacial cleft - phenytoin Cardiac defects - phenytoin and sodium valproate

Question 26

When is vitamin K given to the mother and why in an epileptic pregnancy? WHat is given immediately to the baby at birth and why?

Answer 26

Vitamin K is given from 36 weeks to the mother if she taking liver enzyme enducing anti-epileptics (most apart from sodium valproate) (hopefully also reduces risk of foetal vitK deficiency and haemorrhagic disease of the newborn) 1mg IV vitK is given to the foetus at birth to prevent the reasons above

Question 27

Insulin thought to be safe Requirements change during pregnancy Poor control increases risk of congenital malformations and intra-uterine death Which anti-diabetic drug isnt safe in pregnancy?

Answer 27

Sulfonylureas arent safe in pregnancy due to the increased risk of hypoglycaemia Metofrmin is safe in pregnancy

Question 28

When does blood pressure drop during pregnancy?

Answer 28

Blood pressure drops during the second trimester of pregnancy due to uteroplacental circulation expansion and peripheral vascular resistance decreases

Question 29

Due to the drop in blood pressure during the second trimester of pregnancy, important to monitor anti-hypertensives to ensure the mother is not hypotensive What anti-hypertensives are options during pregnancy?

Answer 29

1st line - labetaolol (avoid in asthma) Methyldopa (avoid in woman with depression) Nifedipine Then Hydralazine can also be given

Question 30

What drug can be given for the nausea and vomiting during pregnancy? how does it work? What drug is given for pain?

Answer 30

Give cyclizine for nausea and vomiting - it is an antihistamine that works via H-1 receptor antagonism Paracetamol is given for pain

Question 31

What are the guidelines for treating a UTI during pregnancy? What is 1st and 2nd line? Is test of cure carried out?

Answer 31

Guidelines 1st or 2nd trimester - give nitrofurantoin 3rd trimester - give trimethoprim 2nd line - cefalexin which can be given in any trimester Test of cure is carried out

Question 32

Why cant trimethorpim be given during the 1st and 2nd trimester of pregnancy? What is its mechanism of action? Why cant nitrofuantoin be given in the 3rd trimester of pregnancy?

Answer 32

Dont give trimethoprim during the 1st or 2nd trimester as it can cause nerual tube defects as it works by blocking folate metabolsim via dihydrofolate reductase (Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF)) Nitrofurantoin cannot be given in the 3rd trimester of pregnancy due to the potential risk of hemolytic anemia in the newborn,

Question 33

What is the leading cause of maternal death in the UK?

Answer 33

Pregnancy has 10-fold increased risk of VTE (vs non-pregnant) VTE is leading cause of maternal death in pregnancy All pregnant women should be assessed for risk of VTE

Question 34

What clotting factors are increased during pregnancy?

Answer 34

Clotting factors VII, VIII, X and fibrinogen therefore affecting both intrinsic and extrinsic clotting pathways

Question 35

Regardless of risk, all women who are pregnant, in labour or in the puerperium should be encouraged to mobilise and be adequately hydrated Those with significant risk factors should receive thromboprophylaxis What drug is given for thromboprophylaxis?

Answer 35

Low mecular weight heparin is given

Question 36

Treat suspected or established DVT or PE with therapeutic dose LMWH Why is warfarin avoided in early and late pregnancy?

Answer 36

Warfarin - * Avoid in early pregnancy - can cause limb and facial defects * Avoid in late pregnancy - can cause haemorrhage during delivery

Question 37

Royal College of Obstetricians and Gyanecologists have guidelines on when to give thromboprophylaxis during pregnancy Different scores correspond to the different times from when to considering starting thromboprophylaxis If the total score >/= 4 antenatally, when is thromboprophyaxis given? If the toal score 3 antenatally, when is thromboprophylaxis given? What score for thromboprophylaxis postnatally?

Answer 37

If total score >/= 4 antenatally - consider thromboprophylaxis from the first trimester

If total score is 3 antenatally, consider thromboprophylaxis from 28 weeks

Patient needs a score of >/=2 postnatally to consider 10 day thromboprophylaxis

Question 38

Most drugs enter breast milk, especially * Small molecules * Fat soluble (lipophilic) drugs Few enter in sufficient quantities to cause a problem What is the foremilk and hindmilk rich in?

Answer 38

Foremilk - rich in protein, sugars and water Hindmilk - rich in calories and fat

Question 39

Some drugs are actively concentrated in breast milk such as what?

Answer 39

Pehnorbarbital (phenobarbitone) - causes suckling difficulties This is an anti-epieptic drug but it can also be given for neonatal asbtinence syndrome

Question 40

What can benzos and bromocriptine cause in the neonate if given in late pregnancy?

Answer 40

Benzos - can cause floppy baby syndrome - hypotonia - or can just cause some drowsiness Bromocriptine - can suppress lactation making feeds difficult

Question 41

34 year old lady * Essential hypertension * BP 164/102mmHg after lifestyle measures * No regular medication * Planning pregnancy in next year * Worried about whether she will have problems due to her BP if she gets pregnant What should be done?

Answer 41

Encourage further lifestyle improvement The options: No treatment but monitor her BP closely during the 2nd trimester or Start on antihypertensives that are known to be safe ie Labetalol or methyldopa

Question 42

26 year old lady * 28 weeks pregnant * Presents with swollen right leg * US scan confirms extensive right DVT How would you treat her?

Answer 42

Elevate the leg and give stockings Advise exercise Start on LMWH

Question 43

How long would the LMWH be continued in this patient with a DVT?

Answer 43

Continue for either 3 months after delivery or 6 months after treatment started - whichever is longer (if delivery is at 40 weeks then this would be pretty equal as the patient was 28 weeks pregnant)

Question 44

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Answer 44

This would be caused by a tetracylcine - do not give in children below 8 years of age (some research suggests 12 years of age)

Question 45

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Answer 45

This child could have had facial acohol syndrome - micrognathia, microcephaly, prominent epicanthal folds, thin upper lip with wide philtrum

Question 46

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Answer 46

Phenytoin - orofacial celft - cleft upper lip and palate

Question 47

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Answer 47

Diethylstilbesterol (DES) - given from 1940 to 1971 Now known to cause vaginal clear cell adenocarcinoma in girls whom mother take the drug while in utero (usually presents around ages 15-20)

Question 48

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Answer 48

Sodium valproate The baby has neural tube defects - spina bifida and anencephaly (carbamezapine can also cause this but less common) Valproate also causes reduced cognitive function in the child