Medical Complications in Pregnancy

Dr Gerry McKayConsultant Physician/Honorary Clinical Senior Lecturer

CORE MEDICAL TRAINEES meeting April 2010

Outline of talk

• Case 1 and causes of maternal death

• Case 2 and causes of maternal morbidity

• Prescribing in Pregnancy– Historical perspective– Clinical Pharmacology

• Case 3

• Conclusions

Case 1 – Maternal mortality

• 39 year old woman at 35 weeks gestation admitted with retrosternal ‘pleuritic’ chest pain radiating through to back with associated nausea

• Had been having dyspepsia and nausea early in pregnancy – treated with gaviscon

• Reviewed 3-4 times over a 36 hour period

• Throughout observations were satisfactory

• Concern raised re: possibility of PE and she was given LMWH and V/Q requested

Case 1 – Maternal Mortality

• During second night of admission complained of more pain – given some analgesia

• Became more unwell, clear something was wrong......

• Cardio respiratory arrest

• Healthy baby delivered by urgent caesarian section during efforts to resuscitate the mother who died

• Post mortem performed and internal case review (and details kept for the CEMACH)

Case 1 – Maternal Mortality

• What was the cause of death?

• What other information might have been helpful?

• Could things have been done differently?

www.cmace.org.uk

Cardiac deaths

Case 2 – Maternal Morbidity

• On call doctor asked to review a patient on the maternity ward

• Patient aged 22 years and 17 weeks gestation

• Admitted with left colicky flank pain and subsequently had episode of haematuria and because of pregnancy sought advice

• U+Es checked on admission – Urea 10 and Creatinine 137

• Gives a history of renal stones and polycystic kidneys

• Obstetric team concerned re: renal function and have admitted her for assessment

Case 2 – Maternal Morbidity

• What do you think is going on?

• What other information do you need?

• What is your management plan?

• What happened with this lady?

Common causes of morbidity

• Haemorrhage

• Thromboembolic disease

• Infection

• Hypertension/pre-eclampsia

• Epilepsy

• Diabetes

• Cardiac disease

• Obesity

Obesity

Key points to assessing pregnant women for medical problems

• A, B, C

• Good history• PC, PMH, DH, FH, SH

• Relevant examination

• Appropriate Investigations

• Make a diagnosis

• Start treatment once you have assessed risk-benefit

Prescribing in pregnancyHistorical perspective

Frances Oldham Kelsey1962

Historical Perspective

• Thalidomide became the active agent of the calming and sleep-inducing drug Contergan that was introduced on to the market on October 1, 1957 in West Germany

• In 1961 it was estimated that up every third West German used Contergan to get to sleep!

Thalidomide

Kefauver Harris Amendment

• Federal Food, Drug, and Cosmetic Act (1938)

– It introduced a requirement for drug manufacturers to provide proof of the effectiveness and safety of their drugs before approval

• UK?– Medicines Act 1968

Historical perspective

• Thalidomide – Conclusions?

– demonstrated that fetal exposure to the drug during critical periods of development resulted in severe limb defects and other organ dysgenesis (especially between days 35 and 50)

– Despite high rates of malformations (20 to 30%) and characteristic pattern, the teratogenicity of thalidomide was not suspected for years

– Has prompted the belief that every drug has the potential to be a new thalidomide

BUT

• In 1998, thalidomide became FDA approved for the acute treatment and suppression of the cutaneous manifestations of erythema nodosum leprosum (ENL)

• Off-label uses for thalidomide include– aphthous stomatitis– Behçet disease– pyoderma gangrenosum– chronic discoid lupus erythematosus– systemic lupus erythematosus– lichen planus– prurigo nodularis– sarcoidosis

Aims of treatment

Historical perspective

An example of the gap between the perception of teratogenic risk and evidence-based proof of safety

Koren et al NEJM 1998;338:1128--37

withdrawn in 1982

Bendectin

What about now?

Isotretinoin

• Introduced in early 1980s for acne• Known teratogen• Appropriate labelling

– it is teratogenic– warnings not to take it around the time of conception– this would be effective in preventing fetal exposure to

the drugs?• Despite explicit warning labels, scores of children

with retinoid embryopathy were born in the years after the drug was introduced

For most drugs manufacturers advise

"Use in pregnancy is not recommended unless the potential benefits justify the potential risks to the fetus."

The process of establishing risk or safety of drugs

• In vitro• Animal studies• First in man!

– Northwick Park Hospital– TGN1412

• Phase I• Phase II• Phase III

Crab-eating Macaque (Macaca fascicularis)

The process of establishing risk or safety of drugs in pregnancy

• Animal studies

– E.g. Insulin glargine (Lantus©)

– Subcutaneous reproduction and teratology studies • in rats and Himalayan rabbits

• The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.

The process of establishing risk or safety of drugs in pregnancy

• Epidemiological studies

– Short term

– Long term

The process of establishing risk or safety of drugs in pregnancy

• Common Methodological issues

– Sample size– Effect of maternal diseases– Recall bias in retrospective studies– Non randomised observational studies– Voluntary reporting– Meta analyses

Pharmacodynamics/Pharmacokinetics

Effect of drugs on the fetus– Fertilization and implantation (up to 17 days)– Organogenesis 18-55 days– Growth and development

Effect of pregnancy on drugs– Drug distribution– Drug elimination

Haemodynamic modifications during pregnancy

• 50% increase in blood volume by end of pregnancy

• Decrease systemic and vascular resistance

• Increase in HR by 10-20 beats/minute

• Increase in cardiac output by 30-50% (mainly achieved by increase in stroke volume)

• Further increase CO at labour/delivery and post partum

Physiological changes in pregnancy

Drug distribution

• Plasma and extracellular volume ↑50% by 3rd trimester

• Changes in plasma protein concentrations eg ↓20% albumin and α-1-acid glycoprotein ↑40% (worsened in pre-eclampsia)– free fraction acidic drugs increased (eg diazepam,

phenytoin and valproate)

Physiological changes in pregnancy

Drug elimination

• Renal plasma flow doubles by the end of pregnancy (significance?)

• Enzyme induction secondary to high progesterone levels– Decrease levels of drugs eg carbamazepine– Lamotrigine decreased plasma levels by 50% in

pregnancy

Counselling women about teratogenic risk

• Doctors need to understand teratogenic risk of a particular drug and to communicate that risk

• Needs to be put in context of background risk and risk of the disease being treated (or not treated!)

Case 3

4th December 2009

Dear Dr Jones,

Please see this 29 year old Para 1 + 0 who is now 10+4 weeks gestation for booking. She has a history of difficult to control epilepsy since aged on a combination of lamotrigine 100mg bd and carbamazepine 400mg bd. Her last seizure was 6 months ago. I have commenced her this week on folic acid.

Yours sincerely

Dr Smith

Aims of treatment

Risk of the drugs

Lamotrigine

Risk of teratogenesis; see also Antiepileptics

Carbamazepine

Risk of teratogenesis including increased risk of neural tube defects; see also Antiepileptics

Risk of the drugs

Antiepileptics

Benefit of treatment outweighs risk to fetus; risk of teratogenicity greater if more than one drug used; important: see also Carbamazepine, Ethosuximide, Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Phenobarbital, Phenytoin, Pregabalin, Primidone, Rufinamide, Topiramate, Valproate, Vigabatrin, Zonisamide

What are the risks?

• Methods

128,049 pregnant women screened at delivery to identify

three groups of infants:

1. those exposed to anticonvulsant drugs

2. those not exposed to anticonvulsant drugs but with a maternal history of seizures

3. those unexposed to anticonvulsant drugs with no maternal history of seizures (control group)

Holmes et al. NEJM 2001;344:1132-38

What are the risks?Results1. The combined frequency of anticonvulsant embryopathy was higher

in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7)

2. The frequency was also higher in 93 infants exposed to two or more

anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1)

3. The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants

Holmes et al. NEJM 2001;344:1132-38

What are the risks?

Conclusion

‘A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself’

Holmes et al. NEJM 2001;344:1132-38

Management of epilepsy in pregnancy

1- Ideally management should begin before conception:• If seizure free consider stopping treatment

• Optimize control on a single agent if possible

• Dose increase likely as pregnancy progresses

• Should you prescribe folic acid supplements?

2-Discuss the possibility of a birth defect (95% likelihood of normal child)

3- No point in changing treatment if presents >8-9 weeks

4- AFP, amniocentesis and a scan around twenty weeks will likely detect any major structural defects

Drugs in pregnancy

NEJM 1998, 338; 1128-36

Conclusions (1)

• Assess pregnant women in the same way as you would if they were not pregnant

• In general treating the mother will be the best thing to ensure that the fetal outcome is successful including doing investigations (even when there is a perceived risk to the mother and/or fetus from the investigation itself)

• Always ask for senior help if you are not sure

Conclusions (2)

• Few drugs cause problems in pregnancy

• Always a balance of

• The physiological changes of pregnancy are only relevant for a few drugs

• Look for further information/report any adverse effects