Reproductive health issues: Evidence

• Overview
• Breastfeeding
• Medication and conception

Overview

• All four guidelines (BAP, CANMAT, NICE, and SIGN) concur that bipolar disorder has significant implications for reproductive health issues, particularly in relation to the teratogenetic risk caused by the medications being taken for the disorder.
• The figures published in the BAP guideline about the ‘risk of major congenital malformations’ differ slightly from those published in the SIGN guideline (BAP: the risk ‘in the general population is surprisingly high at 2% to 4%’; SIGN: ‘The overall risk of major fetal malformation in any pregnancy of approximately 2% is increased two or three-fold in women taking a single anticonvulsant drug’). The CANMAT and NICE guidelines do not give these statistics.
• Most significantly, the BAP guideline details that lithium and valproate can be continued during pregnancy, although preferably in slow-release formulations. The CANMAT guideline also argues that mothers can continue to take lithium as a mood-stabilizer, instead of other anticonvulsants. SIGN concurs with both guidelines in relation to lithium, yet mentions that ‘Valproate should be avoided as a mood stabilizer in pregnancy.’ NICE gives different advice: ‘Do not routinely prescribe for pregnant women: valproate… [or] lithium’, unless the woman experiences severe mania. In this case, ECT and lithium are preferred over valproate.
• SIGN is the only guideline which mentions that: ‘Benzodiazepines should be avoided in the first trimester of pregnancy’.
• BAP and NICE agree that ECT can be ‘safely administered to pregnant women’. SIGN and CANMAT do not mention ECT.

Breastfeeding:

NICE¹

Breastfeeding and care of the infant:
If a woman is taking psychotropic medication:

• advise on the risks and benefits of breastfeeding.
• advise not to breastfeed if taking lithium, benzodiazepines and lamotrigine and offer an alternative prophylactic agent that can be used when breastfeeding (normally an antipsychotic, but not clozapine).
• prescribe an SSRI if an antidepressant is used (but not fluoxetine or citalopram).

Monitor babies whose mothers took psychotropic drugs during pregnancy in the first few weeks for adverse drug effects, drug toxicity or withdrawal (for example, floppy baby syndrome, irritability, constant crying, shivering, tremor, restlessness, increased tone, feeding and sleeping difficulties and rarely seizures). These may be a serotonergic toxicity syndrome, rather than a withdrawal reaction.

CANMAT²

Divalproex and carbamazepine are considered compatible with breastfeeding, with monitoring of liver enzymes, CBC, and platelets to rule out hepatoxicity and haematological toxicity, as necessary. Benzodiazepines, SSRIs, conventional antipsychotics, clozapine and lamotrigine are classified by the AAP as drugs for which the effect on nursing infants is unknown but may be of concern (American Academy of Pediatrics, 2001³ ). There are little or no data on the use of topiramate or gabapentin, and, as these agents are not well proven for the treatment of bipolar disorder, they are not recommended during breastfeeding. There are little data on atypical antipsychotics and the manufacturers do not recommend their use during breastfeeding (Gentile, 2004⁴ ).

SIGN⁵

Similar guidance to NICE.

BAP⁶

Similar guidance to NICE.

Medication and conception:

Unlike CANMAT, NICE, and SIGN, BAP does not mention any issues relating to bipolar disorder and conception:

NICE¹

• Women with bipolar disorder who are considering pregnancy should normally be advised to stop taking valproate, carbamazepine, lithium and lamotrigine, and alternative prophylactic drugs (such as an antipsychotic) should be considered.
• Women taking antipsychotics who are planning a pregnancy should be advised that the raised prolactin levels associated with some antipsychotics reduce the chances of conception. If prolactin levels are raised, an alternative drug should be considered.
• If a woman who needs antimanic medication plans to become pregnant, a low-dose typical or atypical antipsychotic should be considered, because they are of least known risk.

If a woman taking lithium plans to become pregnant, the following options should be considered:

• if the patient is well and not at high risk of relapse – gradually stopping lithium
• if the patient is not well or is at high risk of relapse: switching gradually to an antipsychotic, or stopping lithium and restarting it in the second trimester if the woman is not planning to breastfeed and her symptoms have responded better to lithium than to other drugs in the past, or continuing with lithium, after full discussion of the risks, while trying to conceive and throughout the pregnancy, if manic episodes have complicated the woman’s previous pregnancies, and her symptoms have responded well to lithium.

SIGN⁵

Fertility

No evidence was identified linking bipolar affective disorder and the medications used with an effect on male fertility. Many psychotropic drugs interfere with sexual drive and function, so that there may be an indirect effect on fertility. Dopamine blocking drugs, such as many antipsychotic as well as antidepressant drugs reduce female fertility by increasing prolactin levels and inhibiting menstrual periods.

Contraception

Combined oral contraception – Women taking drugs which induce hepatic enzymes (e.g. carbamazepine) are at increased risk of breakthrough bleeding and contraceptive failure (level 2 evidence), estimated at up to seven pregnancies per 100 woman years (level 4 evidence).

Progestogen-only contraception: Hepatic enzyme-inducing drugs increase progestogen metabolism so that the efficacy of the progestogen-only oral contraceptive cannot be guaranteed. Medroxyprogesterone (Depo-Provera) can be used with enzyme-inducing drugs but the efficacy may be reduced after ten weeks. Implants of progestogen are not effective if given with enzyme-inducing drugs (level 4 evidence).

CANMAT²

Similar guidance to NICE.

References

1. National Institute for Clinical Excellence. The management of bipolar disorder in adults, children and adolescents, in primary and secondary care. National Institute for Clinical Excellence. 2006; July
2. Yatham LN et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disorders. 2005; 7 (3): 5-69.
3. Not specified. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001 Sep; 108 (3): 776-89.
4. Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and lactation. Ann Pharmacother. 2004 Jul-Aug; 38 (7-8): 1265-71.
5. Scottish Intercollegiate Guidelines Network. Bipolar affective disorder: A national clinical guideline. Scottish Intercollegiate Guidelines Network. 2005; May
6. Goodwin GM. Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology. 2003; 17 (2): 149-173.