6.10: Therapeutics in Special Populations: Pregnancy & Lactation

Therapeutics in Special Populations: Pregnancy & Lactation

Managing pharmacotherapy during pregnancy and lactation requires a careful balance between the therapeutic needs of the mother and the potential risks to the developing fetus or breastfed infant. In Australian pharmacy practice, clinical decisions are heavily guided by the Therapeutic Goods Administration (TGA) pregnancy safety categories, local guidelines (such as the Australian Medicines Handbook (AMH) and the Royal Women’s Hospital clinical guidelines), and database systems like LactMed.

TGA Pregnancy Safety Categories

Unlike the older United States FDA system (which has been phased out), the Australian TGA pregnancy safety categorisation system remains the standard for clinical practice. It is critical for the OPRA exam to understand that the TGA categories are not hierarchical (i.e., Category B is not automatically safer than Category C). Instead, the categories are defined by the nature of the data available and the type of risk.

The Critical Distinction of the 'B' Subcategories

A common exam trap is confusing the definitions of B1, B2, and B3. Remember:

• B1 indicates animal studies are negative (no evidence of harm).
• B2 indicates animal studies are lacking or inadequate, but human data show no harm.
• B3 indicates animal studies are positive (showed harm), but human significance remains unclear.

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Key Teratogenic Agents and Clinical Management

Pharmacists must recognise major teratogens and counsel patients appropriately:

1. Sodium Valproate (Category D): Associated with a high risk of neural tube defects (e.g., spina bifida), craniofacial abnormalities, cardiovascular defects, and long-term neurodevelopmental delays (up to 30-40% of children exposed in utero). In Australia, valproate must not be started in female children or women of childbearing potential unless other treatments are ineffective or not tolerated. If used, high-dose folic acid (5 mg daily) must be initiated at least one month before conception and continued through the first trimester.
2. Isotretinoin (Category X): Causes severe retinoid embryopathy (craniofacial, central nervous system, and cardiovascular defects). Female patients must participate in a pregnancy prevention program, use two forms of effective contraception (e.g., a subdermal implant plus a barrier method) starting one month before therapy, during, and for one month after stopping treatment. Monthly pregnancy tests are mandatory.
3. ACE Inhibitors and Angiotensin II Receptor Blockers (ARBs) (Category D): Exposure during the second and third trimesters is associated with fetal renal dysgenesis, oligohydramnios (insufficient amniotic fluid), neonatal anuria, renal failure, skull hypoplasia, and limb contractures. If a patient taking an ACE inhibitor becomes pregnant, the drug must be discontinued immediately and switched to a safer alternative.
4. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) (Category C): Use of NSAIDs (e.g., ibuprofen, diclofenac) in the third trimester (especially after 28-30 weeks) is contraindicated. It can cause premature closure of the fetal ductus arteriosus, persistent pulmonary hypertension of the newborn (PPHN), and fetal renal impairment leading to oligohydramnios.

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Management of Common Gestational Conditions

1. Hypertension in Pregnancy

Hypertension in pregnancy is defined as a systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. It is classified as gestational hypertension (onset after 20 weeks without proteinuria) or pre-eclampsia (onset after 20 weeks with proteinuria or multi-organ dysfunction).

• First-line oral agents: Labetalol, Methyldopa, and Nifedipine (controlled release).
• Aspirin therapy: For women at high risk of pre-eclampsia (e.g., previous pre-eclampsia, chronic hypertension, renal disease, autoimmune disease), low-dose aspirin (100–150 mg daily at night) is recommended starting from 12 weeks gestation until 36 to 37 weeks.
• Contraindicated agents: ACE inhibitors, ARBs, direct renin inhibitors, and spironolactone.

2. Gestational Diabetes Mellitus (GDM)

Diagnosed via a 75 g oral glucose tolerance test (OGTT) at 24-28 weeks gestation.

• First-line management: Medical nutrition therapy and moderate physical activity for 1–2 weeks.
• Pharmacological therapy: If target blood glucose levels (fasting < 5.0 mmol/L, 1-hour postprandial < 7.4 mmol/L, or 2-hour postprandial < 6.7 mmol/L) are not met, pharmacotherapy is indicated.
• Insulin is the gold standard of treatment because it does not cross the placenta. Both short-acting (e.g., aspart, lispro) and intermediate/long-acting insulins (e.g., isophane, detemir) are used.
• Metformin (Category C) may be used as an alternative or adjunct in women who refuse or cannot tolerate insulin, but patients must be counselled that it crosses the placenta.

3. Nausea and Vomiting of Pregnancy (NVP)

• First-line non-pharmacological: Small, frequent, high-carbohydrate, low-fat meals; ginger (up to 1000 mg daily); and pyridoxine (Vitamin B6) 12.5–25 mg up to three to four times daily.
• First-line pharmacological: Doxylamine (a sedating antihistamine, Category A) 12.5–25 mg at night (and optionally in the morning/afternoon if symptoms persist).
• Second-line oral agents: Metoclopramide (Category A) or Prochlorperazine (Category C).
• Refractory cases: Ondansetron (Category B1) is reserved for severe, refractory cases. Current Australian guidelines recommend avoiding ondansetron during the first trimester (up to 10 weeks gestation) due to a small, potential risk of oral clefts, although it can be used later in pregnancy if necessary.

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Drug Transfer into Breast Milk

Most drugs excreted in maternal plasma will transfer into breast milk to some degree. Pharmacists must assess the risk using the Relative Infant Dose (RID):

$\text{RID} = \frac{\text{Infant dose via breast milk (mg/kg/day)}}{\text{Maternal weight-adjusted dose (mg/kg/day)}} \times 100$

• RID < 10% is generally considered clinically safe.
• RID < 1% represents negligible transfer.

Pharmacokinetic Properties Limiting Breast Milk Transfer:

• High molecular weight: Large molecules (e.g., heparin, insulin, monoclonal antibodies like infliximab) do not cross into breast milk in significant amounts.
• High plasma protein binding: Only unbound drug transfers. Highly protein-bound drugs (e.g., warfarin, ibuprofen) remain in maternal circulation.
• Low lipid solubility: Water-soluble drugs cross cell membranes less readily.
• Poor oral bioavailability in the infant: Even if the drug transfers into milk, if the infant cannot absorb it orally (e.g., aminoglycosides, vancomycin), systemic toxicity is highly unlikely.
• Short maternal half-life: Reduces the duration of infant exposure.

Ion Trapping of Weak Bases:

Breast milk is slightly more acidic (pH ~7.2) than maternal plasma (pH ~7.4). Weakly basic drugs (e.g., beta-blockers like metoprolol, opioids like oxycodone) can become unionised in the plasma, cross into breast milk, and then become ionised in the more acidic milk. Once ionised, they cannot easily diffuse back into plasma, leading to 'ion trapping' and higher concentrations in breast milk.

Clinical Advice for Breastfeeding Mothers:

1. Timing of administration: Take oral medications immediately after a feed to allow maternal plasma levels to peak and begin declining before the next feed.
2. Avoid high-risk medications: Avoid codeine (ultra-rapid maternal metabolism can lead to toxic morphine levels in breast milk, causing neonatal respiratory depression and death) and amiodarone (contains high iodine levels, risk of infant hypothyroidism).