Prescription medicine use in pregnancy

Prescription medication use during pregnancy has risen over recent decades in many countries, therefore addressing the lack of robust pregnancy safety data for many medications is essential. Post-marketing studies that use routinely collected healthcare records provide an opportunity to strengthen the evidence base.

This thesis investigates the use and safety of prescription medicines during pregnancy in Aotearoa New Zealand. It includes a specific focus on antidepressants, which are increasingly prescribed in the population, yet have an uncertain safety profile during pregnancy.

The specific aims were to:

1. Describe trends in prescription medication use during pregnancy in New Zealand, with specific consideration of several medicines known to cause foetal harm,
2. Investigate the patterns of use of selective serotonin reuptake inhibitor (SSRI) and serotonin noradrenaline reuptake inhibitor (SNRI) antidepressants during pregnancy and associated adverse foetal and maternal outcomes (including outcomes for mother and child when established SSRI/SNRI use is discontinued during pregnancy), and
3. Establish the method of linking data in the National Maternity Collection with other national collections to carry out pharmacoepidemiological research involving pregnant women, and to describe the strengths and limitations of the method.

The New Zealand Pregnancy Cohort (NZPC) was generated by linking pregnancy records identified in national maternity, hospitalisation, laboratory, and mortality data. A Baby Cohort was established by linking infant records to NZPC pregnancies.

Community-based dispensing records were linked with NZPC members to determine the proportion of pregnancies exposed to prescription medications, including all prescribed medications, those known to cause foetal harm (Category D [increased incidence of foetal malformations or irreversible damage] and Category X [high risk of permanent foetal damage]), and antidepressants. Trends were analysed over calendar time (2005–2015), in different time periods before and during pregnancy, and by maternal characteristics.

With a focus on SSRIs and SNRIs, the study examined associations between antidepressant use and several adverse outcomes, including congenital malformations, persistent pulmonary hypertension of the newborn (PPHN), small for gestational age, preterm delivery, and postpartum haemorrhage.

The NZPC included 941,468 pregnancies with a last menstrual period between 1 January 2005 and 15 March 2015. Approximately two-thirds of the pregnancies ended in a delivery, linkable with 632,090 infant records which formed the Baby Cohort.

The proportion of pregnancies exposed to at least one prescription medication (excluding supplements) increased from 38.5% in 2005 to 67.2% in 2015. Commonly dispensed medications included antibacterials, analgesics, and antinausea/vertigo agents. Category D medication exposure increased from 2.9% to a high of 5.4% in 2011, then declined slightly. Throughout the study period, Category D medication use decreased in the nine months before pregnancy, and continued to decline through pregnancy; with nicotine, paroxetine, and doxycycline being the most commonly used. Also declining prior to pregnancy, Category X medication use during pregnancy was largely isolated to the first trimester, and predominantly consisted of isotretinoin and misoprostol; excluding misoprostol, 0.035% of pregnancies were exposed.

Antidepressant use remained stable in the nine months prior to pregnancy but fell substantially in Trimester 1 and continued to fall during pregnancy, and rebounded in the postpartum period. Use during pregnancy increased from 3.1% to 4.9% over the period 2005 to 2014, with citalopram and fluoxetine (both SSRIs) the most commonly dispensed antidepressants.

SSRI exposure during Trimester 1 was associated with major congenital malformations, particularly cardiac malformations. SSRI use in later pregnancy was associated with PPHN in term infants, preterm delivery, and postpartum haemorrhage. Venlafaxine, the only SNRI funded in New Zealand, was associated with major malformations, clubfoot, PPHN, preterm delivery, and postpartum haemorrhage.

Prescription medication use during pregnancy has increased in New Zealand. The NZPC has proven to be a valuable tool for researching medication use and safety in pregnancy despite the recognised limitations of studies undertaken with routinely collected healthcare data. Future studies should consider validating diagnoses recorded in the National Collections, and undertaking international collaborations to improve statistical power for studies investigating uncommon exposures and outcomes.