Study: Candidiasis drug increases risk of spontaneous abortion

An analysis by Danish investigators published in JAMA shows that taking oral fluconazole during pregnancy is associated with a significant increased risk of spontaneous abortion. Concern had been raised regarding the drug’s safety in pregnant women after case reports linked long-term, exposure to high-dose fluconazole with craniofacial and skeletal birth defects.

Data for the study came from the Medical Birth Register, which contains record of all Danish births, and the National Patient Register, which contains records of all outpatient and inpatient hospital contacts in Denmark. The cohort used by the researchers included all pregnancies ending with singleton live birth, stillbirth, spontaneous abortion, and other abortive outcomes between January 1, 1997 and December 31, 2013. Women who filled oral fluconazole prescriptions before pregnancy onset were excluded from the study.

To limit immortal time bias (a downward bias caused by an artificially low risk of early spontaneous abortions) of very early exposure to oral fluconazole in pregnancy, the specific time windows of exposure and non-exposure in the analyses of spontaneous abortion and stillbirth were gestational weeks 7 to 22 and week 7 to birth, respectively. To control for cofounders, each exposure pregnancy was matched with up to four similar unexposed control pregnancies based on maternal age, gestational age, calendar year, and propensity scores. Cases of spontaneous abortion were defined as pregnancy loss from gestational week 7 to week 22 and cases of stillbirth were defined as pregnancy loss from week 23.

The total cohort consisted of 1,405,663 pregnancies. In the 3315 pregnancies exposed to fluconazole from weeks 7 to 22, there were 147 spontaneous abortions. In the 13246 unexposed matched control pregnancies, there were 563 spontaneous abortions. Fluconazole exposure compared with nonexposure among matched control pregnancies was associated with a significantly higher risk of spontaneous abortion (HR, 1.48; 95% CI 1.23-1.77). A similar risk was observed in unmatched, unexposed pregnancies (HR, 1.49; 95% CI 1.27-1.75).

In the 5382 pregnancies exposed to fluconazole from week 7 to birth, 21 stillbirths occurred. In the 21506 unexposed matched pregnancies, 77 stillbirths occurred. There was not a significant increased risk in this subcohort; for fluconazole-exposed pregnancies vs unexposed, matched pregnancies, the HR was 1.32 (95% CI, 0.82-2.14). For fluconazole-exposed pregnancies vs unexposed, unmatched pregnancies, the HR was 1.44 (95% CI, 0.94-2.21).

In sensitivity analysis for spontaneous abortion, HRs associated with fluconazole doses of 150 mg to 300 mg (standard treatment dosages) and with doses of 350 mg to 5600 mg (higher treatment dosages used for more complicated infections) were 1.47 (95% CI, 1.22-1.77) and 1.55 (95% CI, 0.94-2.58), respectively, (P = .84). For stillbirth sensitivity analysis, the HRs associated with low and high doses were 0.99 (95% CI, 0.56-1.74) and 4.10 (95% CI, 1.89-8.90), respectively. Oral fluconazole-exposed pregnancies were at a significantly increased risk of spontaneous abortion compared with topical azole-exposed pregnancies (130/2823 vs 118/2823, respectively; HR, 1.62 [95% CI, 1.26-2.07]) and compared with pivmecillinam-exposed pregnancies (140/3018 vs 143/3018, respectively; HR, 1.44 [95% CI, 1.14-182]).

The authors mentioned a few strengths and limitations of their study. Among the noted strengths was the large, nationwide cohort of all registered births and abortions across a 17-year span. They also used filled prescriptions to determine exposure and outcome. Among the study’s limitations was the inability to capture very early spontaneous abortions since not many are recognized clinically.

Although oral fluconazole use in pregnancy was associated with an increased risk of spontaneous abortion in this analysis, the association between drug exposure and risk of stillbirth was not as significant. However, the researchers pointed out that this subcohort was quite small and the outcome relatively rare, which could signify imprecise results and indicated that more research is necessary.

What persuades parents to vaccinate for HPV?

Cancer prevention is the number one reason why parents vaccinate their children for human papillomavirus (HPV), no matter their confidence in the procedure, according to results of a survey-based study. The findings, published in Cancer Epidemiology, Biomarkers & Prevention, underscore key points for counseling about vaccination that may resonate with parents.

The conclusions are based on data from a best-worst scaling experiment that the authors devised to evaluate reasons healthcare providers commonly give parents for HPV vaccination. They surveyed 1,177 parents nationwide online in 2016 and asked them to indicate the best and worst reasons for each of 11 tasks. Conditional logistic regression was used to rank the reasons for the sample overall and by low/high vaccine confidence.

Parents said that preventing cancer was the best reason for HPV vaccination (P < 0.001), regardless of their child’s sex, age, or vaccination status. Those three variables also did not influence ranking of messages about safety (4^th place) or the vaccine being a scientific breakthrough (ranked 9^th). Parents of females were slightly more persuaded by the vaccine’s lasting benefits (ranked 2^nd) than were parents of males (ranked 3^rd).

The reasons clinicians give for vaccination that parents viewed as least persuasive were “It is a scientific breakthrough,” “I got it for my own child,” and “Your child is due” (all P < 0.001). Stratified analyses indicated small differences in how often parents with low versus high vaccination confidence endorsed messages (P < 0.001), but the two groups ranked reasons similarly overall.

For perspective on gender-based reasons that parents don’t vaccinate their children for HPV, read about a study presented at this year’s Society of Gynecologic Oncology meeting.

Does prenatal exposure to lithium increase risk of congenital malformations?

According to meta-analysis published in The Lancet Psychiatry, prenatal exposure to lithium after the first trimester significantly increases risk of major congenital malformations. Although antipsychotic drugs are commonly used to treat bipolar disease in the United States, lithium is still widely recommended as first-line treatment.

The multinational study was the largest ever to examine risk of birth defects associated with lithium. The data were taken from six study sites in Denmark, Canada, the United States, the United Kingdom, Sweden, and the Netherlands and the researchers examined congenital malformations such as heart defects and pregnancy complications in 727 lithium-exposed pregnancies. A control group of 21,397 pregnancies in mothers with a mood disorder who were not taking lithium was also included.

Pregnancies were eligible to be included in the study if they resulted in delivery of a live-born singleton between 1997 and 2015, if health-related information was available for both mother and infant and if the mother had a mood disorder (bipolar disorder or major depressive disorder) or if she had been given lithium during pregnancy. (Exposure defined as at least two doses of lithium with one dose taken any time from 1 month before conception until delivery or a single lithium dose during pregnancy when there was at least one other lithium dose within 6 months before or after date of dosage). The primary outcome measures for the study were pregnancy complications, delivery outcomes, neonatal readmission to the hospital within 28 days of birth, and congenital malformations.

The researchers found that lithium exposure was not associated with any of the predefined pregnancy complications or delivery outcomes. However, an increased risk for neonatal readmission within 28 days was seen in the lithium-exposed group compared with the reference group (pooled prevalence 27.5% [95% CI, 15.8-39.1] vs 14.3% [95% CI, 10.4-18.2]; pooled aOR 1.62, [95% CI, 1.12-2.33]). Lithium exposure during the first trimester was associated with an increased risk of major malformations, such as heart defects, neural tube defects, and malformations of the penis (pooled prevalence 7.4% [95% CI, 4.0-10.7] vs 4.3% [95% CI, 3.7-4.8]; pooled aOR 1.71 [95% CI, 1.07-2.72]). For major cardiac malformations, the difference in risk was not significant (2.1% [95% CI0.5-3.7] vs 1.6% [1.0-2.1]; pooled aOR 1.54 [95% CI 0.64-3.70]).

Based on the size and results of their meta-analysis, the researchers believe that physicians must weigh the potential for increased risk of congenital malformations when prescribing lithium to pregnant patients after the first trimester. They believe patients should communicate with their physicians to determine the best treatment plan for bipolar disorder. Antipsychotic medications may be an option, but the researchers cautioned physicians to be cognizant of pregnancy risks associated with potential treatments and to closely monitor the patient’s response to therapy.