Response to letter ‘challenges in assessing the use of antibiotics during pregnancy and risk of congenital malformations’

1.

We thank Cao et al. for their comments on our study titled ‘Use of antibiotics during pregnancy and the risk of major congenital malformations: A population‐based cohort study’.

Many guidelines consider use of doxycycline to be contraindicated during pregnancy or to be a relative contraindication in pregnant women if other agents are available and appropriate for use.1, 2, 3, 4, 5 Since physicians are cognizant of the potential teratogen effects of this antibiotic, the prevalence of doxycycline use was low in our study and in other studies conducted in Quebec by our group earlier.6, 7, 8 However, a supplemental analysis restricting doxycycline exposures during the critical time of cardiac development (first 8 weeks) would have been helpful to reinforce causality.

We acknowledged in our manuscript that multiple testing could potentially explain some of our findings and some of our results should be interpreted with caution since some analyses were underpowered and residual confounding could not be ruled out for many reasons. For example, when the number of events per confounders is small, it may be difficult to fully control for confounding in the analysis.

However, there are important considerations that should be taken into account when interpreting our findings regarding the use of doxycycline in early pregnancy.

First, our results are consistent with a previous study that showed a 2‐fold increased risk of heart defects though it did not reach statistical significance because of low statistical power.9

Second, we recently demonstrated that doxycycline versus penicillin was associated with 3.27‐fold increased risk of spontaneous abortion (a class effect for tetracycline) which is a proxy of severe birth defects.10 This finding is important given that it may explain the small number of birth defects associated with the use of doxycycline reported in previous studies as well.9, 11

Third, our findings support the teratogenicity of doxycycline observed in animal studies which lead many guidelines to contraindicate the use of doxycycline in early pregnancy.12

Fourth, we are aware that residual confounding may explain some of the association observed in our study and this limitation was acknowledged in the original paper as well. As such, we performed an E‐value analysis to assess the extent of residual confounding that would be required to negate the association observed between doxycycline and the risk of ventricular/atrial septal defect in our study.13 The E‐values for the odds ratio and lower confidence bound for the risk of ventricular/atrial septal defect were 5.83 and 2.52 respectively, indicating that substantial unmeasured confounding would be needed to reduce the observed association.

In conclusion, physicians should always prioritize prescriptions of safe antibiotics for the treatment of maternal infection in early pregnancy after weighing the risk and benefits for both mother and fetus even though the risk of cardiac malformations remains small.

COMPETING INTERESTS

The authors have no conflict interest to declare.