Discussion:
Currently, not enough data exists on the safety of many medications in
pregnancy [11]. This lack of safety information in practice leads to
patients having access to only a limited number of medications when they
get pregnant, which are often old, less safe, and less effective
[5].
Unfortunately, information on whether a medication is safe to use in
pregnancy is difficult to come by and is mostly obtained from following
patients who unexpectedly get pregnant while taking a certain
medication, thus already exposing the fetus to the medication [12].
These cases are not easy to find, which is why the group of patients
counseled and followed by our FRAME program provides us with invaluable
knowledge on what happens when pregnant patients are exposed to
medications.
The US Food and Drug Administration (FDA) and the National Institutes of
Health (NIH) released new requirements to encourage inclusion of female
participants in clinical research [13,14]. Despite these guidelines,
the enrollment of pregnant populations and women of reproductive age in
clinical trials continues to be poor, leading to a lack of accurate
pregnancy-specific prescribing information. [4,5,6,1,2,15,16,17].
Even if a medication is believed to not represent a risk for the
developing fetus, many questions on the pharmacology of drugs in
pregnancy remain, which can affect drug response and risk for toxicity.
During pregnancy, a variety of physiological changes take place which
can impact drug metabolism [18] and can lead to drug serum
concentrations outside of their therapeutic windows. In these instances,
utilizing standard dosing regimens (which were defined in non-pregnant
people) can produce unexpected therapeutic failures or toxicities.
Various studies show that PTSD is prevalent in pregnancy [6] and
that maternal PTSD is associated with negative birth or child outcomes,
like low birthweight, preterm birth, and less mother-infant bonding
[19]. Well controlled studies in non-pregnant subjects have reported
that Prazosin results in significant improvement in the number of PTSD
symptoms, including PTSD-associated nightmares [ 20,21, 22]. Despite
this finding, there are still very few and adequate studies that exist
for the safety of Prazosin use in pregnancy, and virtually no data
available on safety of exposure to this drug in the first trimester.
A systematic review conducted by Davidson et al. (2021) [8] looked
at pregnancy Prazosin exposures, but could only locate one
randomized-control trial (conducted in the third trimester of pregnancy)
and 5 cohort studies studying Prazosin use during late pregnancy and
lactation. As the indication for use of Prazosin was mostly for maternal
hypertension, the role of the underlying condition should be considered
in adverse outcomes. The authors of this review noted that Prazosin may
have a greater bioavailability and slower elimination in pregnant
patients and may possibly lead to hypotension when given to patients who
are normotensive and taking Prazosin for PTSD, which may cause fetal
effects. This systematic review failed to find any reports for the use
of Prazosin for the indication of PTSD, and provided few reports with
regards to Prazosin’s use for other indications in the perinatal time
period. The authors concluded that it is best to avoid this drug in
pregnant patients due to the lack of safety information[8].
One of the studies cited in the Davidson review [8] was a 1983 study
that looked at Prazosin use in 8 sujects in the last trimester of
pregnancy [23]. This study found that Prazosin was effective for
blood pressure control and outcomes suggested safety when used in the
last trimester in these women. These data, although older, is still been
used for reference when looking at Prazosin safety. The fact that a
study with a small sample size conducted in 1983 is still one of the
only studies that can be referred to when looking at Prazosin exposure
during pregnancy illustrates the lack of data that currently exists.
However, it is important to highlight that there are no data on the
safety (or effectiveness) of Prazosin use in the first trimester of
pregnancy.
The data presented in our study is the first case series to evaluate
this topic. We did not observe any malformations in the newborns, and
the babies that required brief NICU admission were reported to be doing
well according to mothers who were contacted at follow up, with mothers
reporting normal development of these babies and the NICU admissions
being required as a precaution. There was no indication that the
neonatal complications were related to Prazosin exposure, or that the
rate of NICU admissions differed from that of the general population.
Overall, birthweights in the population studied were within normal
ranges for gestational age, and none were classified as low birthweight
(i.e. <2500g). With regards to additional fetal outcomes, the
proportion of miscarriages (18.2%) did not exceed expected rates based
on normal population proportions [24].
It should be acknowledged that PTSD itself may lead to an elevated risk
of poor outcomes. Ferri at al. (2007) found that PTSD during pregnancy
was significantly associated with low birth weight [25]. A study
conducted by Seng et al (2011) study also found that maternal PTSD was
significantly associated with obstetrical complications such as shorter
gestation and lower birthweight [26]. This is something to keep in
mind with regards to the adverse outcomes reported in our study, given
that there may be reason to expect elevated risk for reasons other than
Prazosin exposure.
Limitations of the present study include a small sample size, thus
limiting analysis to descriptive findings, and the absence of a
comparison group of women not exposed to Prazosin during pregnancy.
Another limitation is the use of self-reported data, collected via phone
call questionnaires, which could be subject to recall bias and social
desirability bias. The above could limit the ability to make any
conclusions regarding safety based on this one small case series. This
study provides preliminary data on the effects of use of Prazosin for
the treatment of PTSD during pregnancy; however, further research is
definitely needed. Future studies of the use of this medication for this
indication in pregnant women are warranted given the prevalence of this
disorder in this population. With larger datasets, accompanied by
statistical analyses and replicated studies, it may be possible to make
more solid safety conclusions. If possible, this medication should still
be avoided during pregnancy, due to its unknown safety profile. However,
if a pregnant woman is exposed to this medication, the lack of adverse
effects or pregnancy complications in this study is reassuring.
Conclusion: There is a lack of current research evidence
regarding drug safety for pregnant women with PTSD. Our study addresses
this lack of information by providing incremental data regarding first
trimester exposure in a more recent time period to inform the literature
and to guide future studies. Although a small sample, this study
contributes observational data on the use of Prazosin for PTSD during
pregnancy and represents an important starting point for amassing more
data to improve the care of pregnant women experiencing this condition.
Furthermore, our results also showed that there were no major congenital
malformations in the cohort that would have raised concern with regards
to this drug’s safety.
1. Heyrana K, Byers HM, Stratton P. Increasing the Participation of
Pregnant Women in Clinical Trials. JAMA. 2018;320(20):2077–2078.
doi:10.1001/jama.2018.1716
2. Scaffidi, J, Mol, BW, Keelan, JA. The pregnant women as a drug
orphan: a global survey of registered clinical trials of pharmacological
interventions in pregnancy. BJOG 2017; 124: 132– 140.
3. Ward R. M. (2001). Difficulties in the study of adverse fetal and
neonatal effects of drug therapy during pregnancy. Seminars in
perinatology, 25(3), 191–195. https://doi.org/10.1053/sper.2001.24567
4. Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, Koren G.
Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review.
PLoS Med. 2016 Nov1;13(11):e1002160. doi: 10.1371/journal.pmed.1002160.
PMID: 27802281; PMCID: PMC5089741.
5. Sun D, Hutson JR, Garcia-Bournissen F. Drug therapy during pregnancy.
Br J Clin Pharmacol. 2020 Nov 17. doi: 10.1111/bcp.14649.
6. Khoramroudi R. (2018). The prevalence of posttraumatic stress
disorder during pregnancy and postpartum period. Journal of family
medicine and primary care, 7(1), 220–223.
https://doi.org/10.4103/jfmpc.jfmpc_272_17
7. Hudson, S. M., Whiteside, T. E., Lorenz, R. A., & Wargo, K. A.
(2012). Prazosin for the treatment of nightmares related to
posttraumatic stress disorder: a review of the literature. The primary
care companion for CNS disorders, 14(2), PCC.11r01222.
https://doi.org/10.4088/PCC.11r01222
8. Davidson, A. D., Bhat, A., Chu, F., Rice, J. N., Nduom, N. A., &
Cowley, D. S. (2021). A systematic review of the use of prazosin in
pregnancy and lactation. General Hospital Psychiatry , 71 ,
134–136. https://doi.org/10.1016/j.genhosppsych.2021.03.012
9. Heyrana K, Byers HM, Stratton P. Increasing the Participation of
Pregnant Women in Clinical Trials. JAMA. 2018;320(20):2077–2078.
doi:10.1001/jama.2018.17716ing
10. Kramer, M. S., Platt, R. W., Wen, S. W., Joseph, K. S., Allen, A.,
Abrahamowicz, M., Blondel, B., Bréart, G., & Fetal/Infant Health Study
Group of the Canadian Perinatal Surveillance System (2001). A new and
improved population-based Canadian reference for birth weight for
gestational age. Pediatrics, 108(2), E35.
https://doi.org/10.1542/peds.108.2.e35
11. David, A. L., Ahmadzia, H., Ashcroft, R., Bucci-Rechtweg, C.,
Spencer, R. N., & Thornton, S. (2022). Improving Development of Drug
Treatments for Pregnant Women and the Fetus. Therapeutic innovation &
regulatory science, 1–15. Advance online publication.
https://doi.org/10.1007/s43441-022-00433-w
12. - Dathe, K., & Schaefer, C. (2019). The Use of Medication in
Pregnancy. Deutsches Arzteblatt international , 116 (46),
783–790. https://doi.org/10.3238/arztebl.2019.0783
13. Heyrana K, Byers HM, Stratton P. Increasing the Participation of
Pregnant Women in Clinical Trials. JAMA. 2018;320(20):2077–2078.
doi:10.1001/jama.2018.17716
14. Food and Drug Administration Draft guidance, pregnant women:
scientific and ethical considerations for inclusion in clinical trials.
Federal Register. 2018.
https://www.govinfo.gov/content/pkg/FR-2018-04-09/pdf/2018-07151.pdf
15. Lippman A. The inclusion of women in clinical trials: are we asking
the right questions?. Women and Health Protection 2006.
http://www.whp-apsf.ca/pdf/clinicalTrialsEN.pdf.
16. Pauker, S. From protection to access: Women’s participation in
clinical trials-conflict, controversy and change. Harvard University’s
DASH repository. 2002.
http://nrs.harvard.edu/urn-3:HUL.InstRepos:8889449.
17. Mastroianni AC, Faden R, Federman S. Women and health research:
ethical and legal issues of including women in clinical
studies.Washington DC: Institute of Medicine, National Academy Press;
1994.
18. 11. Pinheiro, E. A., & Stika, C. S. (2020). Drugs in pregnancy:
Pharmacologic and physiologic changes that affect clinical care.
Seminars in perinatology, 44(3), 151221.
https://doi.org/10.1016/j.semperi.2020.151221
19. Cook, N., Ayers, S., & Horsch, A. (2018). Maternal posttraumatic
stress disorder during the perinatal period and child outcomes: A
systematic review. Journal of affective disorders , 225 ,
18–31. https://doi.org/10.1016/j.jad.2017.07.045
20. Forcada-Guex, M., Borghini, A., Pierrehumbert, B., Ansermet, F.,
Muller-Nix, C., 2011. Prematurity, maternal posttraumatic stress and
consequences on the mother-infant relationship. Early Hum. Dev. 87,
21–26.
21. Raskind M.A., Peskind E.R., Hoff D.J. A parallel group placebo
controlled study of prazosin for trauma nightmares and sleep disturbance
in combat veterans with post-traumatic stress disorder. Biol Psychiatry.
2007;61(8):928–934.
22. Taylor F.B., Martin P., Thompson C. Prazosin effects on objective
sleep measures and clinical symptoms in civilian trauma posttraumatic
stress disorder: a placebo-controlled study. Biol Psychiatry.
2008;63(6):629–632.
23. Rubin, P. C., Butters, L., Low, R. A., & Reid, J. L. (1983).
Clinical pharmacological studies with prazosin during pregnancy
complicated by hypertension. British Journal of Clinical
Pharmacology , 16 (5), 543–547.
https://doi.org/10.1111/j.1365-2125.1983.tb02213.x
24 . Dugas C, Slane VH. Miscarriage. [Updated 2022 Jun 27]. In:
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;
2022 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK532992/24- Schulman J, Braun D,
Lee HC, et al.. Association between neonatal intensive care unit
admission rates and illness acuity. JAMA Pediatr .
2018;172(1):17-23. doi: 10.1001/jamapediatrics.2017.3913
25. Ferri, C.P., Mitsuhiro, S.S., Barros, M.C., Chalem, E., Guinsburg,
R., Patel, V., Prince, M., Laranjeira, R., 2007. The impact of maternal
experience of violence and common mental disorders on neonatal outcomes:
a survey of adolescent mothers in Sao Paulo, Brazil. BMC Public Health
7, 209.
26. Seng, J.S., Low, L.K., Sperlich, M., Ronis, D.L., Liberzon, I.,
2011. Post-traumatic stressdisorder, child abuse history, birthweight
and gestational age: a prospective cohortstudy. BJOG: Int. J. Obstet.
Gynaecol. 118, 1329–1339.