Pharmacists focused on positive patient outcomes. AppaGrapha is a blog by pharmacists and other healthcare professionals intended for patients who desire a fresh focus on health and wellness. AppaGrapha...Discovering Trends. Inspiring Wellness.

Tuesday, February 17, 2015 10:00 pm

While Pain Management in Pregnancy Raises Safety Concerns…FDA Recommendation remains Status Quo

During pregnancy there is a heightened sense of awareness that accompanies the dramatic physical change. Comfort during pregnancy is a relative term and most women will tolerate a great deal of discomfort before they will reach out for relief in the form of medication. Pharmacists have a short list of recommendations and typically refer women to their Ob-Gyn or PCP.

Medication use in pregnancy calls
for careful consideration
(Photo credit: Magnar Kvilhaug)

While accepted professional guidance recommends caution, it is sometimes necessary to use  prescription or OTC medication during pregnancy to treat pain. Neglecting to properly treat severe and persistent pain in pregnancy can result in negative outcomes such as depression, anxiety and high blood pressure in the mother.1 Hence our quandary.

In a recent FDA Drug Safety Communication released January 9, 2015  regarding pain management in pregnant women, the FDC had this to say: 

“The U.S. Food and Drug Administration (FDA) is aware of and understands the concerns arising from recent reports questioning the safety of prescription and over-the-counter (OTC) pain medicines when used during pregnancy.  As a result, we evaluated research studies published in the medical literature and determined they are too limited to make any recommendations based on these studies at this time.  Because of this uncertainty, the use of pain medicines during pregnancy should be carefully considered.  We urge pregnant women to always discuss all medicines with their health care professionals before using them.”

• The FDA reviewed five observational studies that evaluated the risk of the spontaneous loss of a pregnancy before the 20th week and NSAID use.2-6 In the general population, the risk of miscarriage is approximately one in six pregnancies according to the FDA.
Three retrospective case-control studies2-4 of over 100,000 subjects, reported a positive association between NSAID use and miscarriage. However, the FDA’s review was critical  of the methodologic limitations of the studies’ designs and  the consequential difficulty of interpretation of findings.
The remaining two studies reviewed by the FDA included 3835 subjects. Although these two studies were conducted in a prospective manner and free of the design limitations of the retrospective studies, they delivered conflicting findings. One study identified a positive risk association between NSAID use and miscarriage5, while the other study did not identify an increased risk.

Based on these five studies, the FDA declared that they “believe that the weight of evidence is inconclusive regarding a possible connection between NSAID use and miscarriage”.
• In evaluating the possible link between opioid use and neural tube defects, the FDA reviewed two retrospective case-control studies. Over 28,000 women were interviewed in these studies regarding their use of opioids during early pregnancy. 7,8 Both studies found a higher incidence of reported use of opioids in early pregnancy by mothers of infants with neural tube defects than by mothers of infants without neural tube defects. 
Although the FDA acknowledges that both studies were well designed, there is the question of the use of maternal interviews affecting the validity of the findings.
The FDA concluded that “Further investigation of this issue is needed before we can determine whether the weight of evidence supports the presence of an increased risk of neural tube defects related to opioid exposure in early pregnancy.  The absolute risk of neural tube defects is low in the U.S. at about four to six per 10,000 live births.12, 13 Therefore, if true, a two-fold increased risk would represent a small increase in the absolute risk of neural tube defects”.
•  The FDA next examined a prospective study evaluating acetaminophen (APAP) use in pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in children. Outcomes assessed diagnosis of hyperkinetic disorder (HKD) and ADHD medication use beginning at age 5 and maternal reported ADHD-like behaviors at age 7. The study population included 64,322 pregnancies to evaluate HKD and ADHD medication use and 40,916 pregnancies to evaluate child behavior.

The study findings show that mothers who reported any acetaminophen use during pregnancy were more likely to have a child with a diagnosis of HKD, a child using ADHD medication, or report ADHD-like behavior in their children compared to women unexposed to acetaminophen in pregnancy. The association correlates positively with length of exposure.

“This study had a number of methodologic limitations that make the findings difficult to interpret. The authors did not assess overall markers of health, including health care utilization and/or medication utilization in the year prior to and during the index pregnancy, which might make the observed associations incorrect. No information was provided on the acetaminophen strength and number of dosage units taken; therefore, no conclusions can be made regarding a dose-response relationship. The authors also did not assess clinical ADHD diagnoses.  Findings from two other observational studies of neurodevelopment in children exposed to acetaminophen during gestation are conflicting; however, neither of these studies specifically assessed ADHD as an outcome.14, 15

Due to these methodologic limitations and their negative impact on interpreting the findings, the FDA is taking the position that “the weight of evidence is inconclusive regarding a possible connection between acetaminophen use in pregnancy and ADHD in children”.

So until further studies succeed in providing definitive findings on the associated risks of pain medication use during pregnancy, we shall continue to carefully weigh the benefits and risks and proceed with caution when making recommendations. It is a delicate balance.

1. Babb M, Koren G, Einarson A. Treating pain during pregnancy. Can Fam Physician 2010;56:25, 27.
2. Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 2011;183:1713-20.
3. Nielsen GL, Sørensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ 2001;322:266-70.
4. Nielsen GL, Skriver MV, Pedersen L, Sørensen HT. Danish group reanalyses miscarriage in NSAID users. BMJ 2004;328:109.
5. Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 2003;327:368.
6. Edwards DR, Aldridge T, Baird DD, Funk MJ, Savitz DA, Hartmann KE. Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion. Obstet Gynecol 2012;120:113-22.
7. Yazdy MM1, Mitchell AA, Tinker SC, Parker SE, Werler MM. Periconceptional use of opioids and the risk of neural tube defects. Obstet Gynecol 2013;122:838-44.
8. Broussard CS, Rasmussen SA, Reefhuis J, Friedman JM, Jann MW, Riehle-Colarusso T, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol. 2011;204:314.e1-11.
9. Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 2014;168:313-20.
10. Werler MM, Mitchell AA, Hernandez-Diaz S, Honein MA. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol 2005;193(3 Pt 1):771-7.
11. Bateman BT, Hernandez-Diaz S, Rathmell JP, Seeger JD, Doherty MS, Fischer MA, et al.  Patterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the United States.  Anesthesiology 2014;120:1216-24.
12. Wallingford JB1, Niswander LA, Shaw GM, Finnell RH. The continuing challenge of understanding, preventing, and treating neural tube defects. Science 2013;339:1222002.
13. Parker SE, Mai CT, Canfield MA, Rickard R, Wang Y, Meyer RE, et al. Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004-2006. Birth Defects Res A Clin Mol Teratol 2010;88:1008-16.
14. Streissguth AP, Treder RP, Barr HM, Shepard TH, Bleyer WA, Sampson PD, et al. Aspirin and acetaminophen use by pregnant women and subsequent child IQ and attention decrements. Teratology 1987;35:211-9.
15. Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 2013;42:1702-13.