July 2017 FAQs

Is pregabalin effective for the treatment of sciatica pain?

Background

Sciatica, also known as lumbosacral radicular syndrome, ischias, nerve root pain, and nerve root entrapment, is a pain that radiates from the lumbar region downward along the course of the sciatic nerve.^1,2 The sciatic nerve begins at the lumbosacral root through the joining of the fourth and fifth lumbar nerve roots and first 2 sacral nerve roots and extends down the dorsum of the buttock and leg. Sciatica pain is usually unilateral, is primarily worse in the leg, and may be accompanied by numbness and paresthesia. There are various causes of sciatica, the most common being disk herniation; other causes include spondylolisthesis, foraminal stenosis, synovial cysts, piriformis syndrome, gluteal injection-site trauma, obstetrical sciatic compression, and pelvic floor tumors. For about 1 in 3 patients, sciatica pain self-resolves within 2 weeks of onset; pain self-resolves in 75% of patients within 3 months.

Treatment guidelines that focus on the management of sciatica pain are currently lacking. Per 2017 recommendations from the American College of Physicians (ACP), clinicians should recommend non-pharmacologic treatment for acute low back pain with or without sciatica.³ If pharmacologic therapy is initiated, the agents of choice are nonsteroidal anti-inflammatory drugs (NSAIDs) or skeletal muscle relaxants. A 2016 guideline on low back pain from the British National Institute of Health and Care Excellence (NICE) specifies that their treatment recommendations for neuropathic pain should be followed for sciatica pain.⁴ For all types of neuropathic pain (except trigeminal neuralgia), NICE recommends the following initial treatment options: amitriptyline, duloxetine, gabapentin, and pregabalin.⁵

Pregabalin has an unknown mechanism of action but is thought to inhibit excitatory neurotransmitter release by binding to the alpha₂-delta subunit of voltage-gated calcium channels within the central nervous system and modulating calcium influx at the nerve terminals.⁶ Although pregabalin does not bind to gamma-aminobutyric acid (GABA) receptors, it may increase the density of GABA transporter protein and increase the rate of functional GABA transport. Pregabalin is approved for the treatment of various types of neuropathic pain and its role in sciatica is of clinical interest.

The use of pregabalin in the treatment of sciatica pain is not well-established. This article summarizes the currently available literature with this agent.

Literature Review

In 2010, Baron et al published the first randomized, placebo-controlled trial of pregabalin in patients with neuropathic pain associated with chronic lumbosacral radiculopathy.⁷ The results of this study were inconclusive. A few meta-analyses and systematic reviews have attempted to synthesize the minimal evidence with pregabalin for sciatica pain.^8-10 None of these analyses provided compelling enough conclusions to guide clinical treatment decisions.

Since pregabalin is commonly used to treat neuropathic pain conditions and more data on the optimal treatment of sciatica is needed, Mathieson et al conducted a larger randomized, placebo-controlled, double-blind study with pregabalin for acute and chronic sciatica.¹¹ The results of this trial were published in the New England Journal of Medicine in March 2017. Australian patients with moderate-to-severe sciatica were eligible for trial enrollment from September 2013 to March 2015. Patients had to have radiating pain into one leg below the knee, nerve root/spinal nerve involvement according to study-defined criteria, leg pain that was severe enough to cause at least moderate pain or interference with normal daily activities, and pain present for at least 1 week up to 1 year. Major exclusion criteria were pain associated with serious spinal pathology, a planned spinal surgery or procedure, severe depression, or current use of medications for neuropathic pain, anticonvulsants, antidepressants, or sedatives.

Patients were randomized to placebo or pregabalin, which was titrated weekly until week 8 from the initial dose of 75 mg twice daily to a maximum of 300 mg twice daily as tolerated and if needed for pain management.¹¹ In addition to the study medication, patients could receive additional medical care including physical therapy and other analgesic medications. To assess the study’s primary outcome (average leg pain intensity score over a period of 24 hours), patients rated their pain from 0 to 10, with 10 being the worst pain possible, at weeks 2, 4, 8, 12, 26, and 52. Extent of disability was measured weekly using the Roland Disability Questionnaire for Sciatica. Back pain intensity, global perceived effect, quality of life, workplace absenteeism, and health care utilization were other secondary outcomes.

During the 18-month enrollment period, a total of 209 patients (108 pregabalin and 101 placebo) were randomized from 47 sites.¹¹ There were more women in the pregabalin group than the placebo group (62.3% vs 48.5%) but the mean age was similar in both groups (pregabalin 52.4 years, placebo 55.2 years). The S1 and L5 vertebrae were most commonly associated with leg pain in both groups. More than 80% of patients in both groups had dermatomal pain, about 30% had motor deficits, about 35% had neurologic deficits, and about 44% had sensory deficits. At baseline, the mean duration of leg pain was about 63 days in both groups, leg pain intensity was about 6 out of 10, back pain intensity was about 5 out of 10, and disability scores were in the moderate range. For the primary outcome at week 8, there was no significant difference in leg pain intensity between the study arms (adjusted mean difference, 0.5; 95% confidence interval, -0.2 to 1.2; p=0.19). At week 52, there were no statistically significant differences between arms for leg pain intensity, extent of disability, back pain intensity, global perceived effect or quality of life scores (all p>0.05)). Adherence to study drug was about 74% and patient-reported treatment satisfaction was similar between groups. Adverse events were more common with pregabalin than placebo (64.2% vs 42.6%; p=0.002). The most common adverse events were dizziness (39.6% vs 12.9%), dorsalgia (17.9% vs 9.9%), sweating (8.5% vs 7.9%), and malaise (8.5% vs 3%).  

The trial authors concluded that the use of pregabalin for 8 weeks did not relieve sciatica pain compared to placebo but resulted in significantly more adverse events.¹¹ Pregabalin was also no better than placebo after 52 weeks. Several limitations should be considered when interpreting these results. The predetermined sample size was based on a clinically important difference in leg pain intensity of 1.5 points; however, the observed difference was 0.5 points. Whether the nonsignificant primary outcome results were due to a true lack of efficacy of pregabalin or to a lack of power is unclear, although the fact that 72.5% of patients in the pregabalin group used additional analgesic medications supports the conclusion of lack of efficacy. Another limitation is that the duration of pain at baseline was within the 3-month period in which patients often experience spontaneous symptom resolution. Therefore, improvement in pain intensity in the placebo group may have been greater than expected due to natural disease progression.

Gabapentin, which is structurally similar to pregabalin, has also been used in patients with sciatica or similar types of pain.^12-17 Most of the evidence with gabapentin is observational in nature, but an 8-week randomized, placebo-controlled trial in 50 patients with chronic radiculopathy involving the sciatic nerve has been published.¹² The mean duration of symptoms was about 68 months in both groups and all patients had failed prior NSAID therapy. Gabapentin was given at a dose of 900 to 3600 mg per day, in 3 divided doses. Assessments of gabapentin efficacy included: pain location, severity of pain at rest, limitation of spinal flexion, degree of straight leg raising, stretch reflexes, sensory changes, and muscle strength. After 8 weeks of treatment, improvement in all of these parameters was significantly greater with gabapentin than placebo (all p<0.001), except for muscle strength and stretch reflexes. The 8-week results for pain at rest showed no pain to minimal pain in the gabapentin group vs mild-moderate pain in the placebo group. However, it is unclear whether this pain severity scale is validated and the study does not appear to be blinded so there is a potential for bias in these results. Other limitations include a small sample size, minimal safety results, no assessment of quality of life, and limited external validity of the longstanding disease in the study population. Overall, the results of this study do not support the use of gabapentin for the treatment of sciatica pain and these results are not compelling enough to extrapolate to pregabalin.

Conclusion

Evidence to support the use of pregabalin for sciatica is limited. Only 2 randomized clinical trials have evaluated pregabalin in this setting.^7,11 In the most recent randomized, placebo-controlled trial, pregabalin did not produce clinically or statistically significant differences in sciatica pain intensity compared to placebo, but did increase adverse events.¹¹ Although pregabalin is endorsed by some authors and clinical practice guidelines as a treatment option for sciatica pain, currently available literature does not support its use for acute or chronic sciatica. In accordance with recent guidelines, sciatica pain should be managed with nonpharmacologic methods and/or non-opioid analgesics such as NSAIDs.^1,3 If these strategies do not yield adequate pain relief, more invasive, evidence-based interventions such as epidural injections and spinal decompression should be implemented, rather than using oral medications with insufficient evidence of efficacy and safety.^1,9

References

1. Ropper AH, Zafonte RD. Sciatica. N Engl J Med. 2015;372(13):1240-1248.
2. Koes BW, van Tulder MW, Peul WC. Diagnosis and treatment of sciatica. BMJ. 2007;334(7607):1313-1317.
3. Qaseem A, Wilt TJ, McLean RM, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166(7):514-530.
4. National Institute for Health and Care Excellence (NICE). Low back pain and sciatica in over 16s: assessment and management. NICE guideline [NG59]. Published date: November 2016. https://www.nice.org.uk/guidance/ng59. Accessed June 14, 2017.
5. National Institute for Health and Care Excellence (NICE). Neuropathic pain in adults: pharmacological management in non-specialist settings. NICE Guideline [CG173]. Published date: November 2013. Last updated: February 2017. https://www.nice.org.uk/guidance/cg173. Accessed June 14, 2017.
6. Lyrica [package insert]. New York, NY: Pfizer; 2016.
7. Baron R, Freynhagen R, Tölle TR, et al. The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy. Pain. 2010;150(3):420-427.
8. Pinto RZ, Maher CG, Ferreira ML, et al. Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis. BMJ. 2012;344:e497.
9. Lewis RA, Williams NH, Sutton AJ, et al. Comparative clinical effectiveness of management strategies for sciatica: systematic review and network meta-analyses. Spine J. 2015;15(6):1461-1477.
10. Roberston K, Marshman LA, Plummer D. Pregabalin and gabapentin for the treatment of sciatica. J Clin Neurosci. 2016;26:1-7.
11. Mathieson S, Chiro M, Maher C, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med. 2017;376(12):1111-1120.
12. Yildirim K, Sisecioglu M, Karatay S, et al. The effectiveness of gabapentin in patients with chronic radiculopathy. Pain Clinic. 2003;15(3):213-218.
13. Grice GR, Mertens MK. Gabapentin as a potential option for treatment of sciatica. Pharmacotherapy. 2008;28(3):397-402.
14. Yildirim K, Deniz O, Gureser G, et al. Gabapentin monotherapy in patients with chronic radiculopathy: the efficacy and impact on life quality. J Back Musculoskelet Rehabil. 2009;22(1):17-20.
15. Akkurt HE, Gümüş H, Göksu H, Odabaşı ÖF, Yılmaz H. Gabapentin treatment for neuropathic pain in a child with sciatic nerve injury. Case Rep Med. 2015;2015:873157.
16. Cohen SP, Hanling S, Bicket MC, et al. Epidural steroid injections compared with gabapentin for lumbosacral radicular pain: multicenter randomized double blind comparative efficacy study. BMJ. 2015;350:h1748.
17. Robertson KL, Marshman LA. Gabapentin Ssuperadded to a pre-existent regime containing amytriptyline for chronic sciatica. Pain Med. 2016;17(11):2095-2099.

Prepared by:

Elina Delgado, PharmD

PGY1 Pharmacy Practice Resident

July 2017

The information presented is current as of May 26, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What evidence is available to support the use of anti-factor Xa levels instead of activated partial thromboplastin time for monitoring of intravenous unfractionated heparin therapy in adults?

Introduction

Intravenous unfractionated heparin (UFH) is commonly used for anticoagulation in the inpatient setting because of its short half-life and reversibility.¹  The pharmacokinetics of UFH are unpredictable, and the anticoagulant response may vary widely between patients. Therefore, close therapeutic monitoring of intravenous UFH is necessary to avoid complications of bleeding and thrombosis.^2,3 A global clotting assay known as the activated partial thromboplastin time (aPTT) is the most commonly used assay for heparin monitoring.  This assay is a surrogate marker for heparin levels, measuring the time it takes for blood to clot relative to a control value.¹ The therapeutic range for intravenous UFH has been defined as 1.5 to 2.5 times the control aPTT value, but this may vary widely depending on the assay and coagulometer used.^1-3

Limitations of aPTT and Potential Role of Anti-Factor Xa

Many variables can influence the aPTT reading, and correlation between aPTT and heparin level may be poor.¹ Diurnal variation of aPTT is seen in normal individuals, and clotting factor deficiencies influence aPTT results.  The aPTT response to a given level of heparin may be lower in patients with antithrombin deficiency or elevated levels of acute phase reactants, and it may be disproportionately elevated in patients with liver disease or consumptive coagulopathy.  Some conditions may alter the aPTT without changing the risk for bleeding or thrombosis.  Patients with lupus have prolonged aPTTs at baseline due to the presence of lupus anticoagulant, but this prolonged aPTT is not associated with any additional protection from thrombosis.  The measured aPTT also varies widely depending on the particular reagent and coagulometer used.^2,3 According to a guideline from the American College of Chest Physicians, each institution must determine its own therapeutic aPTT range based on the particular reagent and coagulometer being used.³

The anti-factor Xa (anti-Xa) assay has been proposed as an alternative to aPTT for the monitoring of intravenous UFH therapy.  Unlike aPTT, the anti-Xa assay only measures the inhibition of factor Xa.^1,4 It is a more direct measure of heparin activity and is typically used for the initial calibration of institution-specific therapeutic aPTT ranges.  A therapeutic anti-Xa range for UFH has been defined as 0.3 to 0.7 units/mL.  Although data from a retrospective study  correlated an aPTT ratio of 1.5 to 2.5 times control with a reduced risk of recurrent venous thromboembolism, the anti-Xa level itself has not been directly correlated to risk of recurrent thrombosis.^3,5  Anti-Xa assay results are less susceptible to influence from outside factors.¹  Unlike aPTT, anti-Xa levels are not influenced by acute phase reactants, lupus anticoagulant, or deficiencies in specific clotting factors. The measured anti-Xa level still varies across different anti-Xa assays, but the degree of variation between assays is typically much less than what is seen with aPTT assays.^1,3 The anti-Xa assay is more expensive than the aPTT assay, although a reduction in the number of monitoring tests and dose adjustments required with an anti-Xa-based monitoring protocol may partially offset this cost.⁶

Literature Review

Several studies have examined anti-Xa as an alternative to aPTT in the monitoring of intravenous UFH (Table 1). These studies have generally been small and observational in nature. Three retrospective studies found that an anti-Xa UFH monitoring protocol was associated with fewer UFH dose adjustments and fewer monitoring tests.^4,6,7 Vandiver and colleagues found that patients monitored with anti-Xa levels had a higher percentage of values within the therapeutic range.⁷  Similarly, a prospective cohort study found that patients monitored with anti-Xa levels were more likely to be in therapeutic range at least 50% of the time.⁸ A retrospective cohort study of 100 patients found that time to therapeutic heparin level was shorter in patients monitored with anti-Xa levels (28 hours vs. 48 hours, p<0.001), but this finding was not replicated in a more recent prospective cohort study.^4,8

Comparative data for clinical outcomes remains very limited, and the data that does exist does not indicate a clear preference for either strategy.  One small randomized controlled trial in heparin-resistant patients assessed bleeding and thrombosis as primary outcomes and found no difference between aPTT monitoring and anti-Xa monitoring.⁹  In the 2 cohort studies that assessed bleeding, no difference in bleeding incidence was found between patients monitored with anti-Xa and patients monitored with aPTT.^5,8 One large retrospective cohort study found that fewer blood transfusions were required in patients monitored with anti-Xa levels; however, the temporal relationship between UFH therapy and blood transfusion was not clearly delineated in this study.¹⁰ Overall, the 2012 guideline from the American College of Chest Physicians states that more research is needed to determine the most appropriate method for monitoring UFH therapy.³

Table 1.  Key comparative studies of aPTT-based and anti-Xa-based UFH monitoring protocols.

Summary and Conclusions

Results of open-label, retrospective and observational studies have demonstrated that anti-Xa-based monitoring protocols are associated with fewer UFH dose adjustments and fewer monitoring tests compared to aPTT-based monitoring protocols.  Patients monitored with anti-Xa-based protocols are also more likely to be in therapeutic range >50% of the time.  One study found that therapeutic anticoagulation was achieved more quickly with an anti-Xa-based monitoring protocol, but these results were not consistently replicated in subsequent studies.  In general, there is a lack of high-quality evidence comparing anti-Xa-based protocols to aPTT-based protocols.  While aPTT has been correlated to risk of recurrent thrombosis, the correlation between anti-Xa level and recurrent thrombosis has not been formally studied.⁵  The American College of Chest Physicians has stated that more research is required to determine the most appropriate UFH monitoring strategy.³  The limited data on therapeutic outcomes do not demonstrate a preference for either type of monitoring protocol.  In light of the currently available evidence, aPTT-based protocols and anti-Xa-based protocols may both be considered reasonable strategies for the management of IV UFH.

References

1.         Vandiver JW, Vondracek TG. Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy. 2012;32(6):546-558.

2.         Rosenberg AF, Zumberg M, Taylor L, LeClaire A, Harris N. The use of anti-Xa assay to monitor intravenous unfractionated heparin therapy. J Pharm Pract. 2010;23(3):210-216.

3.         Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e24S-43S.

4.         Guervil DJ, Rosenberg AF, Winterstein AG, Harris NS, Johns TE, Zumberg MS. Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother. 2011;45(7-8):861-868.

5.         Fruge KS, Lee YR. Comparison of unfractionated heparin protocols using antifactor Xa monitoring or activated partial thrombin time monitoring. Am J Health Syst Pharm. 2015;72(17 Suppl 2):S90-S97.

6.         Rosborough TK. Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time. Pharmacotherapy. 1999;19(6):760-766.

7.         Vandiver JW, Vondracek TG. A comparative trial of anti-factor Xa levels versus the activated partial thromboplastin time for heparin monitoring. Hosp Pract (1995). 2013;41(2):16-24.

8.         Samuel S, Allison TA, Sharaf S, et al. Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study. J Clin Pharm Ther. 2016;41(5):499-502.

9.         Levine MN, Hirsh J, Gent M, et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med. 1994;154(1):49-56.

10.       Belk KW, Laposata M, Craver C. A comparison of red blood cell transfusion utilization between anti-activated factor X and activated partial thromboplastin monitoring in patients receiving unfractionated heparin. J Thromb Haemost. 2016;14(11):2148-2157.

July 2017

Prepared by:

Laura Koppen, PharmD

PGY2 Drug Information Resident

University of Illinois at Chicago

College of Pharmacy

The information presented is current as of June 9, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Are there any new safety concerns with antibiotics in pregnancy?

There are little clinical data discussing the risks and benefits of many medications in pregnancy despite the extensive research and clinical evidence required for medication approval by the United States Food and Drug Administration (FDA). Less than 10% of drugs approved by the FDA between 1980 and 2010 have enough information to determine the risk of birth defects associated with their use.¹ Many expectant mothers turn to various websites to find medications considered safe in pregnancy, yet many of these published lists have been found to be inaccurate.² Trusted resources such as the Centers for Disease Control (CDC) and the FDA generally instruct patients to consult their physician or pharmacist but the literature for physician or pharmacist guidance is often limited, leaving a lot of these decisions to clinical judgment.

With these issues in mind, the FDA recently made substantial changes to their approach to medication use in pregnancy. As of June 30, 2015, all prescription drugs and biologics submitted for FDA review must include a risk summary, clinical considerations, and data section within the pregnancy and lactation information.³ The pregnancy risk categories A, B, C, D, and X are no longer used for newly approved medications, and prescription medications approved on or after June 30, 2001 will be gradually transitioned from the old risk categories to the new format. Additionally, there are now pregnancy exposure registries which aim to collect further information on the use of medications in pregnancy. There are over 100 registries listed on the FDA website, categorized primarily by medical condition and medications.⁴

While these registries will expand knowledge on medication risk in pregnancy in the future, it is important to critically assess the literature now. Antibiotics are commonly used medications in pregnant women, but only a few drugs in this class are known with certainty to be safe. Recently Muanda and colleagues published a study evaluating the risk of spontaneous abortion with the use of antibiotics during pregnancy.⁵ The authors used the Quebec Pregnancy Cohort database to conduct a nested case-control study using data collected between 1998 and 2009. This database is an ongoing, population-based cohort that prospectively collects data on all pregnancies in women covered under the Quebec Public Prescription Drug Insurance Plan. All women 15 to 45 years of age who had been insured by their providence’s drug plan for at least 12 months before and during their pregnancy were included. Patients on known teratogenic medications as well as any pregnancies terminated by planned abortion were excluded.

In this case-control study, the cases were identified by an International Classification of Diseases (ICD-9 and ICD-10) diagnosis or procedure related to spontaneous abortion before week 20 of gestation.⁵ Spontaneous abortion was determined by clinical detection, and was considered the index date. Each case was associated with 10 controls, matched by gestational age (within 3 days) and year of pregnancy. Antibiotic exposure was assessed by prescription fill between the first day of gestation and the index date, or before the gestation date but with an overlap of the first day of gestation. In attempt to account for the indication for antibiotics, the authors compared the case group to 2 active comparator groups: pregnancies with exposure to penicillins and exposure to cephalosporins. In addition, the authors identified and accounted for many covariates (e.g., area of residence, comorbidities, diagnosis of gynecological issues, use of health services) to further correct for any confounding variables. Overall 182,369 pregnancies were identified, 4.7% of which ended with a clinically detected spontaneous abortion. The women who had a spontaneous abortion were more likely to be older, to be living alone, and to have comorbidities, and infections.

This study ultimately found that macrolides (with the exception of erythromycin), tetracyclines, quinolones, sulfonamides and metronidazole, were associated with an increased risk of spontaneous abortion when used during early pregnancy (Table).⁵ Erythromycin and nitrofurantoin were the only antibiotics in the study not associated with an increased risk of spontaneous abortion. Similar results were seen for most medications when compared to the active control groups (women receiving penicillins and cephalosporins). These findings were similar to those of some previous studies, which found increased risk of spontaneous abortion with azithromycin, clarithromycin, and metronidazole. ^{6- 8}

Table. Risk of spontaneous abortion with select antibiotics.⁵

The authors concluded that their findings may be of use to policy makers when updating guidelines for antibiotic use in the pregnant population.⁵ Despite lacking the rigorous standards of a randomized controlled trial, this study had many positive qualities including a large and diverse population, adequate control groups, and overall valid information sources. However, the study did not take into account the severity of infection or the details of the antibiotic therapy such as duration and dosing. This article has gained a lot of traction and spurred much discussion in the medical community. While Muanda and colleagues identified medications that correlated to an increase risk of spontaneous abortions; they did not take into account other risks such as birth defects or other potential harm to the fetus or mother.  Thorough evaluation of other risks is important when choosing an antibiotic for a pregnant patient. While most penicillins and cephalosporins are generally considered safe during pregnancy, there are some medication classes with conflicting data. ^9,10  The remainder of this FAQ will evaluate the overall safety of the macrolides, sulfonamides, nitrofurantoin, and metronidazole.

Sulfonamides and nitrofurantoin

Urinary tract infections (UTIs) are common infections in the pregnant population and generally warrant treatment. Muanda and colleagues state that based on their study, the use of nitrofurantoin in place of sulfamethoxazole-trimethoprim when treating a UTI during pregnancy is appropriate.⁵ In 2009, Crider and colleagues conducted a similar population-based case control study and found that these 2 drug classes, the sulfonamides and nitrofurantoin derivatives, were significantly associated with multiple birth defects.¹¹ Sulfonamides were associated with anencephaly (adjusted odds ration [AOR] 3.4), hypoplastic left heart syndrome (AOR 3.2), coarctation of the aorta (AOR 2.7), choanal atresia (AOR 8.0), and transverse limb deficiency (AOR 2.5). Nitrofurantoins were associated with anophthalmia or microphthalmos (AOR 3.7), hypoplastic left heart syndrome (AOR 4.2), atrial septal defects (AOR 1.9), and cleft lip with cleft palate (AOR 2.1). Similar to the Muanda study, these authors looked at a large population; however, they relied on women’s accounts of antibiotic use after pregnancy, subjecting the study to recall bias. Furthermore, prescriptions were not confirmed with medical records. This study also failed to address the impact of infection severity as well as other confounding variables. 

Other studies using different epidemiologic methods have drawn varying conclusions about the risk of these medication classes in pregnancy. Goldberg and colleagues used a computerized database to track medications dispensed to women in southern Israel when they conducted their population-based retrospective cohort study.¹² With a large study size of over 100,000 pregnant women and over 1,000 exposed fetuses, they concluded there was no association between nitrofurantoin and risk of major malformations (AOR 0.85l; 95% confidence interval [CI] 0.67 to 1.08). Czeizel and colleagues have published multiple studies evaluating the risk of sulfonamides in pregnancy using various methods. Their 2001 study using the Hungarian Case-Control Surveillance System of Congenital Abnormalities found increased cardiovascular abnormalities in babies born to women who used this medication during the second and third months of pregnancy.¹³ A 2004 study using the same database found a higher rate of cardiovascular malformation and clubfoot with the five different sulfonamides studied.¹⁴ These results were primarily driven by the cardiovascular effects with sulfamethoxydiazine during the second and third months of pregnancy and the increased risk of clubfoot with sulfathiourea throughout pregnancy.

Taking into consideration the above data, the American Congress of Obstetricians and Gynecologists (ACOG) published a committee statement with their overall recommendations.⁹ They concluded that use of nitrofurantoin and sulfonamides during the first trimester (organogenesis of the fetus) is appropriate when no other suitable alternatives are available and recommended providers have a risk-benefit discussion with patients. They determined these medications appropriate for first-line use during second and third trimesters. 

Metronidazole

Another commonly used antibiotic in pregnancy is metronidazole. This antibiotic is used for bacterial vaginosis (BV), trichomoniasis, and inflammatory bowel disease.^15,16 As presented above, the study by Muanda and colleagues found an association between this medication and spontaneous abortion.⁵ Similarly, the PREMET study, a randomized controlled trial at 14 UK hospitals evaluated the association between metronidazole and early preterm labor in asymptomatic women with positive vaginal fetal fibronectin (fFN) in the second trimester of pregnancy.¹⁷ The trial was terminated early as 21% of women in the metronidazole group and 11% in the placebo group (risk ratio [RR] 1.9; p=0.18) delivered before 30 weeks. Additionally, more women in the metronidazole group delivered prior to 37 weeks (62% vs 39%; RR 1.6; p=0.022). A systematic review of 14 studies looking at antibiotics for bacterial vaginosis or trichomonas in pregnancy ultimately determined that metronidazole reduced the risk of persistent infection but increased the incidence of preterm birth.¹⁸ One cohort study identified 228 women exposed to metronidazole and found no increase in the rate of major malformations between the exposure group and control group (1.6% vs 1.4%; p=0.739).¹⁹ ACOG recommends against the use of metronidazole in pregnant women due to studies indicating an increased risk of preterm birth.²⁰  

Macrolides

Muanda and colleagues found that macrolides as a class, with the exception of erythromycin, increase women’s risk of spontaneous abortion.⁵ Other studies, evaluating the risk of major malformations found there was no increased risk associated with azithromycin exposure (malformations occurring in 3.4% of pregnancies) when compared to non-teratogenic antibiotics for similar indications (malformations occurring in 2.3% of pregnancies) and non-teratogenic agents in general (malformations occurring in 3.4% of pregnancies).²¹ Similar results were replicated in a multinational, controlled, observational study looking at all macrolides in the first trimester.²² This study found no significant difference in the rate of major congenital malformations (3.4% vs 2.4%; odds ratio 1.42; 95% CI 0.70 to 2.88; p=0.36) between women exposed to macrolides compared to those who were not. As Chlamydia trachomatis is a common infection treated in pregnancy, a meta-analysis was conducted looking at single-dose azithromycin versus erythromycin or amoxicillin for this indication in the pregnant population.²³ The trials examined focused on efficacy, concluding there was no difference between azithromycin and erythromycin. Although azithromycin was better tolerated than erythromycin, there were no significant differences in neonatal outcomes. ACOG recommends azithromycin as first-line for treatment of chlamydia in pregnancy and also endorses the treatment of Neisseria gonorrhoeae with ceftriaxone and azithromycin.^21,24 Another macrolide, clarithromycin, has been documented to increase the risk of spontaneous abortion, most recently in the Muanda trial but also previously.^5-7 However, authors also noted there was no increased risk for malformations after clarithromycin exposure.^6,7

Conclusion

Treatment of infections in pregnant women is often necessary as untreated infections can lead to serious maternal or fetal complications. Penicillins and cephalosporins are the safest options in pregnancy. Further evaluation of nitrofurantoin and sulfonamides deem them acceptable options especially after the first trimester. Metronidazole use should be limited to symptomatic infections due to the documented risk of preterm birth and spontaneous abortion. Erythromycin is the safest macrolide, while azithromycin has a role in some treatments as well. Clarithromycin, however, should be avoided due to the increased risk of spontaneous abortion. Although there are very few randomized controlled trials in this population, the observational studies above can be extremely helpful in choosing the safest treatment option for pregnant patients. Evidence collection through the newly designed FDA registries will further help add to this body of knowledge. Healthcare providers can enhance the evidence for antibiotic safety by enrolling patients in these registries.

References

1. Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet. 2011;157C(3):175-182.
2. Peters SL, Lind JN, Humphrey JR, et al. Safe lists for medications in pregnancy: inadequate evidence base and inconsistent guidance from Web-based information, 2011. Pharmacoepidemiol Drug Saf. 2013;22(3):324-328.
3. Pregnancy and Lactation Labeling (Drugs) Final Rule. US FDA website. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ucm093307.htm. Published December 3, 2014. Updated November 18, 2016. Accessed May 30, 2017.
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Prepared by:

Rachel Murdock, PharmD

PGY1 Pharmacy Practice Resident

College of Pharmacy

University of Illinois at Chicago

July 2017

The information presented is current as of June 5, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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