Maryann Mazer-Amirshahi, PharmD, MD, MPH
Assistant Professor of Emergency Medicine
Georgetown University School of Medicine
Department of Emergency Medicine,
MedStar Washington Hospital Center
Tamika Auguste, MD
Associate Professor of Obstetrics and Gynecology
Georgetown University School of Medicine
Women’s and Infants’ Services
MedStar Washington Hospital Center
Although pain is a common complaint in the acute care setting, the treatment of pain in the pregnant and postpartum patient is complicated by the limited data regarding the safe and efficacious use of medications in pregnancy and lactation. This is largely because few clinical trials are undertaken during pregnancy due to ethical and legal concerns surrounding drug exposures during pregnancy. At the same time, up to 80% of pregnant women report having taken a medication during the first trimester, when vital organs and bodily structures are being formed. (Mitchell 2011) In addition, the percentage of women taking medications during pregnancy is expected to increase in coming years because women bear children later in life and older pregnant women are more likely to need medications for acute and chronic illness. (CDC 2015)
When prescribing medications for pregnant and postpartum patients, providers must consider–with little guidance–the potential for fetal (or neonatal) and maternal adverse effects as well as the harms of untreated maternal illness or disease. There have been efforts to optimize the use of medications in pregnancy and lactation, including Food and Drug Administration (FDA) guidance for industry to establish registries, improve pregnancy labeling, and promote clinical pharmacokinetic studies in pregnant women. (FDA 2002) One of the most notable recent changes was the abolishment of the traditional A, B, C, D, and X pregnancy categories for prescribing information. The new labeling system that was introduced is based on the complexity of the risk assessment of a drug to be used in pregnancy and underscores that a narrative discussion with consideration of the benefits of the drug is more appropriate than a simple letter designation. (FDA 2004) (Tables 1, 2). This chapter will focus on the management of pain in the acute setting in the pregnant and postpartum patient. Peripartum and chronic pain management will not be discussed.
Regional poison centers (800-222-1222) or drug information centers are up to date resources for pregnancy-related drug questions, as is the MotherRisk Helpline.
Table 1. Revised Pregnancy Information Drug Labeling
-General statement about background risk
-Contact information for pregnancy registry if available
|Fetal Risk Summary
-Based on all available data, this section characterizes the likelihood that the drug increases the risk of developmental abnormalities in humans and other relevant risks
-More than 1 risk conclusion may be needed
For drugs that are systemically absorbed
-When there are human data, a statement describes the likelihood of increased risk based on this data. This statement is followed by a brief description of the findings
-A standard statement describes the likelihood of increased risk based on animal data
For drugs that are not systemically absorbed
-A standard statement that maternal use is not expected to result in fetal exposure to drug
This section provides information on the following topics:
-Known or predicted risk to the fetus from inadvertent exposure to drug before pregnancy is known
Prescribing decisions for pregnant women
-Describe any known risk to the pregnant woman and fetus from the disease or condition the drug is intended to treat
-Information about dosing adjustments during pregnancy
-Maternal adverse reactions unique to pregnancy or increased in pregnancy
-Effects of dose, timing, and duration of exposure to drug during pregnancy
-Potential neonatal complications and needed interventions
Drug effects during labor and delivery
–Human and animal data are presented separately, with human data presented first
-Describes study type, exposure information (dose, duration, timing), and any identified fetal developmental abnormality or other adverse effects
-For human data, includes positive and negative experiences, number of subjects, and duration of study
-For animal data, includes species studied and describes doses in terms of human dose equivalents (provide basis for calculation)
Table 2: Revised Lactation Subsection Information Drug Labeling
If appropriate, include a statement that the use of the drug is compatible with breast-feeding.
-Effects of the drug on milk production
-Whether the drug is present in human milk (and if so, how much)
-The effect of the drug on the breast-fed child
-Ways to minimize exposure to the breast-fed child, such as timing or pumping and discarding milk
-Potential drug effects in the child and recommendations for monitoring or responding to these effects
-Dosing adjustment during lactation
-Overview of data on which risk summary and clinical considerations are based
Drug Therapy in the Pregnant and Postpartum Patient
There are several physiologic changes that occur during pregnancy and in the postpartum periods that have the potential to affect the pharmacokinetics of medications administered during pregnancy and postpartum. A comprehensive list of these changes is provided in Table 3. Although these changes do not uniformly alter the administration of medications, providers must be cognizant of potential dosage adjustments and consult the appropriate references when prescribing, as well as perform therapeutic drug monitoring when indicated to optimize efficacy and avoid toxicity.
The physiologic changes that occur during pregnancy (Table 3) can persist well into the postpartum period. Increased glomerular filtration rate (GFR) and decreases in serum albumin persist in the immediate postpartum period. (Sims 1958). Cardiovascular changes can persist as long as 12 weeks postpartum. (Capless 1991) The reversal of the effects of pregnancy on drug metabolizing enzymes is much more variable, with the activity of some enzymes returning to the pre-pregnancy state nearly immediately and others returning over the course of weeks to months. (Dam 1979)
In addition to the physiologic changes that occur in the mother during pregnancy, one must also consider the impact of pharmacotherapy in the developing fetus. Many small, lipid-soluble, non-polar molecules readily cross the placenta via passive diffusion, whereas larger polar molecules do not. (Plonait 2004) The point during pregnancy at which the exposure to the pharmaceutical occurs is also important. Early in pregnancy, there may be an “all or none” response where the pregnancy may either terminate or continue normally. Most vital organs form between 3 and 8 weeks gestation, so exposures that occur during this time have the potential to cause significant structural malformations. Exposures later in pregnancy may have a greater impact on fetal growth. Medication use near term can also impact the neonate following delivery. For example, maternal use of opioid analgesics near term can cause respiratory depression in the neonate and non-steroidal anti-inflammatory drugs (NSAIDs) may cause premature closure of the ductus arteriosus. Additionally, the duration of exposure may be clinically relevant, as occurs when prolonged use of opioid analgesics results in neonatal abstinence syndrome. (Brent 1995, Tolia 2015) Finally, during the postpartum period, providers should inquire as to whether the infant is being breast-fed and investigate whether the medication is excreted in the breast milk.
Table 3. Major Physiologic Changes that Occur During Pregnancy and Impact on Pharmacokinetic Parameters
|Physiologic Change||Pharmacokinetic Impact|
|Delayed gastric emptying
Decreased gastrointestinal motility
|Delayed but more complete absorption
Lower peak concentrations
|Increased cutaneous blood flow||Increased dermal absorption|
|Increased tidal volume||Increased pulmonary absorption|
|Decreased plasma albumin
Decreased hepatic biotransformation
|Increased free drug concentration|
|Increased fat stores, fluid volume||Decreased free drug concentrations|
|Increased cardiac output, glomerular filtration||Increased renal elimination|
Considerations for Commonly Used Analgesics in Pregnancy
The use of over the counter and prescription analgesics during pregnancy is controversial and poorly informed by data. Few strong recommendations can be made in this domain, and we endorse the position of the United States Food and Drug Administration: “Severe and persistent pain that is not effectively treated during pregnancy can result in depression, anxiety, and high blood pressure in the mother. Medicines including nonsteroidal anti-inflammatory drugs, opioids, and acetaminophen can help treat severe and persistent pain. However, it is important to carefully weigh the benefits and risks of using prescription and OTC pain medicines during pregnancy.” Specific agents are discussed below.
Acetaminophen is the most widely used analgesic during pregnancy. It is administered primarily for the treatment of mild to moderate pain and as an antipyretic. Although the use of acetaminophen has not been associated with fetal malformations, recent epidemiologic studies have suggested a link between maternal acetaminophen use during pregnancy and hyperkinetic and behavioral disorders in children. (Liew 2014) At the same time, there are significant limitations to these data and the associations are weak, reinforcing the need for better controlled trials in the future. Until there are additional high quality data to the contrary, acetaminophen is still considered the safest first line medication for the treatment of mild to moderate pain and fever in pregnancy and during lactation. (de Fays 2015)
Non-Steroidal Anti-Inflammatory Drugs
Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) have not been associated with major congenital malformations; however, their effects on prostaglandin and platelet function can have significant implications for their use during pregnancy. Prostaglandins maintain the patency of the ductus arteriosus and use of NSAIDs near term may cause premature closure of the ductus. Administration of NSAIDs may also prolong labor due to prostaglandin inhibition. (Moise 1988) Peripartum hemorrhage in the mother and neonate may occur due to anti-platelet effects of aspirin and NSAIDs when these medications are administered near term. (Stuart 1982) It is for these reasons that the use of NSAIDs is not recommended in the third trimester of pregnancy.
Data are conflicting but generally support the safety of NSAIDs in the first two trimesters; (Daniel 2014, Damase-Michel 2014) however recommendations and practice patterns are varied. (Babb 2010, Shah 2015, Antonucci 2012) Acknowledging the limitations of the data and absence of consensus, we feel the use of a short course of NSAIDs in early pregnancy is safe and appropriate when thoughtfully applied to patients in pain, including a consideration of the benefits and harms of alternatives (and the harms of under-treating pain). We do not endorse the practice of routine pregnancy testing in women of childbearing age not known to be pregnant prior to the administration of NSAIDs.
There is little evidence to support or discourage the use of topical NSAIDs during pregnancy. Because systemic absorption of these preparations is lower than oral NSAIDs, it is reasonable to use them in the first two trimesters. NSAIDs are considered safe during lactation and are a mainstay in the management of postpartum pain.
Opioid analgesics are commonly prescribed for moderate to severe pain, particularly when non-opioid therapies fail. Opioids have also been used during pregnancy and in the postpartum period to manage acute and chronic pain. Opioid use in pregnant patients is relatively common, with over 1 in 20 pregnant women receiving an opioid during the first trimester. (Bateman 2014) In addition, opioid analgesic use during pregnancy has nearly doubled in the past two decades. (Epstein 2013) Despite the widespread use of opioid analgesics during pregnancy, there are limited data regarding teratogenic effects. The use of codeine during pregnancy has been associated with a small increased risk of cardiac and respiratory malformations. (Shaw 1992). More recent data found that maternal opioid use during pregnancy, particularly during the first trimester was associated with a small but significant increase in congenital heart disease and spina bifida. The most commonly implicated opioids were hydrocodone and codeine. (Broussard 2011) Maternal opioid use at term may cause decreased variability in fetal heart rate and respiratory depression in the newborn. (Rayburn 1989) In women with chronic opioid use during pregnancy, the newborn is at increased risk of developing neonatal abstinence syndrome (NAS), which can lead to a prolonged period of opioid detoxification in the infant after birth. Clinical findings in newborns with of NAS include irritability, poor feeding, and seizures. (Zelson 1973, Tolia 2015)
In recent years, there were exponential increases in opioid analgesic prescribing across a wide variety of demographics, including women of childbearing age. This increase in prescribing was accompanied by a profound increase in opioid misuse, abuse, and fatalities. (Warner 2011) Pregnant women were not exempt from the consequences of opioid use. One study demonstrated that 1% of pregnant near-term women admitted to non-medical use of a prescription opioid analgesic within the past 30 days. (Bateman 2014) Another showed that 6% of pregnant women admitted nonmedical use of opioid analgesics during pregnancy and opioid users had significantly higher rates of psychiatric comorbidities. Prescription drug abuse in women of childbearing age can have significant consequences including unprotected sex, domestic violence, and child abuse. Although prescription drug abuse may not affect parenting ability, it is intuitive that treatment and abstinence are preferred. Unfortunately, patients may be hesitant to disclose their addiction for fear of losing custody of their children. (Committee 2012) Universal screening with brief intervention and referral to treatment is currently recommended for all prenatal patients to improve maternal and fetal outcomes. (Committee 2017).
For these reasons it is important for providers to employ safe and rational opioid prescribing practices when treating pregnant and postpartum patients. Opioid analgesics can be used for similar indications as in the non-pregnant patient, primarily for the treatment of moderate to severe pain when non-opioid therapies fail or are contraindicated. (Committee 2017) If an opioid analgesic is indicated, codeine should be avoided due to its link to cardiac and respiratory malformations. (Shaw 1992) Like prescribing in the non-pregnant patient, pregnant patients should have a risk assessment for prenatal substance abuse performed. An example of a tool for risk assessment for prenatal abuse is presented in Table 4, but all such tools have significant limitations, and clinical judgment should prevail. It is also recommended when opioids are prescribed to use the lowest possible dose for the shortest period of time using only immediate release, short acting formulations, with frequent reassessment and close follow up. Near term, neonatal respiratory depression is the most dangerous consequence of maternal opioid use while in earlier pregnancy, NAS and the development of maternal long term use are the harms of dominating concern.
Table 4. Clinical Screening Tools for Prenatal Substance Use and Abuse
|Parents: Did any of your parents have a problem with alcohol or other drug use?|
|Partner: Does your partner have a problem with alcohol or drug use?|
|Past: In the past, have you had difficulties in your life because of alcohol or other drugs, including prescription medications?|
|Present: In the past month have you drunk any alcohol or used other drugs?|
|Scoring: Any “yes” should trigger further questions.|
Ewing H. A practical guide to intervention in health and social services with pregnant and postpartum addicts and alcoholics: theoretical framework, brief screening tool, key interview questions, and strategies for referral to recovery resources. Martinez (CA): The Born Free Project, Contra Costa County Department of Health Services; 1990.
When an opioid use disorder (either prescription or illicit) is identified in a pregnant patient, she should promptly be referred to a provider with experience in managing addiction, as substance abuse during pregnancy is associated with adverse maternal and fetal outcomes. (Committee 2012, Committee 2017, Messinger 2004, Kaltenbach 1998) Until recently, methadone had been the standard treatment for pregnant patients with opioid addiction. Although methadone maintenance therapy in pregnancy is accompanied by improved fetal outcomes, access to therapy is often limited and requires daily trips to the clinic, which can be burdensome. (Kaltenbach 1998, Winklbaur 2008) More recently, buprenorphine has emerged as a therapeutic alternative to methadone. Buprenorphine has demonstrated effectiveness for medical management of opioid addiction, has fewer restrictions, and a wider safety margin than methadone. (Jones 2012) In addition, buprenorphine maintenance during pregnancy is associated with longer gestation as well as decreased incidence and severity of neonatal abstinence syndrome. (Jones 2010, Meyer 2015) In general, opioid agonist therapy is preferred to medically supervised withdrawal because of lower relapse rates. (Committee 2017)
Opioid analgesics are often used in combination with NSAIDs for the treatment of pain during the postpartum period. Until recently, codeine had been used for the treatment of postpartum pain; however, its use has fallen out of favor due to mounting case reports of infants experiencing toxicity and even death when breastfed by mothers with cytochrome (CYP) 2D6 genetic polymorphisms. (Koren 2006, Madadi 2007) Mothers who are ultra-rapid CYP 2D6 metabolizers of codeine will excrete toxic concentrations of morphine (the active metabolite of codeine) into the breast milk. (Madadi 2009) There are reports of neonatal toxicity associated with maternal oxycodone use, (Timm 2013) and hydrocodone and hydromorphone are also excreted in the breast milk though the actual risk to the neonate is uncertain. (Sauberan 2011) Current evidence suggests it is prudent to avoid codeine altogether during breastfeeding, with efforts to minimize drug exposure to the infant and close monitoring for signs of toxicity when other opioids are used to treat maternal pain. (Lazaryan 2015)
The use of skeletal muscle relaxants in pregnancy remains controversial. Skeletal muscle relaxants such as cyclobenzaprine and methocarbamol were historically categorized as “B” or “C” drugs but quality human data regarding their safe use in pregnancy are lacking. Although it has not been associated with fetal malformations, cyclobenzaprine is associated with premature ductal closure and pulmonary hypertension when used near term. (Moreira 2014) As such, it is recommended to avoid using cyclobenzaprine in the third trimester. There are limited data regarding the use of non-benzodiazepine skeletal muscle relaxants in breastfeeding, although there is not a clear contraindication. The benzodiazepine diazepam is commonly used as a muscle relaxant, but its use in pregnancy is associated with congenital inguinal hernias and cleft palate, although controlled data are lacking. (Rosenberg 1983, Enato 2011) In addition, as with opioids, long-term benzodiazepine use during pregnancy is associated with a NAS and use just prior to delivery can result in respiratory depression of the newborn. (Scanlon 1975) Diazepam is also excreted in the breast milk and can cause sedation because active metabolites accumulate in the newborn. As such, its use is generally not recommended during pregnancy or lactation unless the benefits clearly outweigh the harms. (Erkolla 1972)
Local Anesthetics and Agents Used to Treat Neuropathic Pain
Local anesthetics, such as lidocaine and bupivacaine, are commonly used for analgesia during procedures, and have not demonstrated teratogenic effects when administered during pregnancy. Local anesthetics are also safely used during labor and delivery without adverse effects to the fetus. (Heinonen 1977) They are also used chronically, often topically in patch form, for neuropathic pain, although their efficacy for the latter indication is modest. Their safety is not well studied, but they are presumed to be of minimal risk given their minimal systemic bioavailability, and topical lidocaine has been historically considered a category “B” medication. There is negligible excretion of local anesthetics in breast milk and these medications are considered compatible with breastfeeding. (Zeisler 1986)
Gabapentin, an agent used extensively to treat neuropathic pain, has been used in pregnancy with some success and no evidence of significant fetal toxicity; however, data are limited. (Guttuso 2014) Tricyclic antidepressants have also been used to treat neuropathic pain, but the data regarding safety in pregnancy is limited. There is an association with tricyclic use in pregnancy and prenatal antidepressant exposure syndrome although it appears to be less severe than observed with selective serotonin reuptake inhibitors. (Gentile 2014)
Procedural Sedation in the Pregnant Patient
Pregnant patients may experience illnesses or injuries that require procedural sedation. When managing a pregnant patient who requires procedural sedation, providers must be cognizant of both the physiologic changes that may affect sedation as well as the safety of the medications used. (Table 5) Consultation with a provider with experience in obstetric anesthesia is prudent for patients in late pregnancy who require procedural sedation, particularly in more complicated cases.
Table 5. Physiologic Considerations for Procedural Sedation in Pregnancy
|Physiologic Change||Clinical Implication|
|Increased oxygen consumption||Rapid desaturation; supply oxygen, use capnography|
|Decreased functional residual capacity||Rapid desaturation|
|Airway tissue engorgement/edema||Difficult intubation|
|Weight gain/increased breast size||Difficult intubation|
|Increased gastroesophageal reflux||Aspiration risk; raise head of bed|
|Gravid uterus||Hypotension in supine position; tilt onto left side or displace uterus|
There are several medications that may be used safely and effectively for procedural sedation in the pregnant patient. Rapid-acting benzodiazepines such as midazolam and opioid analgesics such as fentanyl, as well as the sedative propofol can be used without risk of fetal malformations. They do however, carry the risk of respiratory and central nervous system depression in the newborn when used at term. Propofol is pregnancy category “B” and has been used in pregnancy; however, long term outcome and developmental are limited. Propofol may cause maternal hypotension which may compromise the fetus, which requires careful titration and monitoring. (Tajchman 2010)
Low dose ketamine may be considered for use in pregnancy near term, but its use has been associated with uterine contractions and exacerbation of hypertension, and therefore it is not considered a first-line agent. It also carries the risk of neonatal central nervous system depression. (Neuman 2013) Ketamine has also been associated with neuroapoptosis in animal studies, although this phenomenon has not been observed in humans and is likely only relevant during early gestation. Whether there is a risk with use of low-dose ketamine for analgesic purposes has also not been determined. (Bambrink 2012)
Nitrous oxide exposure during the first trimester of pregnancy has been associated with teratogenic effects and spontaneous abortion; however these data are controversial. Given the availability of safer alternatives, nitrous oxide should only be used when there is a contraindication to other therapies or at term. (Neuman 2013)
There are several alternatives to pharmacologic therapy for pain relief in pregnant patients. Biofeedback is a series of educational sessions that increase relaxation and increase awareness of physiologic processes that has been used safely during pregnancy. Acupressure is a massage method that focuses on specific pressure points, and it has been successfully used during pregnancy to treat pain. Acupuncture uses needles to provide intense stimulation to specific points in the body to relieve pain and has been tolerated well in pregnancy. Transcutaneous electric nerve stimulation (TENS) works by stimulating afferent nerves, decreasing pain sensation. Although TENS has been widely used for a variety of painful complaints in pregnancy without any reported adverse effects, controlled data are limited. Should any of these therapies be employed for pain management during pregnancy, patients should be referred to a provider that has experience in treating pregnant patients. (Brucker 1988)
Common Acutely Painful Conditions in Pregnancy
Pelvic girdle pain and low back pain are common complaints occurring in approximately 45% of pregnant patients and up to 25% of postpartum patients. (Wu 2004) Non-pharmacologic therapies can be helpful in treating these conditions. Demonstrating good posture, engaging in targeted exercise, taking frequent breaks from activity, and using proper lifting techniques can prevent exacerbations. (Ostgaard 1994) Use of wedge-shaped pillows during sleep and supportive devices have also been shown to be safe and effective interventions. Physical therapy, TENS, and acupuncture are safe non-pharmacologic options for the treatment of pelvic girdle and low back pain. When pharmacologic therapy is required, acetaminophen is considered first-line therapy. NSAIDs are generally not recommended in third trimester, when these conditions primarily occur. In pregnant patients without evidence of or risk factors for opioid misuse who have severe pain that is refractory to other therapies, it is reasonable to prescribe opioids judiciously, as discussed in other chapters. For refractory pain, epidural anesthesia has been used. (Vermani 2010)
Migraine headaches are the most common type of headache encountered in women of reproductive age, affecting nearly 20% of this patient population. Although the frequency of migraine headaches actually decreases due to hormonal changes during pregnancy, many women will still require treatment during this time. (Granella 2000) Migraines may occur during labor and worsen during the postpartum period, particularly in women who do not breastfeed. Any headache in the pregnant patient should prompt a standard investigation for dangerous causes, in addition to pregnancy related causes such as cerebral venous thrombosis or preeclampsia. (Kvisvik 2011, Banhidy 2007)
Women with migraines can use selected prophylactic therapies during pregnancy; however, some may require acute migraine treatment as well. For mild pain, acetaminophen is considered first-line therapy. For more severe attacks, antiemetics, such as phenothiazines or metoclopramide, can be used. Intravenous magnesium sulfate has also been used as abortive therapy. (Demirkaya 2001) Sumatriptan appears to be safe during pregnancy and lactation and may be considered after other therapies have failed. As with nonpregnant headache patients, opioids should be reserved for those refractory to all other therapies (see headache chapter). (MacGregor 2014) Ergotamine is contraindicated during pregnancy, due to its effects on fetal growth and its association with preterm labor. (Bánhidy 2007b) (Table 6)
Table 6. Preferred Migraine Prophylaxis and Treatment for Pregnant Patients
|Magnesium supplementation||Magnesium sulfate|
|Nonsteroidal antiinflammatory drug|
Sickle Cell Pain Crisis
Pain crises can affect up to 50% of pregnant women with sickle cell disease, with the highest prevalence in the third trimester. These patients often require admission with bed rest, intravenous fluids, and management of hematologic complications. Acetaminophen is the preferred analgesic for mild pain. For moderate to severe pain, cautious use of short acting opioid analgesics (with the exception of meperidine and codeine) is recommended. In order to avoid the aforementioned risks of long-term opioid use in pregnancy. NSAIDs can be used in this population in early pregnancy, but they remain contraindicated in late pregnancy as previously discussed. (Boga 2016)
Lactation Specific Considerations
Drugs are generally transferred into the breast milk via simple diffusion. The amount of drug that diffuses into breast milk is generally less than maternal plasma concentrations and depends on several factors including the molecular weight, lipophilicity, and protein binding of the drug. (Begg 1992) Of commonly used analgesics, acetaminophen and NSAIDs are compatible with lactation. As previously discussed, codeine should be avoided. Ergotamine derivatives are contraindicated during lactation. When prescribing other analgesics to breastfeeding mothers, it is recommended that either the prescribing information or lactation reference be consulted. LactMed is an online reference by the US National Library of Medicine. Infant drug exposure can be minimized by breastfeeding prior to taking medication, when drug levels are the lowest. (Stec 1980)
Summary and Conclusions
Pain is a common complaint during pregnancy and lactation, but data regarding the safety of commonly used medications in this population is limited. Providers should be cognizant of current treatment guidelines as well as fetal risks associated with prescribed medications to ensure safe and efficacious analgesia during pregnancy and lactation. Acetaminophen, local/regional and non-pharmacologic techniques are first line treatments, with NSAIDs appropriate as second line agents except in the third trimester. Opioids carry particular harms in pregnancy and–as in the non-pregnant patient–should be only be used after an explicit consideration of the likelihood of benefit and harm.
The authors report no relevant conflicts of interest.
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