Dental Drug Safety during Pregnancy

Treatment of the dental patient during pregnancy can create many challenges. Knowledge of drug safety during pregnancy is imperative for the dentist. In this paper, we reviewed the risks of commonly used medications in dentistry. Some general guidelines are presented for the most common classes of medications prescribed in the dental office. This should serve as a guide for the dental practitioner who has to treat the pregnant patient.


Introduction
Precautions are necessary when addressing pain or infection for all patients, but special considerations should be taken with the pregnant dental patient.Safety of the fetus is the primary concern with regard to drug administration.It is crucial to understand the toxicity and teratogenic effect of each drug prescribed to a pregnant patient, due to the high concentration of drug that can cross the placenta by simple diffusion and adversely affects fetal development.Several variables, including the mechanism of action and the gestational stage help to narrow the list of ideal drugs to be administered to each pregnant patient.The physiologic changes during pregnancy, drugs that are affected by these changes, and the risks or benefits of each drug are outlined to ensure a safe environment during dental treatment [1].The Food and Drug Administration (FDA) classified each drug commonly used in the dental practice in terms of risk versus reward for a pregnant patient (Tables 1) [2].The five categories limit usage of potentially harmful drugs to the fetus.Category A signifies harm is highly improbable to the fetus after controlled human studies.Therefore, these are the safest drugs to administer.Category B encompasses drugs that have no proven harm in controlled animal testing (or adverse responses in animal studies that were not reproduced when conducting human trials).These drugs can be used during pregnancy if the benefits outweigh the risks.Drugs in category C are not encouraged unless all other options are exhausted.The studies concerning these drugs demonstrated adverse effects in animal studies or the lack of results in human trials.Category D drugs should never be used during pregnancy unless necessary for life-threatening events because the studies regarding them exhibit evidence of harm for the fetus.The drugs in category X may never be used for pregnant women or women who may become pregnant, since studies display fetal abnormalities or evidence of fetal risk [3].No matter the medical condition of the patient, certain drug classes can always be of use concerning pain management and acute needs.Anxiolytic drugs, as the name suggests, decrease anxiety before the initiation of and during the treatment.Among these drugs are sedatives, benzodiazepines, barbiturates and other minor tranquilizers.The verification of these drugs' safety is extremely important to recognize concerning pregnancy due to the large amount of drugs within the category that are contraindicated and in category C, D or X [4].Anesthesia, whether local or general, is always a necessity during dental surgical procedures for patient comfort.This drug category induces temporary unconsciousness, memory loss, pain and sensation loss, or muscle relaxation.As with all drugs, anesthetics should be used with caution during pregnancy due to the physiologic changes of the expecting mother and the capacity of these drugs to cause teratogenic issues for the fetus.Local anesthetics are preferable to general anesthesia due to the lower risk to the developing fetus.Analgesics produce similar effects to anesthesia in terms of pain control.However, they differ from anesthetics because they do not produce sensation loss.Temperature and pressure sensations are still present but the pain response is not initiated.This drug group is imperative in treating post-operative pain and several drugs within this class are relatively safe when given in moderation during pregnancy [5].Ultimately, antibiotics are implemented when signs of systemic involvement are present.They are used to impede the spread of bacterial infections and allow for more rapid wound healing by assisting the immune response.Vigilance is crucial when prescribing antibiotics due to adverse effects on the fetus when the drug crosses the placenta.Certain antibiotic groups are more harmful than others in terms of causing malformations or abnormalities [6].Each of these common drug groups is described below, and the high-risk drugs are explained along with alternatives for treatment during pregnancy.Time should be taken to choose the correct drug for the situation and to provide the safest form of treatment possible.The FDA list of drug safety for pregnant patients should be consulted when considering any medications for that patient [7].

Anxiolytics
Of the many anxiolytics in use, nitrous oxide is the most common within the dental setting to alleviate anxiety.In a healthy patient this drug is rarely contraindicated and has very limited side effects, yet during pregnancy it is currently placed in category C (or not assigned a category according to Hilgers [8]) due to lack of clinical results in human trials for acute use.Chronic exposure to nitrous oxide has proven harmful, which was the cause for placement of scavenging systems in dental offices.Prolonged exposure increases the risk of spontaneous abortions, yet this finding has not been proven with acute use of nitrous oxide.Certain studies have demonstrated an increased incidence of embryonic death leading to spontaneous abortions, growth restrictions, and skeletal abnormalities [5].Therefore, this anxiolytic agent may be used in dire situations, but avoidance of this drug is best.Furthermore, the physiologic changes of the mother may increase risk of hypoxia if nitrous oxide is used.The entire respiratory tract becomes edematous because of the capillary enlargement noted during pregnancy.The result is a decreased residual capacity of about 80% of the normal.Administering nitrous oxide may induce respiratory issues and pregnant patients may be more prone to diffusion hypoxia if the drug is not delivered in a cautious manner [3].Benzodiazepines, commonly used in anxious healthy dental patients, including diazepam (Valium) and lorazepam (Ativan) are category D and should be avoided during pregnancy.These and other benzodiazepines, when administered during the first trimester, can cause congenital malformations concerning the cardiovascular and genitourinary systems as well as an increased risk of cleft palate and lip [9].These drugs have a history of being commonly prescribed during pregnancy, yet they easily cross the placenta and can detrimentally affect the fetus.Neonatal abstinence syndrome, although mostly seen with chronic benzodiazepine use, can occur with a single high dose if administered during the third trimester [10].If anxiolysis is imperative to providing proper treatment during pregnancy, the healthcare provider should stray from the benzodiazepine class.Zolpidem (Ambien) should also be looked upon with extreme caution because it is a category C medication.Although no results have indicated neonatal abnormalities, there is a tendency for pre-term birth and hindered fetal growth with Zolpidem use [11].Buspirone (Buspar) is category B and is a safe alternative to other anxiolytics.Caution should still be taken when prescribing Buspirone to pregnant women presenting with gestational diabetes due to the increased risk of metabolic acidosis.These are not benzodiazepines and therefore do not pose the same fetal risk [12].Midazolam (Versed), commonly used to induce sleepiness, is category D and contraindicated as with other benzodiazepines, described above.Ultimately, these anxiolytic agents should only be used for acute purposes and prolonged use may still be harmful to the fetus.It is imperative to explain the high risk of these drugs to the patient and to attempt to complete the dental treatments without these.In contrast, associations have been made between prolonged stress during pregnancy and spontaneous abortion or pre-term delivery, yet there is no proof of causation [9].

Anesthesia
Regional anesthesia is always preferable to general anesthesia whenever possible during pregnancy.If general anesthesia is unavoidable, it is advantageous to wait until the second trimester and, as always, elective treatment should wait until post-partum.The major risk to the fetus is not congenital abnormalities but spontaneous abortion or growth restriction.Mild maternal hypoxemia may occur during general anesthesia, but this in a prolonged state may cause fetal asphyxia and death [13].Ketamine (Ketalar, produces loss of consciousness) is a category C drug, not to be used unless other options have been exhausted and the benefit outweighs the risk.Ketamine causes an additive effect when interacting with certain drugs leading to an increased blood pressure.Pregnant women have a predisposition for high blood pressure, so ketamine should be avoided.Remifentanil (Ultiva), an opioid, is commonly used during sedation and general anesthesia, is unfortunately a category C drug and should be avoided as well.Propofol (Diprivan, category B) is a reasonable alternative for these previously mentioned drugs and causes unconsciousness.Slight vasodilatation and acute apnea may occur, and should be monitored closely [5].Overall, the drugs used during general anesthesia prove to be high risk during pregnancy, and any manner necessary to avoid this procedure is beneficial to the patient.Pregnancy initiates certain physiologic changes that can alter the benefits or risks of certain drugs.A surge in serum mineralocorticoids sparked by pregnancy causes increased sodium retention leading to high water content, signifying a larger plasma volume.Moreover, the volume of red blood cells increase, but not enough to offset this increased plasma volume.This imbalance leads to "physiologic anemia of pregnancy" [3].Pre-eclampsia can spawn from these physiologic changes as well and is characterized by heightened water retention and elevated blood pressure [14].These temporary issues come into play when deciding the manner of pain control during dental treatment.High blood pressure can affect and be worsened by local anesthetics or, in contrast, insufficient anesthesia.Local anesthesia is overall safe to use during pregnancy, but as always, caution is crucial to maintain a safe environment for mother and fetus.Local anesthetics, like most other drugs, cross the placenta quite readily.Dosages and techniques should be employed to offset systemic circulation of the anesthetics.Blood pressure should be checked at every appointment prior to treatment and should be at  [15].Epinephrine as its own drug is category C and not recommended for pregnant patients.However, epinephrine in the low doses used in dentistry and in conjunction with a local anesthetic is tolerable.The benefits of epinephrine in this situation compensate for the risks.It hinders systemic absorption of the local anesthetic, therefore increasing the duration and depth of anesthesia with less local anesthetic volume [8].Overall, local anesthesia is the method of choice during dental treatment for a pregnant patient.The dosage should be kept to a minimum because of the heightened risk of maternal seizures and hypoxia and aspiration should be implemented in the injection technique to avoid systemic influx of the drug.
Articaine (Septocaine, category C) is classified as an amidetype local anesthetic that should rarely be used in pregnancy, and the benefits need to overshadow the risks significantly.In animal studies, fetal death and fetal skeletal variations occurred only when dosage levels reached four times the maximum recommended dose.Furthermore, articaine increases the risk of methemoglobinemia at high doses in animal trials [14].This data has not been reproduced in human trials.Likewise, the increased concentration of articaine (4%) relative to other local anesthetics will introduce more of the drug into the pregnant patient than alternatives.Mepivicaine (Carbocaine) and bupivacaine (Marcaine) are also considered in category C and should not be used during pregnancy.Both have been shown to cause fetal bradycardia and embryocidal effects at early stages in the gestational period [15].Category B local anesthetics should be the key drugs used during treatment.Prilocaine (Citanest, although category B) is not used frequently due to its association with methemoglobinemiainduced fetal hypoxia.Prilocaine is safer due to its ester-type properties.It is metabolized in the plasma and less of the anesthetic reaches the placenta than an amide-type anesthetic.However, these anesthetics have shorter duration of action because of this property and may not be indicated for longer procedures [10].An increased glomerular filtration rate in pregnant women further exacerbates this property and will speed up metabolism and excretion of the drug [8].Lidocaine (Xylocaine) is also category B and is the most commonly used local anesthetic for dental procedures.There are no contraindications for this drug within normal dosage ranges, but a restrained approach to drug delivery should be practiced.Both prilocaine (1:1 maternal/fetal) and lidocaine (2:1 maternal/ fetal) exhibit high maternal/fetal placental diffusion and only the minimum dosage necessary should be administered [16].

Analgesia
Varying ranges of analgesia are used within the realm of dentistry, and the point within the gestational period is a huge factor in choosing the correct analgesic.Over the counter mild analgesics should be the first line of action.Acetaminophen (Tylenol, category B) is the drug of choice for post-operative pain management.The first trimester poses the greatest risk for fetal abnormalities and malformations.Acetaminophen has proven its benign nature during pregnancy, and furthermore may reduce risk of fetal malformations when prescribed to treat febrile illnesses [17].It does not hinder platelet function or prostaglandin synthesis as with nonsteroidal anti-inflammatory drugs (NSAID).Inhibition of prostaglandin synthesis can lead to a prolonged gestational period and protracted (abnormally slow) labor, and decreased platelet function may increase the risk of prolonged maternal and fetal bleeding.However, the use of acetaminophen during the third trimester is linked to a higher risk for pre-term birth for women with pre-eclampsia only [18].Ibuprofen (Advil) is also category B, yet it is contraindicated during the third trimester (category D).All non-steroidal anti-inflammatory drugs cause a premature closure of the ductus arteriosus during the third trimester even with shortterm use and therefore should be avoided.Acetylsalicylic acid (Aspirin, category C) should be avoided during all stages of the pregnancy.Only cases involving the prevention and progression of pre-eclampsia have displayed benefits from a low-dose aspirin regimen due to its anti-platelet properties [19].Nonetheless, aspirin is not indicated for acute pain needs with regard to dental treatment and post-operative pain management due to its association with peri-natal mortality and growth retardation.The inhibition of prostaglandin synthesis, as with all NSAIDs, can lead to hemorrhage or delivery complications.Furthermore, associations between aspirin and fetal gastroschisis have been stated but not reliably reproduced [20].
When pain management cannot be controlled with over the counter medications, opioid analgesics are the next line of treatment.All opioid analgesics increase the risk of a newborn with neonatal abstinence syndrome.The risk increases with chronic use, but it has still been demonstrated with acute use.Oxycodone (Percocet) can be used with relative safety and is a category B. Hydrocodone (Norco, category C) has exhibited increase risk to fetal respiratory depression at high maternal dosages.Furthermore, use of hydrocodone during the early stages of pregnancy lead to various birth defects [21].All opioids should be used with discretion and close consultation with the patients' health care providers due to the high risk of fetal physical dependence at birth.

Antibiotics
On occasion antibiotics are indicated for treatment of odontogenic and oral infections.The most pressing issue regarding antibiotics and pregnancy revolves around fetal adverse effects leading to malformations or abnormalities.Antibiotics can readily travel through the placenta by simple diffusion due to their low molecular weight and high lipid solubility.Furthermore, due to high plasma to cell ratio the concentration of plasma albumin decreases.This leads to a higher ratio of free-floating antibiotics in the blood, meaning they more readily cross the placenta and reach the fetus at a faster rate.The placental diffusion generates an average placental concentration of 15-20% the plasma concentration in the mother.Conversely, this increased blood volume causes higher glomerular filtration rates and hepatic activity causing rapid metabolism and excretion of the drugs.During pregnancy the increased estrogen concentration also stimulates alteration of the gastrointestinal tract with decreased absorption and delays in emptying.Therefore, fewer antibiotics, and other oral drugs, become bio-available [14].Attention to these altered conditions is necessary to introduce enough of the drug to bring about the warranted effects while still protecting the fetus.
All penicillin types, including amoxicillin (Amoxil) and ampicillin (Principen), are category B due to their mechanism of action.They attack bacterial cell walls, which is not present in the fetus.Penicillinis occasionally prescribed with clavulanic acid (as in the antibiotic Augmentin).This addition has compromised studies with the Coombs test yielding false positives, which implies a higher risk of fetal erythroblastosis.However, studies show no toxic evidence of clavulanic acid with any abnormal alterations at birth.Cephalosporin (Keflex, category B) also acts on bacterial cell wall and are relatively safe during pregnancy.No patterns of malformations or teratogenicity have been detected for either of these antibiotics.Clindamycin (Cleocin) is also category B and creates the same plasma concentration in both pregnant and non-pregnant women.Studies exposing fetuses to clindamycin in the first trimester displayed no correlation between the antibiotic and congenital abnormalities.Erythromycin (Erythrocin) is yet another antibiotic that is category B and is relatively safe to administer during pregnancy [22].However, certain studies have concluded that overdose can lead to pyloric stenosis in the baby.These results are not consistently repeatable and further testing is needed to ensure safety.Erythromycin in its estolate form is category D and should never be prescribed to pregnant women because it increases hepatotoxicity, further intensified by the increased hepatic activity [23].If possible, other category B antibiotics should be substituted for erythromycin [24].Certain antibiotics are potentially harmful to the fetus and should only be prescribed as a last line of defense when there is a life-threatening situation.Studies concerning clarithromycin (Biaxin, category C) exhibit adverse fetal effects in animals and should be avoided.Although not completely repeatable, certain studies displayed an increased risk of cardiovascular defects and cleft palate defects in newborns.Human studies have shown a minor increase in spontaneous abortions with clarithromycin.Quinolones (including Maxequin, Noroxin, Floxin) are yet another category C antibiotic to steer clear of due to its mechanism of action.These antibiotics, including ciprofloxacin (Cipro), affect bacterial gyrase, which has a similar structure to the mammalian version.They readily reach high placental concentrations and cause cartilaginous fetal defects in animal studies [16,24].Although few human studies have been conducted to reveal any adverse effects, it is in the interest of the patient's welfare to pass up these antibiotics.

Conclusion
As with every patient, different treatment considerations may arise.There is no substitute for good clinical judgment and appropriate medical consultation while working closely with the pregnant dental patient's obstetrician and other health care providers.The importance of the utilization of the safest drug possible cannot be stressed enough during pregnancy.Interactions with other drugs and the differing physiologic states and conditions will need to be addressed before finalizing a decision to prescribe any medication.It is imperative to recognize that the pain, anxiety, and infection may lead to a worse scenario than attempting to deliver treatment in a greatly compromised manner [25].Evaluation of every treatment option is imperative.Ultimately, two patients, the mother and fetus, are being treated, and their wellbeing needs to be considered during all phases of treatment.When possible, the patient's obstetrician or primary care provider for their recommendations, since every situation is unique.

Table 1 :
FDA classifications for common medications maximum of 160/110 to initiate any emergency treatment, with elective treatment delayed.Since hypertension is more prevalent during pregnancy and can lead to increased bleeding time, it is important to be vigilant with the amount of local anesthetic and epinephrine given