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Oral Maxillofacial Surg Clin N Am 19 (2007) 207–221 Oral and Maxillofacial Surgery for the Pregnant Patient Thomas R. Flynn, DMDa,*, Srinivas M. Susarla, ABb a Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine and Massachusetts General Hospital, 188 Longwood Avenue, Boston, MA 02115, USA b Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA The purpose of this article is to update oral and maxillofacial surgeons on approaches for perioperative management of the pregnant patient. The general ethical principles that apply in this situation are discussed, followed by the relevant physiologic changes and their treatment implications, the risks of various medications to the mother and fetus, the management of concomitant medical problems in the pregnant patient, appropriate timing of oral and maxillofacial surgery during pregnancy, and management of emergencies during pregnancy. Ethical considerations in the management of the pregnant patient Because treatment of the pregnant patient has the potential to affect the lives of two individuals (the mother and the unborn fetus), certain ethical principles have been developed that govern treatment decisions that oral and maxillofacial surgeons must consider in the care of their pregnant patients. The first ethical principle is the obvious one: the well-being of two patients must be considered. Plan of treatment should be designed to maximize the benefit to the mother while minimizing the risk This article was supported by the Massachusetts General Hospital Department of Oral and Maxillofacial Surgery Education and Research Fund (S.M.S.). * Corresponding author. E-mail address: (T.R. Flynn). to the fetus. This principle is further developed by the following ones. The best support of the fetus is support of the mother. Biologically, we know that the ultimate fetal incubator is the mother’s uterus. Only in certain pathologic conditions, such as placental abruption, does the pregnant uterus fail to meet fetal needs. Thus, a healthy mother provides the best conditions for the delivery of a healthy baby. The mother should not be denied necessary medical or dental care because she is pregnant. As separate individuals with their own rights and responsibilities, mothers have a right to optimum health care. Fortunately, in most clinical situations involving oral and maxillofacial surgery, maternal health care does not have to be sacrificed for the benefit of the fetus. Using currently available medical resources, the fetus is considered viable at 25 weeks’ gestation. In an extreme situation, the fetus can be delivered by cesarean section after 25 weeks in utero, allowing lifesaving medical care to be given to the mother. Although it is frequently necessary for the oral and maxillofacial surgeon to consult with a patient’s obstetrician or other medical specialist in a given clinical situation, these principles provide a framework for the oral and maxillofacial surgeon in medical decision making for the pregnant patient. The risk of an adverse outcome of pregnancy does not seem to be increased in pregnant women who undergo uncomplicated surgical procedures. Complications, such as sepsis or airway compromise, may affect the outcome of the pregnancy. Mazze and Kallen [1] studied the effects of 5405 1042-3699/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.coms.2007.01.006 208 FLYNN & SUSARLA nonobstetric surgical procedures performed in 7200 pregnant women from 1973 to 1981 in Sweden. Head and neck operations comprised 8% of the total, with a fairly even distribution by trimester of pregnancy. General anesthesia was used in 54% of cases, and topical, local, or nerve block anesthesia was used in 9%. Mazze and Kallen [1] found an increased risk of low birth weight, preterm births, and neonatal deaths in women who had undergone surgery. The risk of stillbirth or malformation was not increased. These perinatal morbidities, however, may be attributable to the disease itself, rather than to the adverse effects of surgery and anesthesia, especially considering the fact that 60% of the operations were abdominal or pelvic procedures. Stepp and colleagues [2] identified first-trimester surgery, peritonitis, procedure length, and surgery at 24 weeks’ gestation as factors associated with pre-viable or preterm delivery. The decision to perform surgery and anesthesia on a pregnant woman does carry some risk of an adverse outcome. This decision must be made only after careful evaluation of the benefit to the mother versus the risk to the fetus. and secondarily because of an increase in heart rate [4,5,11–13]. Accompanying this increase in cardiac output is a functional S3 systolic murmur, clinically evident in 90% of pregnant patients [12]. In contrast to changes in cardiac output, blood pressure decreases early in pregnancy, returning to baseline levels by the end of the second trimester [14]. Decreases in systolic and diastolic blood pressure early in pregnancy (to the lowest levels between weeks 16 and 24) are primarily caused by a decrease in systemic vascular resistance, although the mechanism of this decrease is not well established [6,7]. Current data implicate various mediators (eg, progesterone, prostaglandins, and nitric oxide) as causing peripheral vasodilation and venodilation [8,10,14]. Treatment considerations Because of the increased abdominopelvic mass, there is the potential for significant compression of the inferior vena cava by the fetus when the pregnant patient is placed in a supine position. As a result of this compression, venous return to the heart is impaired, causing a decrease in stroke volume and a compensatory baroreceptor reflex to maintain cardiac output. The supine hypotension syndrome is clinically characterized by hypotension, syncope, and bradycardia. Although a patient may not present with signs of supine hypotension syndrome, there is still potential for significant disruption of uteroplacental flow when the patient is supine. To prevent or alleviate supine hypotension, the pregnant patient should be rolled to the left side by 5 to 15 (a position in which the right hip is elevated 10–12 cm) [3,4,10], which can be accomplished by inserting a wedge or pillow under the right hip (Fig. 1). If this does not work to alleviate the hypotension, the patient can be placed in a full left lateral position [3,10]. Respiratory alterations Changes in respiratory physiology in the pregnant patient are partly caused by the increased oxygen demands of the maternal-fetal systems. There are notable increases in tidal volume and minute ventilation rate, which are caused by superior displacement of the diaphragm [3,4,14–17]. As a result of this displacement (which can be up to 3–4 cm), there is a rise in intrathoracic pressure, which leads to an increase in the anteroposterior diameter of the thorax and chest circumference during inspiration [4,15]. Physiology of pregnancy and treatment considerations During pregnancy, the normal physiologic mechanisms for maintaining homeostasis undergo marked changes. Specifically, systemic alterations with respect to the cardiovascular, respiratory, and hematologic systems warrant careful monitoring by the surgeon. Gastrointestinal, renal, and endocrine alterations also warrant mention, because they may require modifications of treatment protocols. A summary of the major physiologic changes is provided in Table 1. Cardiovascular alterations Compared with the nonpregnant female patient, the pregnant patient shows significant changes in blood volume and cardiac output (heart rate and stroke volume) and changes in systemic vascular resistance and blood pressure [3–10]. The total blood volume in the pregnant patient can increase by up to 50% by 32 weeks’ gestation. This rise can be attributed primarily to a rise in plasma volume and secondary anemia [4,9,10]. In the third trimester (gestational weeks 25–33), an increase in cardiac output is apparent, primarily because of an increase in stroke volume ORAL AND MAXILLOFACIAL SURGERY FOR THE PREGNANT PATIENT 209 In addition to the increases in ventilation, there are concomitant decreases in oxygen reserves and increases in oxygen demand. Decreases in the oxygen reserves are significant because they predispose the mother and fetus to hypoxia [4,12,17]. Although hypercapnea is not a typical physiologic change in pregnant women, dyspnea is a relatively common occurrence [4,16,17]. Up to 50% of patients exhibit this clinical sign by the middle of the second trimester, and up to 75% exhibit it by the middle of the third trimester [16]. Hyperventilation is also a common finding in the pregnant patient and is present in approximately 40% of patients late in pregnancy [4,18]. In addition to changes in pulmonary physiology, there are significant mucosal changes in the upper airways. The mucosa of the upper airways has a tendency to become friable and edematous. Up to one third of pregnant women experience severe rhinitis, which predisposes them to frequent nosebleeds and upper respiratory tract infections [3,4]. It has been suggested that increased serum estrogen concentrations contribute to the episodes of rhinitis seen in pregnant women [4,19]. Treatment considerations Because of the effects of hyperventilation, a pregnant patient can present with a mild respiratory alkalosis [3,20]. Research has demonstrated that 25% of pregnant patients develop moderate hypoxemia and some develop an abnormal alveolar-arterial oxygen gradient when placed in the supine position [3,21]. Ventilation patterns and patient position must be adjusted for the pregnant patient so as to avoid hypoxemia [3,22]. Hematologic alterations Hematologic changes in the gravid patient include an increase in the number of erythrocytes and leukocytes, erythrocyte sedimentation rate, and most of the clotting factors, causing a hypercoagulable state [4,12,23,24]. There is also a relative decrease in blood hemoglobin concentration [4,12]. Although plasma volume and erythrocyte volumes increase in the gravid patient, the increase in volume of the plasma exceeds that of the erythrocyte, which leads to a physiologic anemia [4,25]. It is thought that increased levels of circulating catecholamines and cortisol contribute to the leukocytosis seen in pregnancy [4,23]. Treatment considerations Given the relative increase in many of the clotting factors (VII–X) and a decrease in anticlotting factors (XI, XIII), pregnant women are at an increased risk for thromboembolic events [3,4,26]. It has been reported that pregnant women have a fivefold increase in the likelihood of thromboembolic events, compared with nonpregnant patients [3,27]. The increased risk is caused by the hypercoagulable state and compression of venous return from the lower extremity by the uterus, which results in venous stasis and predisposes patients to thrombus formation [3]. Approximately 0.10% of pregnant patients have thrombus formation; up to 20% of these women develop a pulmonary embolism, with a 12% to 15% mortality rate [3,28,29]. The treatment of choice for a pregnant patient with a confirmed thromboembolic event (deep venous thrombosis or pulmonary embolism) is anticoagulant therapy. Anticoagulant prophylaxis is recommended for pregnant patients with a history of thromboembolic disease. For these patients, low molecular weight heparin is preferred because it does not cross the placenta (unlike Coumadin), has a much more predictable dose response because of low protein-binding (unlike unfractionated heparin), and has been demonstrated to be more effective than heparin for prophylaxis and less likely to cause major spontaneous bleeding [3,30,31]. Gastrointestinal alterations The most prominent gastrointestinal changes occurring in the gravid patient are related to changes in intragastric pressure, hormonal changes, and alterations in hepatic function. Gastrointestinal changes include increased frequency of nausea/vomiting and episodes of pyrosis (heartburn). Approximately two thirds of pregnant patients complain of nausea and vomiting, with the peak frequency at the end of the first trimester [3,32]. Excessive vomiting has been reported to occur in less than 1% of all pregnancies [32]. Pyrosis has been reported to occur in up to 70% of pregnant women and is thought to be the result of increases in intragastric pressure (caused by the presence of the fetus) and concomitant decreases in smooth muscle tone of the lower esophageal sphincter [3,33]. Loss of lower esophageal sphincter tone is thought to be caused by the inhibition of motilin production by high levels of progesterone. In addition to contributing to pyrosis, loss of lower esophageal sphincter tone and increased intragastric pressure have been linked to slowing of gastric emptying rates [3,34]. 210 Table 1 Physiologic changes in pregnancy System Cardiovascular Blood volume (L) FLYNN & SUSARLA Nonpregnant patient Pregnant patient 4.5–5.0 6.2–6.7 Direction of change [ Special considerations Increased uterine mass / compression of IVC / venous stasis and increased risk for deep venous thrombosis Decreased amplitude of T-waves on electrocardiogram Extra heart sounds / systolic S3 murmur Heart rate (beats/min) 70 Æ 10 80 Æ 10 [ Cardiac output (L/min) Systemic vascular resistance (dyne/cm/sec) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulmonary Tidal volume (mL) 4.3 Æ 0.90 1530 Æ 520 6.2 Æ 1.0 1210 Æ 266 [ Y 120 80 110 (trimester 1–2) Y (trimester 1–2) 50–60 (trimester 1–2) Y (trimester 1–2) 500 700 [ Minute ventilation (L) 7 10 [ Increased mucosal fragility / increased risk of airway edema, epistaxis with manipulation of nasal airway Decreased PaO2 while supine / increased risk of hypoxia,decreased functional residual capacity,progesterone-induced hyperventilation Hypercoagulable state / increased risk for thrombosis/embolism Leukocytosis Physiologic anemia due to increased circulating volume Generalized immunosuppression Hematologic Erythrocyte count (cells/mm3) Leukocyte count (cells/mm3) Serum hemoglobin (g/100 mL) Erythrocyte sedimentation rate (mm/h) Gastrointestinal/Hepatic Total protein (g/dL) 4–5 Â 105 4.8–6.5 Â 105 [ 5–9 Â 103 12–16 5–12 Â 103 11.5–12.3 [ [ 0–20 0–20 No change 6.5–7.5 5.7–6.5 Y Albumin (mg/dL) 3.2–3.8 2.4–3.1 Y Loss of lower esophageal sphincter tone / increased risk of reflux disease Decreased gastric motility (continued on next page) ORAL AND MAXILLOFACIAL SURGERY FOR THE PREGNANT PATIENT 211 Table 1 (continued ) System Alkaline phosphatase (IU/L) Aspartate aminotransferase (IU/L) Alanine aminotransferase (IU/L) Cholesterol (mg/dL) Triglycerides (mg/dL) Renal Renal plasma flow Glomerular filtration rate (mL/min) Nonpregnant patient Pregnant patient 30–115 0–42 100–210 O72 Direction of change [ [ Special considerations Increased intragastric pressure Loss of intravascular protein / decreased oncotic pressure / peripheral edema 0–48 O48 [ 120–190 76–92 420 100 Æ 18 190–330 205–247 695 150 Æ 30 [ [ [ [ Increased glomerular filtration rate Urinary stasis / increased risk of urinary tract infections Serum creatinine (mg/dL) 0.8–1.2 Blood urea 8–25 nitrogen (mg/dL) 1.2–1.8 !15 [ Y Alterations in hepatic function include decreases in total protein and albumin levels and increases in serum alkaline phosphatase, cholesterol, triglyceride, bilirubin, and aminotransferase (AST, ALT) levels [13,35,36]. The reported frequency of abnormal liver function tests as a result of pregnancy is approximately 3% [35]. Treatment considerations For the pregnant patient with frequent or excessive vomiting, morning appointments should not be scheduled [4]. Patients also should be advised to avoid foods that could initiate nausea/ vomiting, especially fatty foods [37,38]. Frequent episodes of vomiting can result in dehydration and electrolyte imbalances. Patients with frequent vomiting should be encouraged to drink electrolyte-rich fluids, such as commercially available sports drinks [37,38]. Increased episodes of gastric reflux and regurgitation warrant special consideration, because they can lead to aspiration of gastric contents and, in some cases, death [3,39]. Although it has been demonstrated that the acidity of the gastric aspirate is directly correlated with mortality, currently no evidence supports the use of antacids or histamine antagonists to reduce mortality from aspiration [40–44]. In this regard, prevention of aspiration of gastric contents during surgery should be the major focus of the practitioner. Changes in the serum concentration of liver proteins, particularly albumin, can lead to peripheral edema caused by loss of oncotic pressure. Because of concomitant hemodynamic changes in blood pressure, extremity edema should be monitored carefully before and during treatment of the pregnant patient. Renal alterations The pregnant patient typically has increased renal plasma flow and glomerular filtration rate and a slight decrease in serum creatinine levels and blood urea nitrogen [4,10,45,46]. Pregnant Fig. 1. The risk of supine hypotensive syndrome can be minimized during treatment by the insertion of a wedge or pillow under the right hip. 212 FLYNN & SUSARLA patients urinate more frequently and have a greater risk of urinary tract infections [3,4,45,46]. Increases in renal plasma flow primarily are caused by increases in blood volume and peak at 60% to 80% above normal levels during the second trimester and decrease thereafter [3,47]. The concomitant increase in glomerular filtration rate is 30% to 50% and occurs in the first trimester and remains at these levels until term [3,47]. As a result of the increased filtration, clearance of creatinine, uric acid, and urea is increased, which results in a decline in serum creatinine and blood urea nitrogen. Treatment considerations Given the increased frequency of urination normally seen in the pregnant patient, patients should be asked to void before starting treatment. Asymptomatic bacteriuria in the pregnant patient can progress to urinary tract infection and eventually pyelonephritis if untreated [3,48,49]. Before placing urinary catheters in a pregnant patient, the surgeon should evaluate the patient for potential risk factors for asymptomatic bacteriuria: age of parity, sexual activity, presence of sickle cell trait, and low socioeconomic status [3,49]. Because of alterations in renal plasma flow and glomerular filtration rate, any medications that are cleared by renal excretion should have their doses adjusted accordingly to account for increased clearance rates [3]. Medications in pregnancy The US Food and Drug Administration (FDA) drug classification system is described in Table 2. The current US FDA system of Table 2 Pregnancy risk categories for pharmacologic agents US FDA category A B Explanation Human pregnancy studies are available and demonstrate no risk to the fetus. Studies in animals demonstrate no fetal risk, but human studies are inadequate to determine risk. Animal studies demonstrate fetal toxicity, but human studies are inadequate. The benefit of use may exceed the risk. Human studies demonstrate fetal toxicity. The benefit of use may exceed the risk. Fetal abnormalities have been demonstrated in humans. The benefit of use does not exceed the risk. classification of the teratogenic potential of drugs is becoming outdated, however, because of the limited data on which the classification of many medications is based and because of the slow updating of a given drug’s classification as new information becomes available. Because of these problems, the US FDA is developing an evidence-based rating system that is not yet available. Current and accurate information can be obtained from academic centers or a fee-based online reproductive toxicity service. Known teratogens Fortunately, there is a small number but a wide variety of drugs that are teratogens (ie, drugs that can cause either structural or functional birth defects). Several categories of drugs are known to be teratogenic, including alcohol, tobacco, cocaine, thalidomide, methyl mercury, anticonvulsant medications, warfarin compounds, angiotensin-converting enzyme (ACE) inhibitors, retinoids, and certain antimicrobial agents. Table 3 lists the more commonly known teratogens, the birth defects with which they have been associated, and reasonable alternative medications. Ethyl alcohol Ethyl alcohol is probably one of the most potent teratogens. Approximately 70% of Americans use alcohol socially, and a recent survey indicated an average use of 12.8% during pregnancy [50–52]. A safe threshold dose of alcohol during pregnancy has not been established, but current data suggest that binge drinking and chronic ingestion of large quantities of alcohol carry the highest risk of inducing fetal alcohol syndrome. Fetal alcohol syndrome consists of behavioral disturbances and neurologic, cardiac, and spinal defects. Craniofacial anomalies are prominent in fetal alcohol syndrome and include absent or hypoplastic philtrum, broad or elongated upper lip, flattened nasal bridge, hypoplastic upper lip vermilion, micrognathia, microphthalmia, and short nasal dorsum. Alcoholic women who ingest eight or more drinks daily throughout pregnancy have a 30% to 50% risk of delivering a child with all of the features of fetal alcohol syndrome [50–52]. Tobacco Cigarette smoke contains multiple potential teratogens, including nicotine, cyanide, thiocyanate, carbon monoxide, cadmium, and lead. These substances may be directly toxic to the fetus and C D X ORAL AND MAXILLOFACIAL SURGERY FOR THE PREGNANT PATIENT 213 Table 3 Known teratogens and substitute drugs or therapies for them Teratogen Ethyl alcohol Tobacco Cocaine Thalidomide Methyl mercury Anticonvulsants (all) Hydantoin Carbamazepine Valproic acid Lamotrigine Phenobarbital Topiramate Warfarin (eg, Coumadin) Fetal risk Fetal alcohol syndrome Low birth rate, cleft lip and palate Placental abruption, cognitive delay Micromelia Microcephaly Brain damage Orofacial clefts, cardiac malformations Fetal hydantoin syndrome Spina bifida Neural tube defects Neural tube defects Urinary malformations Abnormalities in all subjects Warfarin embryopathy (midface and long bone deficiency) spontaneous abortion Oliguria, renal dysgenesis, lung and limb abnormalities Spontaneous abortion Multiple malformations Dental staining Nephrotoxicity Ototoxicity Nephrotoxicity Ototoxicity Substitute drug/therapy 12-step recovery Smoking cessation 12-step recovery Contraception in two forms Avoid/minimize fish intake Avoid dental amalgam? Some risk from epilepsy itself Avoid multidrug therapy Heparin Angiotensin-converting enzyme inhibitors Retinoids Tetracycline Aminoglycosides Vancomycin Discontinue before eighth week Contraceptive implants Discontinue before conception Clindamycin Beta-lactams Carbapenems Beta-lactams Teicoplanin Quinupristin/dalfopristin Linezolid Beta-lactams Carbapenems Lidocaine bretylium Fluoroquinolones Amiodarone Chondrotoxicity Hypothyroidism may have vasoactive effects, or reduce oxygen levels, which damages the fetus. Smoking has been associated with a dose-dependent reduction in fetal growth, resulting in low birth rate. It has also been associated with cleft lip and palate in many individuals who carry polymorphism in the transforming growth factor gene [51]. These individuals, when exposed prenatally to cigarette smoke, have twice the risk of combined cleft lip and palate and four to seven times the risk for cleft palate alone. Substance abuse The National Household Survey on Drug Use reported that 6.4% of women of childbearing age and 2.8% of pregnant women use illicit drugs. Marijuana accounted for 75% of drug use and cocaine for 10%. One in 20 pregnancies have been associated with cocaine abuse by the Centers for Disease Control and Prevention [52]. Cocaine causes vasoconstriction and hypertensive effects, which can result in myocardial infarction, cardiac dysrhythmias, stroke, seizure, and sudden death in the mother. Abruption of the placenta is the most commonly reported complication of pregnancy in cocaine abusersdfourfold that of nonusers [53]. Cocaine also has significant detrimental effects on cognitive and psychomotor development, which persist at least until age 4 [54]. Antiepileptic therapy Of itself, epilepsy carries an increased risk of fetal malformations. Most frequently reported birth defects are orofacial clefts and cardiac malformations [55]. Clefts develop almost ten times more often in fetuses of women who have 214 FLYNN & SUSARLA epilepsy than in the general population. High serum levels of antiepileptic medications and the use of multiple anticonvulsants increase the risk of fetal malformations. Fetal hydantoin syndrome is characterized by midfacial anomalies, including upturned nose, mild midface hypoplasia, and long upper lip with thin vermilion border. Other antiepileptic medications have been associated with fetal abnormalities. Associations have been reported between the use of valproic acid and spina bifida. Oral clefting increases with the use of phenobarbital, and various cardiac abnormalities are linked to other antiepileptic medications [55,56]. Hypertension The angiotensin-converting enzyme inhibitors frequently have been associated with fetal abnormalities. These drugs interrupt the renin-angiotensin system and impair the urinary concentrating ability in the fetus, which can result in renal ischemia, renal tubular dysgenesis, and anuria. Lack of urine production can result in a decreased amount of amniotic fluid, which then prevents normal lung development and causes contractures of the limbs. Recent studies indicated that even first-trimester exposure to angiotensin-converting enzyme inhibitors is associated with an increased risk of fetal abnormalities. Discontinuation of angiotensin-converting enzyme inhibitors before conception is strongly recommended [57]. Warfarin compounds, such as Coumadin, cause a dose-dependent risk of fetal damage. Ginsberg and Hirsh [58] performed an analysis of 186 studies involving 1325 exposed pregnancies. They found that 9% of fetuses exposed to warfarin compounds suffered permanent deformity or disability, and 17% of the fetuses died. Infants who survive are subject to warfarin embryopathy. Such individuals have nasal and midface hypoplasia and defects in the epiphyses of the long bones, especially the femur. Vitale and colleagues [59] found that warfarin embryopathy, including increased rate of spontaneous abortion, was significantly associated with warfarin doses larger than 5 mg [58]. Currently, unfractionated heparin and low molecular weight heparins are the agents of choice for anticoagulation in pregnancy. Low molecular weight heparins have been used safely without monitoring in nonpregnant patients; however, because of documented changes in the pharmacokinetics of these agents in pregnancy, monitoring with antiXa levels is necessary in pregnancy to maintain target therapeutic ranges [60]. Other teratogens Thalidomide Perhaps the most notorious teratogenic drug is thalidomide. In 20% of fetuses exposed during the first trimester of pregnancy, thalidomide produces micromelia, or shortening of limbs. Thalidomide was withdrawn from the market until recently, when immunomodulating uses were found for the drug. It has been used in the treatment of cutaneous lupus erythematosus, graft-versus-host disease, and certain malignancies. It is recommended that reproductive-aged women who must take thalidomide use two highly effective forms of birth control. Birth defects have been reported recently in children of women taking thalidomide who experienced contraceptive failure [61]. Mercury Although mercury is not currently used as a drug, environmental exposures to methyl mercury have resulted in a range of birth defects, from developmental delay to microcephaly and severe brain damage. The US FDA currently recommends that pregnant women not eat fish that accumulate mercury from the food chain, such as shark, swordfish, king mackerel, tuna, and tile fish [62]. They also should restrict their intake of other fish that are low in mercury. Drugs used in oral and maxillofacial surgery Oral and maxillofacial surgeons encounter pregnant patients in daily practice. Understanding the safety aspects of commonly used and prescribed medications minimizes adverse outcomes. Local anesthetic agents Lidocaine and other commonly used local anesthetic agents have not been associated with fetal malformations. The main concern in using these agents in a pregnant patient is overdose with increased vascular volume and permeability. The potential for local anesthetic toxicity is higher in pregnancy. Maximum allowable dosage should be reduced proportionally [63]. Epinephrine should be used judiciously in patients with pregnancy-associated hypertension. The recently revised maximum recommended doses of commonly used local anesthetic preparations for dental use are listed in Table 4. ORAL AND MAXILLOFACIAL SURGERY FOR THE PREGNANT PATIENT 215 Table 4 Maximum recommended doses of dental local anesthetic agents Anesthetic agent (1.8-mL cartridge contains n mg) Lidocaine 2% with 1:100,000 epi (36) Mepivacaine 3% (54) Prilocaine 4% Æ vasoconstrictor (72) Articaine 4% with epi 1: 100K or 200K (72) Bupivacaine 0.5% with 1:200,000 epi (9) Maximum recommended dose (mg) 4.4/kg (2.0 mg/lb) 300 mg maximum 4.4/kg (2.0 mg/lb) 300 mg maximum 6.0/kg (2.7 mg/lb) 400 mg maximum 7.0/kg (3.2 mg/lb) 5.0/kg for children aged 4–12; 500 mg maximum 1.3/kg (0.6 mg/lb) 90 mg maximum Maximum no. of cartridges 8 5.5 5.5 between the use of salicylates, such as aspirin, and fetal anomalies. Low-dose aspirin has been used to prevent pre-eclampsia, with no identifiable cardiac defects [66]. Among the nonsteroidal anti-inflammatory drugs, ibuprofen, naproxen, and ketoprofen have been used most frequently in pregnancy. Use of these drugs in early pregnancy has been associated with an increased risk of cardiac septal defects [67]. By inhibiting prostaglandin synthesis, they also may cause dystocia and delayed parturition. In general, nonsteroidal anti-inflammatory drugs should be avoided, especially during late pregnancy. Narcotic analgesic agents Fortunately for oral and maxillofacial surgeons, narcotic analgesic agents have not been associated with fetal anomalies. They can, however, cause neonatal narcotic withdrawal syndrome when the mother is addicted to narcotics. Antibiotics Common antibiotics Perhaps the most common reason an oral and maxillofacial surgeon is called on to treat a pregnant patient is infection. The teratogenic potential in humans ranges from none (penicllins) to unlikely (amoxicillin, chlorenphenicol, doxycycline, and rifampin) to undetermined (clindamycin, gentamycin, and vancomycin). The quinolones have been associated with irreversible arthropathy and cartilage erosion in fetuses of multiple animal species. The fluoroquinolones are not recommended for treatment of oral and maxillofacial infections in the child or pregnant patient. The macrolides, such as erythromycin, azithromycin, and clarithromycin, do not cross the placenta to any significant extent. They do not cause fetal anomalies. The tetracyclines are to be avoided in the pregnant patient and in children up to 12 years of age because of permanent dental staining. Metronidazole is an antianaerobic antibiotic that has previously been shown to be carcinogenic and mutagenic in certain bacteria. In more than 17,000 fetuses exposed to metronidazole in the first trimester, however, there was no increase in the rate of congenital anomalies [68,69]. Another analysis by Burtin and colleagues [69] found no increased teratogenic risk with the use of metronidazole [68]. Use of metronidazole seems justified for significant oral and maxillofacial infections in the pregnant patient. 7 (2 for children aged 4–12) 10 Data from Malamed SF. Handbook of local anesthesia. 5th edition. St. Louis: Mosby; 2004. General anesthetic agents Fortunately, most general anesthetic agents have low teratogenic potential. These drugs are discussed fully in the accompanying article on anesthesia for the female patient. Mazze and Kallen [1] studied 720,000 pregnant women who underwent 5405 nonobstetric operations and found no association between anesthesia exposure and adverse fetal outcome. In most studies, nitrous oxide, halothane, ketamine, methohexital, etomidate, and thiopental have been found to be safe. Likewise, curare and succinylcholine have not been associated with human teratogenic effects. Nitrous oxide has been implicated in decreased fertility and spontaneous abortion in women with an occupational exposure to it [64]. More recently introduced scavenging and ventilation methods may reduce this problem. Analgesic agents Acetaminophen is the most widely used analgesic agent in pregnancy. It has not been associated with increased risk of congenital anomalies [65]. Some data implicate salicylates in cases of spontaneous abortion and fetal gastroschisis, but most investigators have not found any association 216 FLYNN & SUSARLA Antifungal agents Nystatin and clotrimazole have not been associated with congenital defects when they are used for vaginal candidiasis. Pregnant women demonstrate an increased susceptibility to vaginal colonization and infection by yeast, and antifungal therapy is often required. The use of topical agents for treatment of superficial fungal infections is safe and efficacious. Some data, however, raise concerns with the use of various systemic antifungal agents, including griseofulvin and ketoconazole, which may be associated with fetal malformations and should be avoided in pregnancy. Amphoterocin B remains the drug of choice for the treatment of deep and life-threatening fungal infections in pregnancy [70]. Antiviral agents Acyclovir and valacyclovir are antiviral antibiotics that can be used to treat herpetic infections. The limited information available, most of which is for acyclovir, indicates no increase in fetal anomalies and no distinctive pattern of fetal defects, although further research is required to clarify the safety spectrum of these agents. Topical use of acyclovir results in minimal systemic absorption. When a significant benefit is expected, these antiviral agents may be used [71,72]. Steroidal anti-inflammatory drugs Prednisone and prednisolone have been used clinically in pregnant women, especially for treatment of severe asthma, without adverse effects on the fetus [73]. Triamcinolone and beclomethasone are teratogenic in animals but have not been associated with fetal defects in humans [74]. Oral and maxillofacial surgery for the pregnant patient Dentoalveolar and elective procedures Given the significant alterations in physiology seen in the pregnant patient and the high cost of adverse events (especially considering risks to mother and child), oral and maxillofacial surgical treatment of the pregnant patient should be undertaken only in emergent situations. Elective procedures (eg, cosmetic surgery, orthognathics) should be delayed until the postpartum period. Some elective and emergent dentoalveolar procedures are more safely accomplished during the second trimester. This practice avoids potential teratogenic concerns associated with early pregnancy and the physiologic problems and patient position concerns seen in the third trimester. Dentoalveolar surgery should be directed toward the relief of pain, elimination of infection and neoplasia, and repair of traumatic injuries. If treatment is to be rendered, the patient should not be placed in the supine position because of the possibility of supine hypotensive syndrome and the increased risk of deep venous thrombosis. Ideally, the patient should be positioned in the left lateral decubitus position, with the right hip elevated approximately 15 (6–12 inches) above the surface of the chair (Fig. 1) [3]. In the event of a syncopal episode or if cardiopulmonary resuscitation is required, patient positioning is paramount. The left lateral displacement of the uterus can be accomplished manually by a member of the resuscitating team by tilting the table/chair laterally or by placing a wedge under the right hip (Fig. 1). This step is especially important during cardiopulmonary resuscitation. Judicious selection of pharmaceutical agents should be made to minimize the risk of complications to the mother and fetus (see previous discussion). Oral radiography and radiation safety Animal and human studies have demonstrated that adverse events related to radiation exposure, such as congenital fetal abnormalities, require a radiation dose of R10 Gy (5 Gy in the first trimester, when organogenesis is initiated) [3]. It has been estimated that the dose to the fetus is approximately 1/50,000 of that to the mother’s head [75–78]. Given these estimates, the estimated radiation exposure to the fetus from a full mouth series, panoramic film, computed tomogram of the head and neck, and chest films are in the range of 1 Â 10À5 to 1 Â 10À2 Gy [4]. The exposure of any radiographic films required for management of the pregnant patient in most situations should not place the fetus at increased risk. Adequate shielding and protective equipment must be used at all times [75–78]. Trauma Trauma occurs in 5% of pregnancies. Motor vehicle accidents account for more than 50% of all cases of trauma during pregnancy. They are responsible for 82% of fetal deaths caused by trauma [79]. In general, a multidisciplinary approach involving maternal and fetal medicine, neonatology, anesthesiology, and intensive care ORAL AND MAXILLOFACIAL SURGERY FOR THE PREGNANT PATIENT 217 medicine is essential for optimizing outcomes in cases of severe trauma [80]. Domestic violence is another potential concern when a pregnant woman suffers maxillofacial trauma. The pregnancy may place additional stresses on the mother’s significant relationships and living situation. The oral and maxillofacial surgeon is often the first practitioner to see and evaluate these patients and should be prepared to identify and appropriately refer victims of domestic violence to prevent future injuries [81]. The treatment of maxillofacial trauma in the gravid patient is not significantly different than in other patients, with the following exceptions: Maternal and fetal stability must be assessed. Obstetric examination, consultation, and clearance are often required in these patients. The need for fetal monitoring must be determined. Definitive airway control by intubation or tracheotomy may be required when the patient’s ability to maintain her own airway is questionable. Once the patent is stable, extraoral and intraoral examinations are accomplished. If facial fractures are present, rigid fixation of maxillary and mandibular fractures is advisable to avoid or minimize the period of maxillomandibular fixation. This approach allows the restoration of adequate nutrition as rapidly as possible and minimizes aspiration risk [3]. The mucosa of the oral cavity and the oropharynx must be evaluated carefully because it is more friable and hemorrhagic than normal. Infections Head and neck infections should be managed aggressively in the gravid patient. There is a mild degree of immunosuppression in pregnancy, and sepsis is known to occur more frequently in pregnant than nonpregnant women. Severe septic complications that occur in pregnancy are associated with an increased risk of adverse fetal outcomes [1]. Early incision and drainage of odontogenic infections are indicated, as is appropriate use of antibiotics (see previous discussion). Primary concern should be given to airway security [82–84]. Pathology Mucosal and skin changes are commonly seen during pregnancy and are secondary to hormonal alterations. The most common changes include increased pigmentation in the maxillofacial region, gingival disease, pyogenic granuloma, and changes in salivary gland physiology [4,85,87]. Changes in the pigmentation of the skin (melasma) in the maxillofacial region, which typically appear as bilateral brown patches, begin to appear in the first trimester and are seen in most pregnant women [88,89]. Increases in estrogen and progesterone have been suggested to cause the alterations in pigmentation, although the true mechanism remains unclear [85,86]. Gingival changes in the pregnant patient include pregnancy gingivitis and gingival hyperplasia [85,86]. Pregnancy gingivitis is typically an exacerbation of a pre-existing condition, and it primarily affects the marginal gingiva and interdental papillae [4,85]. Gingival hyperplasia is thought to be caused by increased capillary permeability within the gingiva because of increased amounts of circulating estrogen [4,85–87]. Pregnancy tumor, or pyogenic granuloma, is a swelling that typically occurs on the labial aspect of the dental papilla in approximately 1% to 5% of pregnant women [90–92]. Pyogenic granulomas are more likely to occur during the first or second trimesters and usually resolve in the postpartum period [90,91]. Hormonal changes that result in increased angiogenesis and local factors, such as plaque-induced gingivitis, are thought to play an etiologic role [91]. Salivary changes in the pregnant patient include changes in the pH and composition of salivary secretions [4,92]. There are conflicting data regarding changes in salivary flow rates, with some studies suggesting no change and others suggesting decreases in whole stimulated salivary flow rates [92]. The pH of salivary secretions in a pregnant patient tends to be lower than that of a nonpregnant patient [92,93]. Salivary secretions in the pregnant patient contain higher concentrations of potassium and estrogen and lower concentrations of sodium [92,93]. Research has demonstrated that increases in salivary estrogen levels can lead to increased rates of desquamation of the oral mucosa, which allows increased bacterial proliferation and promotes dental decay [92]. An increasing body of evidence suggests that untreated periodontal disease in the pregnant patient is associated with adverse pregnancy outcomes, including preterm delivery and low birth weight [94–96]. Although many studies have evaluated this association and have controlled for potential confounders, a suitable causal explanation has not yet been established [95]. The pregnant patient should be strongly encouraged to maintain good oral hygiene to minimize these effects. Fortunately, 218 FLYNN & SUSARLA References [1] Mazze RI, Kallen B. Reproductive outcome after anesthesia and operation during pregnancy: a registry study of 5405 cases. Am J Obstet Gynecol 1989; 161:1178–85. [2] Stepp KJ, Sauchak KA, O’Malley DM, et al. Risk factors for adverse outcomes after intraabdominal surgery during pregnancy. Obstet Gynecol 2002;99: 23S. [3] Turner M, Aziz SR. Management of the pregnant oral and maxillofacial surgery patient. J Oral Maxillofac Surg 2002;60:1479–88. [4] Suresh L, Radfar L. Pregnancy and lactation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97(6):672–82. [5] Mabie WC, Di Sessa TG, Crocker LG, et al. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994;170:849–56. [6] Lee W. Cardiorespiratory alterations during normal pregnancy. Crit Care Clin 1991;7:763–75. [7] Hunter S, Robson SC. Adaptation of the maternal heart in pregnancy. Br Heart J 1992;99(Suppl): 540–3. [8] Chu ZM, Beilin LJ. Mechanisms of vasodilation in pregnancy: studies of the role of prostaglandins and nitric oxide in changes of vascular reactivity in the in situ blood perfused mesentery of pregnant rats. Br J Pharmacol 1993;109:322–9. [9] Theunissen IM, Parer JT. Fluid and electrolytes in pregnancy. Clin Obstet Gynecol 1994;37:3–15. [10] Duvekot JJ, Peeters LL. Maternal cardiovascular hemodynamic adaptation to pregnancy. Obstet Gynecol Surv 1994;49(Suppl):S1–14. [11] Baron WM, Lindheimer MD, editors. Medical disorders during pregnancy. 2nd edition. St Louis (MO): Mosby; 1995. p. 129. [12] Thornburg KL, Jacobson SL, Giraud GD, et al. Hemodynamic changes in pregnancy. Semin Perinatol 2000;24:11–4. [13] Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 1989;161:1439–42. [14] Clapp JF 3rd, Capeless E. Cardiovascular function before, during, and after the first and subsequent pregnancies. Am J Cardiol 1997;80:1469–73. [15] Contreras G, Gutierrez M, Beroiza T, et al. Ventilatory drive and respiratory muscle function in pregnancy. Am Rev Respir Dis 1991;144:837–41. [16] Garcia-Rio F, Pino JM, Gomez L, et al. Regulation of breathing and perception of dyspnea in healthy pregnant women. Chest 1996;110:446–53. [17] McAuliffe F, Kametas N, Costello J, et al. Respiratory function in singleton and twin pregnancy. BJOG 2002;109:765–9. [18] Skatrud JB, Dempsey JA, Kaiser DG. Ventilatory response to medroxyprogesterone acetate in normal subjects. J Appl Physiol Respir Environ Exerc Physiol 1978;44:393–44. Fig. 2. Intraoral view of a peripheral ossifying fibroma in a pregnant dentist. Although it had been noted before the pregnancy began, its growth accelerated during the pregnancy. most oral pathologic conditions are benign, slow growing, and non–life threatening. An example is depicted in Fig. 2. The definitive management of most oral pathologic conditions can be deferred until either the middle trimester or after delivery. More aggressive lesions and malignancies require expedient treatment. An individualized, multidisciplinary approach to such cases is required. Summary Practicing oral and maxillofacial surgeons must consider the well-being of mother and fetus without compromising the quality of care provided to the mother. As our knowledge of the physiology and applicable pharmacology unfolds, oral and maxillofacial surgeons can apply accepted principles and new discoveries to treatment decisions for the pregnant patient. In summary, oral and maxillofacial surgeons should avoid elective surgery in the pregnant patient, if possible. Routine dental health procedures should be accomplished before conception in planned pregnancies and during the middle trimester in unplanned pregnancies. Oral and maxillofacial surgeons may be called on to treat urgent or emergent cases involving trauma, infection, and pathology whose treatment cannot be postponed. Active treatment is directed toward optimizing maternal health while minimizing fetal risk. Acknowledgments The authors wish to acknowledge the editorial assistance of Monica Garrison. ORAL AND MAXILLOFACIAL SURGERY FOR THE PREGNANT PATIENT 219 [19] Camann WR, Ostheimer GW. Physiological adaptations during pregnancy. Int Anesthesiol Clin 1990; 28:2. [20] Hankins GDV, Clark SL, Harvey CJ. Third-trimester arterial blood gas and acid base values in normal pregnancy at moderate altitude. Obstet Gynecol 1996;88:347. [21] Awe RJ, Nicotra MB, Newsom TD. Arterial oxygenation and alveolar-arterial gradients in term pregnancy. Obstet Gynecol 1979;53:182. [22] Barron WM. Medical evaluation of the pregnant patient requiring nonobstetric surgery. Clin Perinatol 1985;12:481–96. [23] Branch DW. Physiologic adaptations of pregnancy. Am J Reprod Immunol 1992;28:120–2. [24] Hamaoui E, Hamaoui M. Nutritional assessment and support during pregnancy. Gastroenterol Clin North Am 2003;32:59–121. [25] Sifakis S, Pharmakides G. Anemia in pregnancy. Ann N Y Acad Sci 2000;900:125–36. [26] Hanly JG. Antiphospholipid syndrome: an overview. CMAJ 2003;24(168):1675–82. [27] NIH Consensus Development Congress. Prevention of venous thrombosis and pulmonary embolism. JAMA 1986;256:744–9. [28] Letsky EA, DeSwiet M. Thromboembolism in pregnancy and its management. Br J Haematol 1984; 57:543–52. [29] Rutherford SE, Phelan JP. Thromboembolic disease in pregnancy. Clin Perinatol 1988;13:719– 39. [30] Barbour L. Current concepts of anticoagulant therapy in pregnancy. Obstet Gynecol Clin North Am 1997;28:499–521. [31] Hunt MG, Martin JN, Martin RW. Perinatal aspects of abdominal surgery for nonobstetric disease. Am J Perinatol 1989;6:412–7. [32] Sherman P, Flaxman SM. Nausea and vomiting of pregnancy in an evolutionary perspective. Am J Obstet Gynecol 2002;185(Suppl):s190–7. [33] Calhoun BC. Gastrointestinal disorders in pregnancy. Obstet Gynecol Clin North Am 1992;4: 733–44. [34] Christofides ND, Ghatei MA, Bloom SR. Decreased plasma motilin concentrations in pregnancy. Br Med J 1982;285:1453. [35] Ch’ng CL, Morgan M, Hainsworth I, et al. Prospective study of liver dysfunction in Southwest Wales. Gut 2002;51:876–80. [36] Martin C, Varner MW. Physiologic changes in pregnancy: surgical implications. Clin Obstet Gynecol 1994;37:241–55. [37] Koch KL, Frissora CL. Nausea and vomiting during pregnancy. Gastroenterol Clin North Am 2003; 32(1):201–34. [38] Koch KL. Gastrointestinal factors in nausea and vomiting of pregnancy. Am J Obstet Gynecol 2002;186(5 Suppl):S198–203. [39] Crawford JS, Oppit LJ. A survey of anesthetic services to obstetrics in the Birmingham Hospital. Reg Anesth 1976;31:56–9. [40] Bond VK, Stoelting RK, Gupta CD. Pulmonary aspiration syndrome after inhalation of gastric fluid containing antacids. Anesthesiology 1979;51: 452–3. [41] Gibbs CP, Banner TC. Effectiveness of Bicitra as a preoperative antacid. Anesthesiology 1984;61: 97–9. [42] Gibbs CP, Spohr L, Shmidt D. The effectiveness of sodium citrate as an antacid. Anesthesiology 1982; 57:44–6. [43] Hodgkinson R, Glassenberg R, Joyce TH III. Comparison of cimetidine with antacid for safety and effectiveness in reducing gastric acidity before elective cesarean section. Anesthesiology 1983;59: 86–90. [44] Yau G, Kan AF, Gin T. A comparison of omeprazole and ranitidine for prophylaxis against aspiration pneumonitis in emergency caesarean section. Anaesthesia 1992;47:101. [45] Dafnis E, Sabatini S. The effect of pregnancy on renal function: physiology and pathophysiology. Am J Med Sci 1992;303:184–205. [46] Davidson JM. Renal disorders in pregnancy. Curr Opin Obstet Gynecol 2001;13:109–14. [47] Davidson JM, Shiells EA, Philips PR, et al. Serial evaluation of vasopressin release and thirst in human pregnancy: role of human chorionic gonadotropin in the osmoregulatory changes of gestation. J Clin Invest 1988;81:798–806. [48] Diokno AC, Compton A, Seski J. Urologic evaluation of urinary tract infection in pregnancy. J Reprod Med 1986;31:23–6. [49] Mikhail MS, Anyaegbunam A. Lower urinary tract dysfunction in pregnancy: a review. Obstet Gynecol Surv 1995;50:675–83. [50] Cunningham FG, Leveno KJ, Bloom SL, et al. In: Williams obstetrics. 22nd edition. New York: McGraw-Hill; 2005. [51] Shaw GM, Velie EM, Schaffer D. Risk of neural tube defect affected pregnancies among obese women. JAMA 1996;275:1093–6. [52] Ebrahim SH, Gfroerer J. Pregnancy-related substance use in the United States during 1996–1998. Obstet Gynecol 2003;101:374–9. [53] Shiono PH, Klebanoff MA, Nugent RP, et al. The impact of cocaine and marijuana use on low birth weight and preterm birth: a multicenter study. Am J Obstet Gynecol 1995;172:19–27. [54] Singer LT, Minnes S, Short E, et al. Cognitive outcomes of preschool children with prenatal cocaine exposure. JAMA 2004;292:1021. [55] Wyszynski DF, Beaty TH. Review of the role of potential teratogens in the origin of human nonsyndromic oral clefts. Teratology 1996;53(5): 309–17. 220 FLYNN & SUSARLA [56] Arpino C, Brescianini S, Robert E, et al. Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposure. Epilepsia 2000;41(11):1436–43. [57] Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354(23):2443–5. [58] Ginsberg JS, Hirsh J. Anticoagulants during pregnancy. Annu Rev Med 1989;40:79–86. [59] Vitale N, DeFeo M, DeSanto LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33:1637–41. [60] Casele HL. The use of unfractionated heparin and low molecular weight heparins in pregnancy. Clin Obstet Gynecol 2006;49(4):895–905. [61] Castilla EE, Ashton-Prolla O, Barreda-Mejia E, et al. Thalidomide, a current teratogen in South America. Teratology 1996;54:273–7. [62] Burger J, Stern AH, Gochfeld M. Mercury in commercial fish: optimizing individual choices to reduce risk. Environ Health Perspect 2005;113(3): 266–71. [63] Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doss of local anesthesia: a multifactorial concept. Reg Anesth Pain Med 2004;299: 564–75. [64] Boivin JF. Risk of spontaneous abortion in women occupationally exposed to anaesthetic gases: a metaanalysis. Occup Environ Med 1997;54:541–8. [65] Thulstrup AM, Sorensen HT, Nielsen GL, et al. Fetal growth and adverse birth outcomes in women receiving prescriptions for acetaminophen during pregnancy: Euromap Study Group. Am J Perinatol 1999;16(7):321–6. [66] Di Sessa TG, Moretti ML, Khouri A, et al. Cardiac function in fetuses and newborns exposed to low dose aspirin during pregnancy. Am J Obstet Gynecol 1994;171:892–900. [67] Ofori B, Oraichi D, Blais L, et al. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-controlled study. Birth Defects Res B Dev Reprod Toxicol 2006; 77(4):268–79. [68] Piper JM, Mitchell EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynecol 1993;82:348–52. [69] Burtin P, Taddio A, Ariburnu O, et al. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynecol 1995;172:525–9. [70] Moudgal VV, Sobel JD. Antifungal drugs in pregnancy: a review. Expert Opin Drug Saf 2003;2(5): 475–83. [71] Raborn GW, McGaw WT, Grace M, et al. Oral acyclovir and herpes labialis: a randomized, doubleblind, placebo-controlled study. J Am Dent Assoc 1987;115:38–42. [72] Moomaw MD, Cornea P, Rathbun RC, et al. Review of antiviral therapy for herpes labialis, genital herpes and herpes zoster. Expert Rev Anti Infect Ther 2003;1(2):283–95. [73] Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986;78:349–53. [74] Dombrowski MP, Brown CL, Berry SM. Preliminary experience with tramcinolone acetonide during pregnancy. J Matern Fetal Med 1996;5:310–3. [75] Brent RL. The effects of embryonic and fetal exposure to x-rays, microwaves and ultrasound. Clin Obstet Gynecol 1983;26:484–510. [76] Freeman JP, Brand JW. Radiation doses of commonly used dental radiographic surveys. Oral Surg Oral Med Oral Pathol 1994;77:285–9. [77] Little JW, Falace DA, Miller CS, et al, editors. Dental management of the medically compromised patient. 6th edition. St Louis (MO): Mosby; 2002. p. 303. [78] Richards AG. Dental x-ray protection. Dent Clin North Am 1968 Nov;631–41. [79] Mattox KL, Goetzl L. Trauma in pregnancy. Crit Care Med 2005;33(10 Suppl):S385–9. [80] Cole DE, Taylor TL, McCullough DM, et al. Acute respiratory distress syndrome in pregnancy. Crit Care Med 2005;33(10 Suppl):S269–78. [81] Bach TL, Dierks EJ, Ueeck BA, et al. Maxillofacial injuries associated with domestic violence. J Oral Maxillofac Surg 2001;59:1277–83. [82] Flynn TR, Shanti RM, Levy M, et al. Severe odontogenic infections: I. Prospective report. J Oral Maxillofac Surg 2006;64:1093–103. [83] Flynn TR, Shanti RM, Hayes C. Severe odontogenic infections: II. Prospective outcomes study. J Oral Maxillofac Surg 2006;64:1104–13. [84] Lawrenz D, Whitley B, Helfrick J. Considerations in the management of maxillofacial infections in the pregnant patient. J Oral Maxillofac Surg 1996;54: 474–85. [85] Hugoson A. Gingivitis in pregnant women: a longitudinal clinical study. Odontol Revy 1971;22:65–84. [86] Soory M. Hormonal factors in periodontal disease. Dent Update 2000;27:380–3. [87] Wong RC, Ellis CN. Physiologic skin changes in pregnancy. J Am Acad Dermatol 1984;10:929–40. [88] Kauh YC, Zachian TF. Melasma. Adv Exp Med Biol 1999;455:491–9. [89] Errickson CV, Matus NR. Skin disorders of pregnancy. Am Fam Physician 1994;49:605–10. [90] Neville BW, Damm DD, Allen CM, et al, editors. Oral and maxillofacial pathology. 3rd edition. Philadelphia: W B Saunders; 2002. p. 329–30, 447–49. [91] Yuan K, Wing LY, Lin MT. Pathogenetic roles of angiogenic factors in pyogenic granulomas in pregnancy are modulated by female sex hormones. J Periodontol 2002;73:701–8. ORAL AND MAXILLOFACIAL SURGERY FOR THE PREGNANT PATIENT 221 [92] Laine M, Tenovuo J, Lehtonen OP, et al. Pregnancyrelated changes in human whole saliva. Arch Oral Biol 1988;33:913–7. [93] Salvolini E, Di Giorgio R, Curatola A, et al. Biochemical modifications of human whole saliva induced by pregnancy. Br J Obstet Gynaecol 1998; 105:656–60. [94] Lopez NJ, Smith PC, Gutierrez J. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: a randomized controlled trial. J Periodontol 2002;73:911–24. [95] McGaw T. Periodontal disease and preterm delivery of low birth-weight infants. J Can Dent Assoc 2002; 68:165–9. [96] Goepfert AR, Jeffcoat MK, Andrews WW, et al. Periodontal disease and upper genital tract inflammation in early spontaneous preterm birth. Obstet Gynecol 2004;104(4):777–83.