Critical Care Obstetrics part 65 pdf

Fetal Effects of Drugs Commonly Used in Critical Care 629 Wolff – Parkinson – White syndrome. Its mechanism of action is based on changing ion channels in order to suppress the AV node. It has a short half - life of 0.6 – 1.5 seconds. Given this short elimination half - life, there are no studies examining placental transfer. One survey suggests that a higher dose of adenosine is required in pregnant women, likely representing the effect of the increased volume of distribution [50] . Intravenous adenosine may produce fl ushing, chest pain, and dyspnea. These side effects are transient and resolve in 5 – 20 seconds [51] . Given this data, it is an ideal cardiovascular drug in pregnancy. Fetal effects of adenosine are transient. There are varied reports of the effect of adenosine on fetal heart tracings from no change to short episodes of fetal bradycardia [52,53] . Given these transient changes, it is suggested that adenosine should be administered in conjunction with fetal heart rate monitoring [48] . To date, there are no reports of human teratogenesis secondary to adenosine use. There are no data specifi cally evaluating adenosine and lactation. Again, given the short elimination half - life and use in acute settings, it is likely present in negligible amounts in human breast milk. Amiodarone Amiodarone is a class III antiarrhythmic agent. It is commonly used in maternal or fetal ventricular tachycardia/fi brillation and atrial fi brillation. It works by prolonging phase III of the cardiac action potential. It also has β - blocker and calcium channel blocker - like activity at the level of the SA and AV nodes. Amiodarone and its major active metabolite, mono - N - desethyl- amiodarone, have long mean elimination half - lives of 53 and 61 days, respectively [54] . They also have large volumes of distribution. Studies have documented placental transfer of amiodarone with approximately 25% of active drug still found in cord blood [55] . These pharmacokinetic aspects of amiodarone predispose it to more maternal and fetal side effects. Maternal side effects include thyroid abnormalities, liver dysfunction, skin discolor- ation, and most importantly idiopathic pulmonary fi brosis. Despite the increased volume of distribution during pregnancy, it is not clear if the risk of the side effects is increased with pregnancy. In a study of 12 in utero exposed fetuses, six had fi rst - trimester exposure. One of the six infants was born with congenital nystagmus. Another infant with amiodarone exposure at 20 weeks had developmental delay, hypotonia, hypertelorism and micrognathia. This infant was exposed to multiple drugs during pregnancy [56] . Yet, there are no conclusive studies linking amiodarone and human teratogenicity. There are multiple reports of different fetal side effects linked to in utero amiodarone exposure. Amiodarone is 37% iodine by weight with a chemical structure that is similar to thyroxine [57] . Consequently, a common fetal side effect is congenital goiter with hypo - or hyperthyroidism. In a recent 2004 review of neonatal thyroid dysfunction and amiodarone exposure, the authors examined 69 reported cases of amiodarone use pregnancy. Duration of use ranged from 2 days to 40 weeks. Of all these cases, 23% of the infants developed hypothyroidism requiring varying pancuronium. In the fetal therapy literature, there is a well - documented short - term fetal response to the administration of pancuronium to the fetus. In addition to decreased movement, a decrease in heart rate variability and accelerations is observed [43] . It has been reported that fetal heart variability can be reduced by 60% [44] . These changes are temporary and revert to normal after the fetus has recovered from the drug. Although not statistically signifi cant, pancuronium proves to have a more signifi cant neonatal effect on 15 - min Neurologic Adaptive Capacity Scores than vecuronium, with 29% of those neonates exposed to pancuronium having normal NACS versus 73% of those born exposed to vecuronium [45] . Pancuronium can be used during pregnancy. There are no reports on pancuronium and human lactation. Vecuronium Like pancuronium, vecuronium is a non - depolarizing curaremi- metic neuromuscular blockade agent. It has a similar mechanism of action and is used in general anesthesia protocols for surgeries including cesarean sections. Vecuronium is also used for fetal immobility during intrauterine blood transfusions. There is a report of in utero use of vecuronium for fetal MRI [46] . In term pregnant women, the half - life of vecuronium is an average of 36 minutes with an onset of action of 125 – 175 seconds [40] . Vecuronium has a lower mean cord to maternal venous concentration ratio than pancuronium with average ratios between 0.11 and 0.14 [40] . The decreased fetal uptake of vecuronium gives it an advantage over pancuronium in the treatment of parturients. In direct comparisons between pancuronium and vecuronium, retrospective data shows that vecuronium displayed no fetal heart rate changes [47] . As with pancuronium, there are no reports of human congenital malformations linked to vecuronium. There are no studies evaluating vecuronium and human lactation. Cardiovascular d rugs Acute or chronic cardiovascular disease poses a signifi cant risk to the parturient. In the UK, heart disease is the leading indirect cause of maternal mortality, causing 16.5% of all maternal deaths during the period of 1997 – 1999 [48] . In the United States the maternal mortality rate is 13.1 per 100 000 live births as of 2004 [49] . A majority of those deaths were due to cardiovascular causes. It is important to emphasize that in the case of acute cardiovascular collapse of a pregnant woman, the potential fetal effects of drugs can become secondary to maternal health. To evaluate specifi c therapeutics related to this fi eld, this section will divide the drugs by functional classes. ACLS d rugs Adenosine Adenosine is a ubiquitous nucleoside. It has been used in pregnancy for the therapy of supraventricular tachycardias including Chapter 44 630 outcomes with in utero exposure of epinephrine. In an acute life - threatening situation, one may consider the use of epinephine in the parturient. There are also no studies showing epinephrine secretion in human milk. Diltiazem and o ther c alcium c hannel b lockers Diltiazem is a calcium channel blocker. In acute settings, it is used to control ventricular rate in atrial fi brillation. It is also used to terminate supraventricular or reentrant tachycardias. Placental transfer of diltiazem has not specifi cally been investigated in humans. There are no studies conclusively linking diltiazem with human congenital abnormalities. One study of 78 women exposed to calcium channel blockers cites a slightly higher risk of congenital malformations [70] . Limb malformations were seen in two of the neonates. The authors note that these fi ndings were likely not due to the calcium channel exposure. Animal studies have shown more signifi cant association with limb abnormalities and fetal loss [71,72] . These fi ndings have not been substantiated in humans. The use of diltiazem is considered compatible with pregnancy. Data concerning diltiazem and breastfeeding are based on one lactating woman [73] . The reported milk to plasma ratio was 1.0. The American Academy of Pediatrics considers diltiazem compatible with breastfeeding [58] . Verapamil is a calcium channel blocking agent and is an alternative drug to terminate paroxysmal supraventricular tachycardia. It is used to control the ventricular response in atrial fi brillation, atrial fl utter, or multifocal atrial tachycardia. The fetal to maternal drug concentration ratio is reported at 0.1 – 0.2 [74] . In the aforementioned study, the 25 neonates exposed to verapamil had no associated congenital abnormalities [67] . One case of unexplained fetal death has been associated with verapamil in the transplacental treatment of fetal supraventricular tachycardia [75] . Thus, verapamil can be used in pregnancy. There have been no reports of fetal effects secondary to the transfer of drug through human milk. It is considered safe for breastfeeding [31] . Ibutilide Ibutilde has been used for the treatment of supraventricular tachycardias like atrial fi brillation and atrial fl utter. It works by prolonging the cardiac action potential. Little is known about the use of ibutilide in pregnancy. One review suggests that class III antiarrhythmic drugs like ibutilide have similar teratogenic effects as phenytoin including distal digital defects and orofacial clefts [76] . These data and others show this effect in animal studies [77] . To date, there are no human studies on ibutilide concerning its potential effects on the human fetus and lactation. In an ICU setting with few alternative treatments, one may consider the use of ibutilide in the parturient. Lidocaine Lidocaine has multiple uses in medicine. In the cardiovascular realm, it is used to treat cardiac arrest secondary to ventricular durations of replacement (5 weeks – 20 months). Only two infants developed hyperthyroidism [55] . Growth restriction has also been seen in multiple series. It is not clear if this fi nding is secondary to amiodarone, the cardiac polypharmacy to which these fetuses were exposed, or the underlying condition requiring treatment. Given these fi ndings, it is recommended that amiodarone be used only in refractory cases [58] . Recommendations about the use of amiodarone during breastfeeding are controversial. The WHO Working Group on Drugs and Human Lactation discourage the use of amiodarone in breastfeeding patients given the clinically effective concentrations in human milk [59] . In contrast, the American Academy of Pediatrics states that amiodarone may be used as long as maternal doses are minimized and the infant is monitored for thyroid disturbances [60] . Clearly, amiodarone should be used cautiously during breastfeeding. Atropine Atropine is an anticholinergic agent that is frequently combined in a variety of pharmaceutical products. In the setting of advanced cardiac life support, atropine is used for the treatment of sinus bradycardia, pulseless electrical activity, and asystole. Atropine has a half - life of 2 hours. Atropine is known to cross the placenta [61] . Despite this, the connection of human congenital anomalies and atropine is not well established. The rate of congenital abnormalities with the use of atropine has been reported at 4.2% [62] . This data from the Collaborative Perinatal Project illustrates that this rate of abnormalities is not dependent on the trimester of exposure. More recent fi ndings quote a small risk of skeletal malformations with exposure, yet it is not clear from the data if this is due to teratogenicity or maternal toxicity of atropine [63] . Atropine has been associated with changes in fetal heart rate and a decrease in fetal breathing [64] . Despite these fi ndings, there are no studies conclusively linking poor fetal outcomes with the use of atropine. In settings of no alternative treatments and an acute life - threatening situation, one may consider the use of atropine in the parturient. There are no studies linking atropine exposure through breast milk and neonatal toxicity. The American Academy of Pediatrics deems atropine compatible with breastfeeding [31] . Epinephrine Epinephrine is a sympathomimetic drug with a wide variety of uses. In the critical care setting, it is used in anaphylaxis, bradycardia, and cardiac arrest. Epinephrine does cross the placenta. Early reports have associated epinephrine with human congenital abnormalities. More recent studies show that there is no increase in congenital abnormalies with epinephrine exposure in any trimester of pregnancy [65] . Inguinal hernia is the only abnormality that has been specifi cally linked to epinephrine exposure [66] . Animal studies have linked epinephrine to uterine hypoperfu- sion, cardiovascular malformations, and cleft palate [67 – 69] . There have been no studies to substantiate these fi ndings in humans. In addition, there are no studies discussing neonatal Fetal Effects of Drugs Commonly Used in Critical Care 631 who underwent bypass surgery and was treated with dobutamine. No adverse fetal effects were noted [89] . There are no studies describing the effect of dobutamine during breastfeeding. Isoproterinol Isoproterinol is a β - receptor agonist. It has positive chronotropic and inotropic effects. It is a vasodilator and bronchodilator. Isoproterinol or isoprenaline is used in asthma and heart failure. It has also been investigated for the in utero treatment of fetal complete heart block [90] . There are no studies that link isoproterinol with human teratogenesis. Caution should be used in pre - eclamptic patients as it has a more pronounced chronotropic effect in this particular population [91] . There are no studies evaluating breastfeeding with isoproterinol. Milrinone and a mrinone Milrinone and amrinone are newer inotropic phosphodiesterase III inhibitors used in acute heart failure and cardiogenic shock. There are no studies evaluating congenital malformations or breastfeeding in milrinone - or amrinone - exposed human fetuses. Diuretics Furosemide Furosemide is a loop diuretic used in congestive heart failure during pregnancy. It has also been investigated as a diuretic in postpartum pre - eclamptic hypertension [92] . It also been shown to increase fetal urine production and has been used to evaluate fetal hydronephrosis [93] . The placental transfer of furosemide is well documented [94] . Furosemide does bind to fetal albumin and slightly increases free bilirubin thereby theoretically increas- ing the risk of kernicterus [95] , although there have been no studies verifying an increased risk of kernicterus in furosemide - exposed fetuses. Neonatal sensorineural hearing loss has been associated with furosemide exposure in one study [96] , but this association has not been substantiated in a more recent study [97] . These negative effects of furosemide were found in small studies. Also, there are no human studies correlating human congenital malformations to furosemide. Given this information, furosemide is considered safe for use in pregnancy. It is excreted in human milk. No studies have reported untoward effects of furosemide transmitted through breastfeeding. Hydrochlorothiazide Hydrochlorothiazide (HCTZ) is a thiazide diuretic used to treat hypertension. It is known to cross the placenta [98] . HCTZ has been correlated with neonatal thrombocytopenia [99] . Yet there are no recent studies confi rming this report. In addition, it has been shown to induce maternal hyperglycemia with resultant neonatal hypoglycemia [100] . Glucose levels should be checked in neonates exposed to hydrochlorothiazide. One study suggests that HCTZ decreases placental perfusion. Consequently, it is suggested that pregnant women chronically on HCTZ may continue fi brillation or fl utter. It is a class I antiarrhythmic that blocks sodium channels. The placental transfer of lidocaine has been reported with fetal to maternal concentration ratios of 50% [78,79] . There are no human studies reporting specifi c congenital abnormalities connected with lidocaine. Data from the Collaborative Perinatal Project shows no increase of congenital abnormalities with in utero exposure to lidocaine [60] . Small amounts of lidocaine have been shown to be excreted in human breast milk. Therefore, lidocaine is unlikely to cause any untoward effects on the neonate and may be used during breastfeeding [80] . Procainamide Procainamide is a class I antiarrhythmic drug which works by blocking sodium channels. It is used in a wide variety of arrhythmias including recurrent ventricular tachycardia and fi brillation. It is also used to treat fetal tachycardias in utero [81,82] . There are no studies reporting any human teratogenicity. In addition, little procainamide is secreted in human milk, making it safe for breastfeeding [83] . Other c ardiovascular d rugs Inotropes Digoxin Digoxin is a digitalis glycoside that is used to slow the ventricular response in atrial fi brillation and atrial fl utter. It is used in a wide variety of maternal and fetal arrhythmias. The placental transfer of digoxin has been well documented [84] . Multiple studies have shown that there are no congenital malformations associated with digoxin exposure in any trimester [85,86] . Digoxin is transferred to human milk at 2 – 4% of the maternal dose [57] . There have been no adverse fetal effects published from digoxin through maternal milk. It is considered safe in breastfeeding [31] . Dopamine Dopamine is a natural postganglionic sympathetic transmitter in renal vessels. As a catecholamine, it increases cardiac contractility for the treatment of congestive heart failure and increases arterial pressure in treatment of shock. There are no studies that link dopamine with human teratogenesis. There are cases of the treatment of acute renal failure during pregnancy using dopamine. There are no reported adverse effects on the fetus related to its use [87,88] . Dopaminergic agents have been used to suppress lactation. Yet, there are no studies investigating dopamine and its effects on breastfed babies. Dobutamine Dobutamine is a synthetic catecholamine that affects α 1 - and β 1 - receptors. It is commonly used to treat heart failure and shock to increase cardiac output with a decrease in ventricular fi lling pressure. There are no studies specifi cally investigating the use of dobutamine in pregnancy. There are no studies linking human teratogenesis with dobutamine. One report describes a parturient Chapter 44 632 trimester as ACE inhibitors. Because of skeletal abnormalities, effects on the fetal renal system and associated fetal death, ARBs are contraindicated in pregnancy [111] . There are no human studies evaluating ARBs and lactation. Labetalol and o ther β - b lockers Labetalol has both α - and β - receptor blocking activity. During pregnancy, it is used for the treatment of mild to severe hypertension. Labetalol crosses the placenta. The pharmacokinetics of oral labetalol in hypertensive pregnant women have been studied. Labetalol has rapid absorption with peak concentrations at 20 minutes after ingestion. The half - life is 1.7 hours. It has also been found at 50% of the maternal concentration in cord blood [112] . There are no studies linking labetalol to human congenital malformations. The reports of adverse fetal or neonatal affects of labetalol have been controversial. There are reports that labetalol is associated with intrauterine growth restriction, bradycardia, or hypoglycemia; yet, there are other studies that refute these fi ndings [113,114] . According to a recent Cochrane review, the effectiveness of β - blockers in general were evaluated in the treatment of mild to moderate hypertension during pregnancy. When compared to placebo, β - blockers decrease the risk of severe hypertension and the need for additional antihyperten- sives. When labetalol was analyzed for maternal and fetal outcomes, including cesarian section rates, Apgar scores, and fetal deaths, in comparison to hydralazine, labetalol faired better than or the same as hydralazine [103] . Given the data, labetalol is an acceptable fi rst - line drug to use for blood pressure control during pregnancy. Labetalol is transferred in human milk in small concentrations and is considered compatible with breastfeeding [31] . Nitroglycerin Nitroglycerin is a smooth muscle relaxant and a potent vasodilator. It is used in the treatment of angina and severe hypertension. It has previously been used as a uterine relaxant for multiple indications including external version and preterm contractions [115,116] . The successful use of nitroglycerin treatment of myocardial infarction during pregnancy has also been reported [117] . There are no studies linking nitroglycerin to human teratogenesis. Fetal heart rate abnormalities including fetal heart decelera- tions have been reported with the use of nitroglycerin [118] . Yet these fi ndings should not restrict the use of nitroglycerin in pregnancy. Given its short duration of action and its use in life - threatening conditions, a clinician should consider the use of nitroglycerin during these conditions in pregnancy safe. There are no studies investigating the use of nitroglycerin during breastfeeding. Nitroprusside Nitroprusside is a powerful vasodilator used to treat hypertensive emergencies and heart failure. Its most important side effects are those caused by the accumulation of cyanide, namely metabolic acidosis, arrhythmias, hypotension, and death. There are no its use, but HCTZ should not be initiated in the middle of pregnancy [101] . For the treatment of hypertension, there are other fi rst - line agents that may be used instead of HCTZ. HCTZ may also be considered a second - line agent for fl uid overload diuresis. There is no data showing that HCTZ should be contraindicated in pregnancy. HCTZ is excreted in small amounts in human milk. No studies have reported untoward effects of HCTZ transmitted through breastfeeding. It has been associated with decreased milk production. Therefore, it has been suggested that it should be not be used in the fi rst month of breastfeeding [102] . Vasodilators Hydralazine Hydralazine is a direct - acting vasodilator. It often used to control blood pressure in cases of gestational hypertension or pre - eclampsia. Hydralazine crosses the placenta with cord blood drug concentrations higher than maternal serum concentrations [103] . There are no studies linking human congenital abnormalities with in utero exposure. Case reports indicate that the use of hydralazine has been associated with abnormal heart tracings [104] , fetal premature atrial contractions [105] , and neonatal thrombocytopenia [106] . Yet, these case reports do cause suffi cient concern to restrict the use of hydralazine in pregnancy. Hydralazine is transferred to breast milk in small amounts [93] . No studies have reported untoward neonatal effects of hydralazine transmitted through breastfeeding. Enalapril and o ther a ngiotensin c onverting e nzyme i nhibitors Enalapril is an angiotensin - converting enzyme (ACE) inhibitor used for the treatment of hypertension and congestive heart failure. Enalapril and other ACE inhibitors are known to cross the placenta. When used in the second and third trimesters, ACE inhibitors are correlated with decreased fetal urine production, hypotension and fetal death [107,108] . There is a small risk of congenital malformations. There are multiple cases reporting the underdevelopment of skull bones and other skeletal abnormalities. In addition, IUGR and pulmonary hypoplasia have been associated with in utero exposure to ACE inhibitors [109] . Because of these fi ndings, ACE inhibitor use in pregnancy is contraindicated. A study of 209 infants with fi rst - trimester only exposure to ACE inhibitors showed an increased risk of major congenital malformations (RR = 2.71, 95% CI 1.72 – 4.27), primarily of the cardiovascular and central nervous systems, when compared to those infants with no exposure to antihypertensive agents [110] . Enalapril and other ACE inhibitors are secreted in small amounts in breast milk. They are considered compatible with breastfeeding by the American Academy of Pediatrics [31] . Losartan and o ther a ngiotensin r eceptor b lockers Losartan is an angiotensin receptor blocker also used in the treatment of heart failure and hypertension. Losartan and other ARBs have a similar fetal side - effect profi le in the second and third Fetal Effects of Drugs Commonly Used in Critical Care 633 same has been found in low molecular weight heparins. Therefore, there is no potential for teratogenicity due to heparins alone. It considered safe for use in pregnancy during any gestational age [127] . There have been no studies linking heparin with congenital defects. Known side effects related to heparin are osteoporosis and heparin - induced thrombocytopenia. Heparin - induced thrombocytopenia is an immune mediated disorder that in high - risk populations has an incidence of 3 – 5%. The risk of HIT is 10 times higher with the use of unfractionated heparin versus low molecular weight heparin. With regard to use in pregnant patients, the incidence of HIT is 0.9%. [128] In general, routine platelet monitoring is not recommended in pregnant patients unless they are at high risk for HIT as defi ned by The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy [129] . Thirty per cent of patients on long - term heparin therapy have decreased bone density leading to osteopenia [130] . Overall, the risk of osteopenia is low in pregnant patients because the majority of patients are on prophylactic doses of UFH or LMWH. There are data to show that this risk of osteoporosis may be lower with use of LMWH [112] . Thrombolytic t herapy Historically, the use of thrombolytic therapy has been considered relatively contraindicated during pregnancy. Risks include abrup- tion, abortion, uterine bleeding, and postpartum hemorrhage. There are no large controlled trials evaluating the use of thrombolytics during pregnancy. There are only case series and case reports of their use with different indications. More than 200 pregnancies have been reported with an overall maternal mortality of 1%, fetal loss rate of 6%, and preterm delivery incidence of 6% [131] . Most reported cases have involved streptokinase and urokinase. The relative safety of those thrombolytics have led authors to consider tissue plasminogen activator safe in pregnancy. In a series of 172 pregnant patients exposed to thrombolytics, all infants were found to be normal on initial exams [132] . There are no studies evaluating tissue plasminogen activator for human teratogenesis and use during pregnancy. Streptokinase has been shown to cross the placenta in very small amounts [133] . There are no studies linking streptokinase with congenital malformations. Use during breastfeeding has not been specifi cally evaluated with thrombolytics. It is not known if these agents cross into breast milk. Endocrinologic e mergencies Endocrinologic emergencies are commonly seen in the ICU setting. Some of the important emergencies include diabetic ketoacidosis, Addisonian crisis, myxedema coma, and thyroid storm. Although altogether less common than cardiopulmonary reasons for admis- sion to the ICU, they still represent signifi cant patient morbidity and mortality [134] . This section will review some of the common drugs involved in the treatment of these emergencies. studies linking human teratogenesis with nitroprusside. The use of nitroprusside during pregnancy has been reported for aneurysm surgery and severe pre - eclampsia. Transient fetal bradycardia was the only side effect reported. In addition, cyanide levels in fetal cord blood have not shown toxic levels [119,120] . In a setting of no alternative treatments and an acute life - threatening situation, one may consider the use of nitroprusside in the parturient as long as cyanide levels are monitored appropriately. There are no studies investigating the use of nitroprusside during breastfeeding. Anticoagulation Warfarin and c oumarin d erivatives Warfarin and coumarin derivatives are used for oral anticoagulation. They inhibit the synthesis of vitamin K dependent clotting factors II, VII, IX, and X. Warfarin is a class D drug with known patterns of embryopathy. The clinical picture of fetal warfarin syndrome includes nasal hypoplasia, epiphyseal stippling, hypoplasia of nails and fi ngers, low birth weight, mental retardation, and seizures. The critical time for warfarin teratogenicity is between 6 and 9 weeks [121] . In a study evaluating the exposure of coumarin derivatives throughout pregnancy, the authors report an increased risk of spontaneous abortions and stillbirth [122] . Neurological delay related to intracranial hemorrhage has also been associated with in utero warfarin exposure. Only 70% of exposed pregnancies are expected to have a normal infant [31] . Warfarin in utero exposure should be avoided during pregnancy. In cases where maternal mortality is higher, such as parturients with mechanical heart valves, the use of warfarin may be considered. In a large literature review of anticoagulation for parturients with mechanical heart valves, the authors evaluated three main regimens: (i) warfarin only; (ii) heparin during the fi rst trimester then warfarin; and (iii) heparin only. The data show that maternal death rates increase between regimens 1, 2, and 3 (1.8%, 4.2%, and 15.0%, respectively). In addition, the rate of embryopathy is halved if heparin is used in the fi rst trimester (3.4%) and the rate is zero if no warfarin is used at all [123] . These data are based on the best available studies which lack prospective trials. Based on these data, the American College of Chest Physicians recom- mends heparin in the fi rst trimester then warfarin or aggressive dose heparinoids throughout the pregnancy [124] . In the particular subgroup of women with high risk mechanical valves, the use of warfarin during pregnancy is very likely warranted. The studies regarding breast milk transfer have not shown any transfer of the drug to human milk [125] . It is considered safe for breastfeeding. Heparins Heparin is a large, heterogenous sulfated glycosaminoglycan with a molecular weight ranging between 5000 and 30 000 Da. It acti- vates antithrombin III to inhibit clotting factors most notably factor Xa. Because of its large molecular weight, heparin does not cross the placenta, nor is it transferred to breast milk [126] . The Chapter 44 634 Methimazole is another antithyroid medication that is used in the treatment of thyroid storm. Three times more methimazole is known to cross the placenta than PTU [146] . The correlation of congenital malformations and methimazole exposure is controversial. There are some studies that suggest that exposure is correlated with aplasia cutis. Other studies do not show any increase in specifi c defects [147] . Methimazole is excreted in human milk in small amounts and is safe for breastfeeding [31] . Mannitol Mannitol is an alcohol derived from glucose that is used to treat different manifestations of cerebral edema. There are no studies evaluating human congenital malformations and mannitol. In addition, there are no studies evaluating mannitol and breastfeeding. Conclusion As with any treatment in medicine, a consideration of therapeutic risks and benefi ts to the patient is important. This consideration is further complicated in pregnant patients by altered physiology. In addition, those caring for pregnant patients also must invari- ably care for another patient, the fetus. Due to the paucity of data of therapeutics in pregnancy, there are few medications such as ACE inhibitors and angiotensin receptor blockers that are clearly contraindicated in pregnancy. This therapeutic dilemma forces the clinician to rely on judgement of the clinical situation with an evaluation of the best possible data. In the realm of the ICU where life - threatening conditions are commonplace, it is important to remember that when a mother is not optimally treated for an acute life - threatening condition, the fetus will be placed at increased risk, as well. In cases where acuity is less of an issue, then consideration of fetal morbidities should become of para- mount importance. References 1 Martin SR , Foley MR . Intensive care in obstetrics: qn evidence - based review . Am J Obstet Gynecol 2006 ; 195 : 673 – 689 . 2 Baron TH , Ramirez B , Richter JE . Gastrointestinal motility disorders during pregnancy . Ann Intern Med 1993 ; 118 : 366 – 375 . 3 Mattison DR . Physiologic variations in pharmacokinetics during pregnancy . In: Drug and Chemical Action in Pregnancy: Pharmacologic and Toxicologic Principles . New York : Thieme - Stratton , 1984 : 74 – 86 . 4 Little BB . Pharmacokinetics during pregnancy: evidence - based maternal dose formulation . Obstet Gynecol 1999 ; 93 : 858 – 868 . 5 Dunlop W . Serial changes in renal haemodynamic during pregnancy . Br J Obstet Gynaecol 1981 ; 8 : 1 – 9 . 6 Mattingly JE , Alessio JD , Ramanathan J . Effects of obstetric analgesic and anesthetics on the neonate . Pediatr Drugs 2003 ; 5 : 615 – 627 . Insulin Insulin is pancreatic peptide that is used in the treatment of hyperglycemia and diabetes. It is a key element in the treatment of diabetic ketoacidosis. There are no studies linking the use of insulin specifi cally to human congenital malformations. Many studies are confounded by rate of malformations related to uncontrolled diabetes itself [135] . Insulin does not cross the placenta and is not transmitted in the milk. It is considered safe for pregnancy and breastfeeding [33] . Corticosteroids: h ydrocortisone and d examethasone Stress doses of hydrocortisone are used to treat emergencies like Addisonian crisis and myxedema coma [127] . Corticosteroids like hydrocortisone and dexamethasone are known to cross the placenta and are used for fetal lung maturity induction [136] . Epidemiologic studies have shown a correlation between use of corticosteroids and oral clefting with odds ratios between 3 and 5 [137] . Repeat doses of corticosteroids for fetal lung maturity have been correlated with poor fetal growth [138] . These negative effects are seen in chronic administrations. Yet, the use of corticosteroids should not be restricted in pregnancy. The total amount of corticosteroids used for Addisonian crisis treatment has not been specifi cally studied for congenital malformations. An acute use of corticosteroids,does not require prolonged fetal evaluation. If corticosteroids are used chronically, one may consider an ultra- sound to evaluate appropriate growth and anomalies. Small of amounts of corticosteroids have been found in human milk, but they are considered compatible with breastfeeding [31] . Thyroxine Intravenous thyroxine can be used to reverse hypothyroidism in myxedema coma. Thyroxine is known to cross the placenta and has been used to treat fetal hypothyroidism and goiter [139] . The Collaborative Perinatal Project has not demonstrated any signifi - cant birth defect association with the use of thyroxine during any trimester [140] . Thyroxine is known to be transmitted through human milk in small doses and is considered safe for breastfeeding [141] . Antithyroid m edications: PTU and m ethimazole Propylthiouracil is used to treat hyperthyroidism with thyroid storm. It is considered the drug of choice for the treatment of hyperthyroidism in pregnancy in the USA [142] . It is known to cross the placenta and can cause transient neonatal hypothyroidism or fetal goiter [143] . There are no studies correlating PTU to congenital malformations. Long - term follow - up on children who had been exposed to PTU in utero has shown no decrease in motor or intellectual function [144] . For the treatment of thyroid storm and hyperthyroism, PTU is considered safe in pregnancy [31] . PTU is excreted in the human milk in small amounts with no known neonatal effects [145] . It is considered safe for breastfeeding. Fetal Effects of Drugs Commonly Used in Critical Care 635 26 Baldessarini RJ . Drugs and the treatment of psychiatric disorders In: Gilman AG et al., eds. Goodman and Gilman ’ s The Pharmacological Basis of Therapeutics , 8th edn. New York : Macmillan , 1990 : 384 . 27 Sexson WR , Barak Y . 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