There have been no reports of fetal effects secondary to the transfer of drug through human milk.. There are no studies linking atropine exposure through breast milk and neonatal toxicit
Trang 1Wolff – 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 elimi-nation 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 lacta-tion 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 distribu-tion 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 amio-darone 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 -
doc-umented short - term fetal response to the administration of
pan-curonium 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
sig-nifi 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
concen-tration 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
preg-nancy for the therapy of supraventricular tachycardias including
Trang 2outcomes 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 com-patible with breastfeeding [58]
Verapamil is a calcium channel blocking agent and is an alter-native drug to terminate paroxysmal supraventricular tachycar-dia 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 vera-pamil 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
second-ary to amiodarone, the cardiac polypharmacy to which these
fetuses were exposed, or the underlying condition requiring
treat-ment Given these fi ndings, it is recommended that amiodarone
be used only in refractory cases [58]
Recommendations about the use of amiodarone during
breast-feeding 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
abnor-malities 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,
brady-cardia, 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
tri-mester 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
Trang 3who 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 isopro-terinol 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 con-genital malformations to furosemide Given this information, furosemide is considered safe for use in pregnancy
It is excreted in human milk No studies have reported untow-ard 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 sug-gested 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
breast-feeding [80]
Procainamide
Procainamide is a class I antiarrhythmic drug which works by
blocking sodium channels It is used in a wide variety of
arrhyth-mias 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
trans-ferred 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
treat-ment 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
Trang 4trimester 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 pharmacokinet-ics 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 neona-tal affects of labeneona-talol 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 preg-nancy 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 out-comes, 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 vasodila-tor 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 myo-cardial infarction during pregnancy has also been reported [117] There are no studies linking nitroglycerin to human teratogene-sis 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
preg-nancy [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
produc-tion 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
concen-trations [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
abnormali-ties 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
contraindi-cated 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
treat-ment of heart failure and hypertension Losartan and other ARBs
have a similar fetal side - effect profi le in the second and third
Trang 5same 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, aborabrup-tion, uterine bleeding, and postpartum hemorrhage There are no large controlled trials evaluating the use of thrombo-lytics 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 evaluat-ing tissue plasminogen activator for human teratogenesis and use during pregnancy Streptokinase has been shown to cross the pla-centa 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
aneu-rysm surgery and severe pre - eclampsia Transient fetal
bradycar-dia 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
par-turient 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
anticoagula-tion 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,
hypo-plasia 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
consid-ered 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
mater-nal 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
particu-lar 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
Trang 6Methimazole 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 con-troversial 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 impor-tant 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
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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
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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 :
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5 Dunlop W Serial changes in renal haemodynamic during
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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
pla-centa 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
cortico-steroids 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
hypothyroid-ism 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
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