Norepinephrine Pregnancy and Breastfeeding Warnings
Norepinephrine Pregnancy Warnings
Because norepinephrine (NE) is an endogenous catecholamine, its relationship to adverse pregnancy outcomes is difficult to determine. Moreover, it is usually only used in dire situations that may otherwise portend fetal risk. Some experts do not advocate the use of NE during pregnancy except in life-threatening situations. In the case of hypotension associated with anesthesia during pregnancy, some experts recommend ephedrine. In other situations in which a vasopressor is needed to treat life-threatening hypotension, a more effective agent such as dopamine is considered the drug of choice. NE crosses and is metabolized by the human placenta. In vitro data have shown that 12% of a radiolabeled dose of NE appears in the fetal blood. Data regarding a similar compound, epinephrine, have shown that, in high concentrations, the drug can cause both maternal and fetal glycogenolysis and elevated blood glucose concentrations. An increased frequency of uterine contractions has been associated with NE. Animal data indicate that epinephrine may cause decreased placental blood flow, increasing the risk of fetal hypoxemia. There has been an interesting debate in the medical literature as to whether endogenous catecholamines play an etiologic role in placental insufficiency, preeclampsia or toxemia of pregnancy. Two retrospective studies are available regarding epinephrine. Data from the Collaborative Perinatal Project (CPP) revealed an overall hospital-standardized relative risk for any malformation associated with epinephrine of 1.71. The CPP retrospectively reviewed 189 cases of first trimester exposure to epinephrine among 50,282 mother-child pairs, and found an incidence of malformations of 22 of 189. When the entire gestational period was studied, 11 malformed children were observed (9.85 were expected) from 508 users of epinephrine. The standardized relative risk of malformations associated with the use of epinephrine used anytime during pregnancy was 1.12. These data reveal evidence of an association between the use of epinephrine and congenital malformations, although underlying diseases were not accounted for in the analysis. The second study, the Michigan Medicaid Birth Defects Study (MMBDS) revealed no evidence of an association between the use of epinephrine and congenital malformations (written communications, Franz Rosa, Food and Drug Administration, 1994). The MMBDS is a retrospective study of 229,101 deliveries between 1985 and 1992. Of the 229,101 deliveries, 35 were exposed to epinephrine during the first trimester. No defects were observed.
Norepinephrine has been assigned to pregnancy category C by the FDA. Neither animal reproduction studies nor controlled human pregnancy studies are available. Norepinephrine should only be given during pregnancy when benefit outweighs risk.
Norepinephrine Breastfeeding Warnings
There are no data on the excretion of norepinephrine into human milk. A similar compound, epinephrine is known to be excreted into human milk. Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
References for pregnancy information
- Costa A, De Filippis V, Voglino M, Giraudi G, Massobrio M, Benedetto C, Marozio L, Gallo M, Molina G, Fabris C, et al "Adrenocorticotropic hormone and catecholamines in maternal, umbilical and neonatal plasma in relation to vaginal delivery." J Endocrinol Invest 11 (1988): 703-9
- Divers WA, Wilkes MM, Babaknia A, Hill LM, Quilligan EJ, Yen SS "Amniotic fluid catecholamines and metabolites in intrauterine growth retardation." Am J Obstet Gynecol 141 (1981): 608-10
- Davies J, Robson JM, Sullivan FM "Effects of drugs on placental function and their relation to congenital abnormalities." Proc R Soc Med 62 (1969): 317-8
- Saarikoski S "Fate of noradrenaline in the human foetoplacental unit." Acta Physiol Scand Suppl 421 (1974): 7-8,36-48,69-70
- Barden TP, Stander RW "Effects of adrenergic blocking agents and catecholamines in human pregnancy." Am J Obstet Gynecol 102 (1968): 226-35
- Blouquit MF, Sturbois G, Breart G, Grill C, Sureau C, Roffi J "Catecholamine levels in newborn human plasma in normal and abnormal conditions and in maternal plasma at delivery." Experientia 35 (1979): 618-9
- Norstrom A, Bryman I "Uptake of 3H-norepinephrine in different segments of the human non- pregnant and pregnant uterus." Gynecol Obstet Invest 27 (1989): 26-8
- Tuncel N, Aydin Y, Tikiz H "The effect of three products of cigarette smoke (cyanide, thiocyanate and nicotine) on the concentration-response curves of 5- hydroxytryptamine, norepinephrine and epinephrine in the isolated human umbilical veins and arteries." Pharmacol Toxicol 74 (1994): 84-8
- Sodha RJ, Proegler M, Schneider H "Transfer and metabolism of norepinephrine studied from maternal-to- fetal and fetal-to-maternal sides in the in vitro perfused human placental lobe." Am J Obstet Gynecol 148 (1984): 474-81
- Donders GG, Missiaen L, Zuspan FP, Van Assche FA "Uterine norepinephrine levels are correlated with contraction force, but not with the occurrence of preeclampsia." Gynecol Obstet Invest 30 (1990): 207-11
- Tunbridge RD, Donnai P "Plasma noradrenaline in normal pregnancy and in hypertension of late pregnancy." Br J Obstet Gynaecol 88 (1981): 105-8
- "Product Information. Levophed Bitartrate (norepinephrine)." Sanofi Winthrop Pharmaceuticals, New York, NY.
- Abboud T, Artal R, Sarkis F, Henriksen EH, Kammula RK "Sympathoadrenal activity, maternal, fetal, and neonatal responses after epidural anesthesia in the preeclamptic patient." Am J Obstet Gynecol 144 (1982): 915-8
- Natrajan PG, McGarrigle HH, Lawrence DM, Lachelin GC "Plasma noradrenaline and adrenaline levels in normal pregnancy and in pregnancy-induced hypertension." Br J Obstet Gynaecol 89 (1982): 1041-5
- Pinto RM, Lerner U, Pontelli H, Rabow W "Action of epinephrine and norepinephrine on contractile activity of the three separate layers of the human uterus." Am J Obstet Gynecol 102 (1968): 333-9
- Morgan CD, Sandler M, Panigel M "Placental transfer of catecholamines in vitro and in vivo." Am J Obstet Gynecol 112 (1972): 1068-75
- Peleg D, Munsick RA, Diker D, Goldman JA, Ben-Jonathan N "Distribution of catecholamines between fetal and maternal compartments during human pregnancy with emphasis on L-dopa and dopamine." J Clin Endocrinol Metab 62 (1986): 911-4
- Saarikoski S, Castren O "Distribution and metabolism of H 3 -noradrenaline in various tissues of the human foetus in the foetoplacental unit." Acta Obstet Gynecol Scand Suppl 9 (1971): suppl9:60
- Hobel CJ, Parvez H, Parvez S, Lirette M, Papiernik E "Enzymes for epinephrine synthesis and metabolism in the myometrium, endometrium, red blood cells, and plasma of pregnant human subjects." Am J Obstet Gynecol 141 (1981): 1009-18
- Puolakka J, Kauppila A, Tuimala R, Jouppila R, Vuori J "The effect of parturition on umbilical blood plasma levels of norepinephrine." Obstet Gynecol 61 (1983): 19-21
- Senties L, Arellano G, Casellas A, Ontiveros E, Santos J "Effects of some vasopressor drugs upon uterine contractility in pregnant women." Am J Obstet Gynecol 107 (1970): 892-7
- Bell C "Control of uterine blood flow in pregnancy." Med Biol 52 (1974): 219-28
- Divers WA Jr, Wilkes MM, Babaknia A, Yen SS "An increase in catecholamines and metabolites in the amniotic fluid compartment from middle to late gestation." Am J Obstet Gynecol 139 (1981): 483-6
- Reviriego J, Fernandez-Alfonso MS, Marin J "Actions of vasoactive drugs on human placental vascular smooth muscle." Gen Pharmacol 21 (1990): 719-27
- Castren O, Saarikoski S "The effect of some different factors on the metabolism of H3- noradrenaline in placental, adnexal and foetal tissue homogenates." Acta Obstet Gynecol Scand 48 (1969): suppl3:151+
- Nandakumaran M, Gardey C, Rey E, Challier JC, Panigel M, Olive G "Transfer of ritodrine and norepinephrine in human placenta: in vitro study." Dev Pharmacol Ther 4 (1982): 71-80
- Jouppila R, Puolakka J, Kauppila A, Vuori J "Maternal and umbilical cord plasma noradrenaline concentrations during labour with and without segmental extradural analgesia, and during caesarean section." Br J Anaesth 56 (1984): 251-5
- Amy JJ, Karim SM "Intrauterine administration of L-noradrenaline and propanolol during the second trimester of pregnancy." J Obstet Gynaecol Br Commonw 81 (1974): 75-83
- Divers WA Jr, Wilkes MM, Babaknia A, Yen SS "Maternal smoking and elevation of catecholamines and metabolites in the amniotic fluid." Am J Obstet Gynecol 141 (1981): 625-8
- Nylund L, Lagercrantz H, Lunell NO "Catecholamines in fetal blood during birth in man." J Dev Physiol 1 (1979): 427-30
- Kudo T, Roux JF "Catecholamine excretion in the urine of term pregnant women and the newborn." J Reprod Med 4 (1970): 237-42
- Eliot RJ, Lam R, Leake RD, Hobel CJ, Fisher DA "Plasma catecholamine concentrations in infants at birth and during the first 48 hours of life." J Pediatr 96 (1980): 311-5
- Phillippe M, Ryan KJ "Catecholamines in human amniotic fluid." Am J Obstet Gynecol 139 (1981): 204-8
- Zuspan FP "Urinary excretion of epinephrine and norepinephrine during pregnancy." J Clin Endocrinol Metab 30 (1970): 357-60
- Iisalo E, Castren O "The enzymatic inactivation of noradrenaline in human placental tissue." Ann Med Exp Biol Fenn 45 (1967): 253-7
- Zuspan FP, Abbott M "Identification of a pressor substance in amniotic fluid. I. Role of epinephrine and norepinephrine." Am J Obstet Gynecol 107 (1970): 664-72
- Wansbrough H, Nakanishi H, Wood C "The effect of adrenergic receptor blocking drugs on the human uterus." J Obstet Gynaecol Br Commonw 75 (1968): 189-98
- Eneroth-Grimfors E, Lindblad LE, Westgren M, Etzell BM, Bevegard S "Iontophoresis of vasoactive drugs. Effect on peripheral blood flow during pregnancy." Acta Obstet Gynecol Scand 70 (1991): 25-8
- Berkowitz R, Coustan D, Mochizuki T. "Handbook for Prescribing Medications During Pregnancy. 2nd ed." Boston, MA: Little, Brown, and Company (1986): 242
- Schulman H "The comparative actions of uterine inhibiting drugs." Am J Obstet Gynecol 130 (1978): 684-8
- Burba JV "Catechol O-methyltransferase activity in the human placenta and liver." Can J Physiol Pharmacol 57 (1979): 213-6
- Falconer AD, Lake DM "Circumstances influencing umbilical-cord plasma catecholamines at delivery." Br J Obstet Gynaecol 89 (1982): 44-9
- Altura BM, Malaviya D, Reich CF, Orkin LR "Effects of vasoactive agents on isolated human umbilical arteries and veins." Am J Physiol 222 (1972): 345-55
References for breastfeeding information
- "Product Information. Epinephrine Hydrochloride Injection (epinephrine)." Abbott Pharmaceutical, Abbott Park, IL.
- "Product Information. Levophed Bitartrate (norepinephrine)." Sanofi Winthrop Pharmaceuticals, New York, NY.
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