Most people, including many health care providers, assume that if the FDA
approves a drug for marketing then the FDA has determined that drug is
free from harm or injury to the person receiving the
drug. They do not know that the U.S. Food and Drug Administration (FDA)
bases its approval of a drug on whether he benefits of the drug outweigh
the risks. The FDA has no
written standards for evaluating or documenting the safety of drugs
approved for use in obstetric care.
LITTLE
MORE THAN A DOZEN DRUGS HAVE BEEN APPROVED BY FDA FOR USE IN
OBSTETRIC CARE; however more than six have had their FDA labeling removed
from the PHYSICIANS DESK REFERENCE (PDR) by their manufacturers. The PDR
is the only publication that must publish the text of an FDA approved
label of a drug exactly as it appears in the drug's package insert.
The FDA acknowledges that there is major underreporting of adverse drug
effects, so neither the FDA nor the public has any way of knowing how
frequently adverse drug effects occur. As
a consequence,
few women realize the inherent risks of oxytocic drugs to themselves and
their babies. NONE of the drugs used in obstetric care has been proven
safe for the fetus exposed to the drug in utero.
The FDA
acknowledges drugs trapped in the infant's brain can alter how the nerve
cells in the brain mature and how the cells carry out functions.
Drugs administered to the mother, including
oxytocin, rapidly filter across the placental membranes and enter the
blood, brain and other major organs of the fetus within minutes of
administration to the mother during pregnancy, labor and birth.
As the time of birth nears, the fetal brain is
relatively large and rich in blood vessels, and the cerebral blood flow is
relatively high in comparison with that of the adult brain. These factors
increase the transfer of drugs given to the mother to the fetal
circulation, brain and central nervous system. If drugs slow the fetal
heart rate and the oxygen saturation of the fetal blood is depleted below
the physiologic level, the transfer of drugs administered to the mother,
and hence to the fetus, is increased.
The one
minute APGAR score and the newborn's time to sustained respiration are
important barometers of how the fetus fared in utero. Babies
born from calm, easy or natural births usually have a better APGAR.
A six week follow up of newborn infants in the U.K.
found that bupivacaine, administered in the form of an epidural block,
adversely altered brain function in a significant number of newborn
infants
throughout the six week testing period. A subsequent evaluation in the
U.S. found essentially the same results.
"Off-label" is
pharmaceutical jargon meaning that the drug is being used to treat a
condition for which the FDA has NOT approved the drug for that treatment. Terbutaline, for example, has not been approved by the FDA to treat
premature contractions, yet the drug is frequently used "off
label" to treat the condition, rather than use
Ritodrine, which has been approved for such treatment.
While drugs such as codeine,
morphine, hydromorphone, promethazine, codeine,
fentanyl citrate, phenergan, terbutaline, etc, are sometimes used
"off label" in obstetric care, they have not been approved by
the FDA for obstetric use. Fentanyl
in low levels is often part of the epidural mixture given in
hospitals.
FOLLOWING
IS A LIST OF DRUGS APPROVED BY THE FDA FOR USE DURING SOME,
BUT NOT ALL, OBSTETRIC PROCEDURES.
CERVIDIL (dinoprostone PGE2)
Approved by FDA as a cervical ripener in patients at
or near term in whom there is a medical or obstetrical indication for the
induction of labor.
Dinoprostone vaginal insert is a thin flat, rectangular polymeric slab
with a long tape to serve as a retrieval system. Cervidil is inserted into
the vagina in order to "ripen" the cervix. The patient
must remain in the recumbent position for two hours after insertion. The
drug gradually causes the rigid cervix to become softened, yielding and
dilated to allow passage of the fetus through the birth
canal.
The use of Cervidil is not without risk. Therefore the drug should only be
administered by trained obstetrical personnel in a hospital setting with
appropriate obstetrical care facilities. Since Cervidil
is a prostaglandin that can augment the activity of oxytocic drugs, the
two drugs should not be administered at the same time. Cervidil must be
removed before oxytocin administration is initiated and the patient's
uterine activity must be carefully monitored for uterine hyperstimulation.
The label also notes that uterine hyperstimulation, sustained uterine
contraction, fetal distress, or other fetal or
maternal adverse reactions should be a cause for consideration of removal
of the insert.
Cervidil should not be administered to women with a history of previous
cesarean section or uterine surgery in light of the potential risks for
uterine rupture and associated obstetrical complication. If uterine
hyperstimulation is encountered, or if labor commences, the vaginal insert
should be removed. Cervidil should also be removed prior to amniotomy (the
artificial rupture of membranes).
If the mother's membranes have ruptured, the chemical stimulation
of contractions can increase fetal intracranial pressure. Cervidil is
contraindicated when prolonged contractions of the uterus may be
detrimental to uterine integrity and fetal safety.
During a normal contraction the
maternal blood vessels that carry oxygenated blood through the uterine
wall to the placenta are constricted. During these periods of diminished
blood flow the oxygen in the mother's blood, stored up in the placenta's
intervillous space between contractions, maintains the fetal brain with a
relatively constant supply of oxygen. Any uterine stimulant or drug which
foreshortens these oxygen-replenishing intervals between contractions, by
making the contractions too long, too strong, or too close together,
increases the likelihood that fetal brain cells will be adversely affected.
Uterine activity, fetal status and the progression of cervical dilatation
and effacement should be carefully monitored.
DEMEROL
(meperidine Hcl) -
Approved by FDA for obstetrical analgesia.
Demerol (meperidine), called
Pethidine in Europe, is a narcotic analgesic used to relieve moderate
to severe pain. The drug has multiple actions similar to those of
morphine. Demerol crosses the
placenta and enters the fetal circulation, brain and other organs within
minutes of administration to the mother. Demerol also appears in breast
milk.
The major risks of meperidine, as with other narcotic analgesics, are
respiratory distress, circulatory depression, respiratory arrest, shock
and cardiac arrest. Overdose of meperidine can result in
hypertension, severe respiratory depression, cyanosis, coma and death.
Therapeutic doses of meperidine have occasionally precipitated
unpredictable, severe and occasionally fatal reaction in patients who
have received such agents within 14 days. Other adverse reactions noted in
the label/package insert are hyperexcitability, convulsions, bradycardia
or tachycardia (slowing or speeding of the fetal heart),
hyperpyrexia (high fever), hypertension or hypotension (high or low blood
pressure), coma, severe respiratory depression, and cyanosis (bluish
discoloration of skin due to diminished oxygen).
If meperidine is given intravenously, the injection should be given very
slowly,preferably in the form of a diluted solution. Rapid intravenous
injection of narcotic analgesics, including meperidine,
increases the incidence of adverse reactions such as severe respiratory
depression, apnea, hypotension, peripheral circulatory collapse and
cardiac arrest. Meperidine should not be administered intravenously unless
a narcotic antagonist and the facilities for assisted or controlled
respiration are immediately available.
The package insert states that the major hazards of meperidine, as with
other narcotic analgesics, are respiratory depression, circulatory
depression, respiratory arrest, shock and cardiac arrest.
Under "Nervous System" the package insert cites adverse effects
such as euphoria, dysphoria, weakness, headache, agitation, tremor,
uncoordinated muscle movements, severe convulsions, transient
hallucination and disorientation, and visual disturbances. The inadvertent
injection of the drug about a nerve trunk may result in sensory-motor
paralysis which is usually, but not always, transitory.
Under "Cardiovascular" the package insert cites adverse effects
such as tachycardia, bradycardia, palpitation, hypertension, syncope, and
phlebitis following intravenous injection.
Urinary retention and pruritus (itching) are also noted by the
manufacturer.
FETAL EFFECTS:
When used as an
obstetrical analgesic, meperidine crosses the placental barrier and can
produce depression of respiration and psychophysiologic function in the
newborn. Resuscitation
may be required."
Meperidine rapidly filters across
the placental membranes and enters the blood, brain and other organs of
the fetus within seconds or minutes of administration to the mother. Drug
induced alterations in the brain chemistry of the fetus can cause the
fetal heart to slow or to speed up to non-physiological levels. The drug's
official label notes that meperidine, like all pain relieving drugs, tends
to increase cerebral spinal fluid pressure.
(a) meperidine given to the mother during labor can impede the normal
transfer of oxygen from the mother's circulation to that of her fetus,
(b) prolonged oxygen depletion can cause the fetal brain to swell,
(c) the drug can interfere with the newborn infant's normal ability to
self- regulate his/her internal temperature, or
(d) a severely narcotized newborn infant is more prone to aspirate its
gastric fluids if the drug has blunted or paralyzed his protective gag
reflex.
MARCAINE (bupivacaine hcl)
Used in Epidurals. Or SENSORCAINE
LABOR AND DELIVERY: Local
anesthetics rapidly cross the placenta, and when used for epidural, caudal
or pudendal block anesthesia, can cause varying degrees of maternal, fetal
and neonatal toxicity... Adverse reactions in the parturient, fetus
and neonate involve alteration of the central nervous system, peripheral
vascular tone and cardiac function..."
Under "ADVERSE REACTIONS. Neurologic" the
official labeling continues:
Epidural analgesia can cause
disruptions in normal uterine function that cannot always be completely
corrected by the use of oxytocin. Forceps or vacuum extraction of the
baby, or the use of fundal pressure (external pressure applied to the
mother's lower abdomen) to help push the baby out) are common when a woman
cannot feel the urge to push because of an epidural.
Forceps and vacuum extraction carry risks to both mother and baby,
as does fundal pressure. Fundal pressure increases the likelihood of
uterine inversion, and that an episiotomy will be extended into a rectal
tear. Fundal pressure has the potential to increase fetal intracranial
pressure if the membranes have ruptured.
Bupivacaine administered to the mother during labor can have prolonged
adverse effects on the early development of the exposed offspring.
Immediately after delivery, infants with greater exposure to bupivacaine
in utero were most likely to be cyanotic and unresponsive to their
surroundings. Visual skills and alertness decreased significantly with
increases in the cord blood concentration of bupivacaine, particularly on
the first day of life, but also throughout the next six weeks. Adverse
effects of bupivacaine levels on the infant's motor organization, his
ability to control his own state of consciousness and his physiological
response to stress were also observed."
METHERGINE
(Methylergonovine maleate)
Methergine acts directly on the
smooth muscle of the uterus and increases the resting tone, rate and strength
of uterine contractions. Methergine is used to induce a rapid and
sustained spasmodic uterine contraction to shorten the third stage of
labor and reduce blood loss.
The manufacturer of Methergine acknowledges that the drug can result in
sudden and severe blockage of blood to the heart. The
use of Methergine has diminished because of the drug's action to constrict
blood vessels.
NAROPIN (ropivacaine hcl)
(used for epidural)
Naropin rapidly filters across the
placental membranes and enters the blood, brain and other organs of the
fetus within seconds or minutes of being administered to the childbearing
woman. The onset, depth, and duration of sensory block are similar to
bupivacaine. When used for epidural block Naropin can cause varying
degrees of maternal, fetal and neonatal toxicity.
The manufacturer of Naropin cautions that resuscitative equipment, oxygen
and other resuscitative drugs should be immediately available when Naropin
is administered. A well-recognized risk of lumbar epidural block
anesthesia is the unintentional injection of local anesthetic into the
subarachnoid space and tissue surrounding the spinal cord.
Epidural anesthesia has been shown
to prolong the second stage of labor by removing the laboring woman's
reflex urge to bear down or by interfering with her motor function.
During lumbar epidural block, occasional unintentional penetration of
the subarachnoid space by the catheter or needle may occur resulting in
(a) the depression of the myocardium, a major muscle within the
heart), (b) decreased cardiac output, (c) heart block, (d) hypotension
(non-physiological drop in blood pressure), and (e) non-normal heart rates
such as bradycardia, tachycardia, arrhythmias, and
fibrillation, and cardiac arrest.
In addition, the unintentional penetration of the subarachnoid space by
the catheter or needle during lumbar epidural block may result in
subsequent neurologic reactions such as (a) spinal block of varying
magnitude (including high or total spinal block), (b) hypotension
secondary to spinal block, (c) urinary retention, (d) urinary incontinence
(loss of bladder control), (e) loss of perineal sensation in the vagina,
and (f) loss of sexual function. Other neurological adverse effects
include persistent anesthesia, abnormal
sensations, weakness, paralysis of the lower extremities, and fecal
incontinence (loss of sphincter control), all of which may have slow,
incomplete or no recovery.
Other reported adverse effects in
the woman during labor include septic meningitis, meningismus
(meningitis-like fever but no infection), slowing of labor, loss of the
bearing down reflex during labor, increased incidence of forceps or vacuum
extraction, cranial nerve palsies due to traction on nerves from loss of
cerebrospinal fluid, and headache. A high spinal in the laboring woman
is characterized by paralysis of the arms, loss of consciousness,
respiratory paralysis and slowing of the heart.
Epidural anesthesia has been
reported to prolong the second stage of labor by
removing the laboring woman's reflex urge to bear down or by interfering
with motor function. Injection of repeated doses of local anesthetic may
cause significant increases in blood levels with each repeated dose due to
slow accumulation of the drug.
NUBAIN
(nalbuphine HCl)
Nubain is a potent analgesic which
relieves pain but does not remove it. The analgesic potency of Nubain is
essentially equivalent to that of morphine on a milligram basis. The
manufacturer advises that Naloxone, a drug used to counteract the effect
of nubain, resuscitative and intubation equipment and oxygen should be
readily available.
When the drug is administered to the mother during labor and delivery she
may experience nervousness, depression, restlessness, crying, euphoria,
floating, hostility, unusual dreams, confusion, faintness, hallucination,
dysphoria, feeling of heaviness, numbness, tingling, sense of unreality,
hypertension, hypotension, bradycardia, tachycardia (non physiological
increase in heart rate), respiratory depression, and dyspnea (labored
breathing).
Allergic Reactions: Increased allergic reaction leading to respiratory
distress, and other serious hypersensitivity reactions have been reported
following the use of Nubain and may require
immediate, supportive medical attention. These reactions may include
shock, respiratory distress, respiratory arrest, bradycardia, cardiac
arrest, hypotension, or laryngeal edema, stridor (high pitched breathing),
bronchospasm, wheezing, edema, rash, pruritus (itching), nausea, vomiting,
diaphoresis (profuse sweating), weakness and shakiness.
Adverse fetal effects of Nubain include fetal bradycardia (slowing of the
fetal heart rate) and fetal arrhythmias (abnormal fetal heart rate).
Severe and prolonged fetal heart bradycardia has been reported following
fetal exposure to Nubain. Permanent neurological damage attributed to
fetal bradycardia has occurred. The manufacturer suggests that
administering naloxone (Narcan) to the mother during labor has normalized
these effects in some cases. However, naloxone is not FDA approved for use
during labor.
Neonatal effects of Nubain include respiratory depression at birth, apnea
(cessation of breathing), cyanosis (severe reduction of oxygen in the
fetal blood) and hypotonia (diminished tone of skeletal
muscles). Severe and prolonged fetal bradycardia (non-normal slowing of
the fetal heart rate) has been reported. Permanent neurological damage
attributed to fetal bradycardia has occurred.
NUMORPHAN (oxymorphone HCl) Approved by
FDA for the relief of moderate to
severe pain in obstetric care.
Numorphan is an opioid, a synthetic opiate analgesic that is indicated
(FDA approved) for preoperative medication, for
support of anesthesia, and for obstetrical analgesia. The analgesic action of
Numorphan is ten times that of morphine sulfate. Opioid analgesics
such as Numorphan exert their principal pharmacologic effects on the
central nervous system and the gastrointestinal tract. Pinpoint pupils are
a common sign of opioid overdose, while extreme dilatation of the pupils
may be seen with worsening hypoxia.
Numorphan should be used with caution during labor. Opioid analgesics
cause the pooling of blood in the extremities and can adversely effect the
heart by decreasing the flow of blood returning to the
heart. Non-normal fetal heart rate patterns can occur with the use of
Numorphan. Opioids can (a) cause respiratory depression, (b) elevate
cerebrospinal fluid pressure, (c) depress the cough or gag reflex, (d)
slow digestion in the small intestine, (e) disrupt function of the colon,
(f) diminished the normal amount of urine secreted by the body, and (g)
induce spasms in the urinary tract causing difficulty with urination.
PITOCIN
(oxytocin) (See
article on Pitocin)
RITODRINE
Approved by the FDA f to manage
preterm labor in suitable patients.
When administered intravenously, Ritodrine will decrease uterine activity
and prolong gestation in the majority of suitable patients. Intravenous
infusion of 0.05 to 0.30 mg/min or single oral doses of
10 to 20 mg/min decrease the intensity and frequency of uterine
contractions.
Ritodrine Hydrochloride, once sold under the brand name Yytopar, is the
only tocolytic drug approved by the FDA to forestall premature labor. The
manufacturer cautions that IV administration of Ritodrine
should be supervised by persons having knowledge of the pharmacology of
the drug and who are qualifiedto identify and manage complications of drug
administration and pregnancy. Beta-adrenergic
drugs such as Ritodrine increase cardiac output. Even in a normal healthy
heart this added demand can lead to a reduction in the flow of oxygenated
blood to the myocardial muscle - the major muscle in
the heart. This disruption in blood flow can result in myocardial necrosis
(death of heart muscle); non-physiological heart rates, such as
arrhythmias, atrial and ventricular contractions, ventricular
tachycardia; and heart pain, with or without EEG changes. Because
cardiovascular responses are common and more pronounced during intravenous
administration of Ritodrine, cardiovascular effects,
including maternal pulse rate and blood pressure and fetal heart rate,
should be closely monitored.
The label of Ritodrine notes that pulmonary edema (accumulation of fluid
in the lungs) has been reported in patients treated with Ritodrine and
cautions that patients must be closely monitored in the
hospital, and sometimes after the delivery of the infant. Maternal death
from this condition has been reported.
Ritodrine contains sodium metabisulfite, a
sulfite which may cause an allergic-type reaction, including serious
allergic symptoms that can become life-threatening.
When Ritodrine is used for the management of preterm labor in a patient
with premature rupture of the membranes, the benefits of delaying delivery
should be balanced against the potential risks of development of
chorioamnionitis (inflamation of fetal membranes).
Ritodrine crosses the placenta,
enters the fetal circulation, brain and other major fetal organs. How this
alteration of brain chemistry affects the neurologic development of the
exposed offspring is unknown. The label of Ritodrine notes that
neonatal symptoms of hypoglycemia and ileus (intestinal obstruction due to
inhibition of bowel motility) are infrequently reported. Although clinical
studies did not demonstrate a risk of permanent adverse fetal affects from
Ritodrine, the possibility cannot be excluded; therefore, Ritodrine should
be used only when clearly indicated.
SCOPOLAMINE
HYDROBROMIDE
Scopolamine is a sedative and
tranquilizing depressant to the central nervous system. The drug can
produce restlessness, hallucinations, or delirium, especially in the
presence of severe pain.
The manufacturer advises in the label that Scopolamine crosses the
placenta and that use during labor may cause respiratory depression in the
neonate, and that Scopolamine may contribute to neonatal hemorrhage due to
a drug induced reduction in the clotting factor (fibrin) in the neonates
blood.
SUFENTA
(sufentanil citrate)
Sufenta is FDA approved
for epidural administration as an analgesic combined with low dose
bupivacaine during labor and vaginal delivery.
Sufenta is a potent opioid. The drug can produce muscular rigidity that
involves the skeletal muscles of the neck, trunk and the extremities. The
manufacturer warns that skeletal muscle rigidity is
related to the dose and speed of administration of Sufenta. The drug can
cause respiratory drive to decrease and airway resistance to increase. At
high doses, a pronounced decrease in pulmonary exchange
and apnea (transient cessation of breathing) may be produced.
The FDA approved label/package insert of Sufenta cautions that the drug
should be administered incrementally and that the proper placement of the
needle or catheter in the epidural space is
essential. The intravascular injection of Sufenta can result in a serious
overdose including acute muscular rigidity in the trunk area, and apnea
(impaired respiration). A intrathecal injection of the full sufentanil/bupivacaine
epidural dose and volume can result in a serious overdose, including acute
truncal muscular rigidity and apnea that can, in turn, produce effects of
high spinal anesthesia
including prolonged paralysis and delayed recovery and death.
The FDA label advises that (a) the most serious and significant effect of
an overdose of Sufenta is respiratory depression, (b) that the intravenous
administration of an opioid antagonist such as naloxone
should be employed as a specific antidote to manage respiratory
depression, and (c) that respiratory depression can recur in the
postoperative period.
The patient must be carefully and continuously monitored since the
duration of respiratory depression produced by Sufenta may last longer
than the countering effects of the opioid antagonist. If the
patient's gag reflex continues to be blunted by the opioid after the
effects of the opioid antagonist has worn off, there is increasing
possibility that the patient may aspirate her stomach contents, which
could result in neurologic injury or death.
Respiratory depression may be intensified when Sufenta is administered in
combination with volatile inhalation agents and or other central nervous
system depressants such as barbiturates,
tranquilizers, and other opioids.
Indwelling catheters appear to be
standard with the use of epidural Sufenta in order to avoid urinary
retention. The return of normal bladder activity may be delayed.
