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Efficacy of Cocaine in Pregnanacy 125
and as of 2004, in the United States alone water-soluble inactive forms benzoylecgo-
there are an estimated 1 million first-time nine and ecgonine methylester. Any patient
users each day. Porter and Porter4 esti- with altered liver function, including preg-
mated at least 4.6 million female cocaine nant women and their fetus, neonates and
users accounting for 750,000 exposed people with preexisting liver disease are at
pregnancies and births each year. The risk for a potentiation of the effect of
commonly used form, crack, is almost cocaine due to decreased metabolism. Un-
pure cocaine formed through ‘‘cooking’’ fortunately, cocaine users often have con-
the cocaine rocks with water and sodium comitant habits, and the combination of
bicarbonate, chemically producing the al- cocaine and alcohol increases the vascular
kalinized form of cocaine. Once ‘‘cooked’’ risk. The combined use of cocaine and
the cocaine separates from the solution. alcohol leads to the formation of cocathey-
This form, known as crack from the char- lene, which has been demonstrated to in-
acteristic noise made during the cooking crease the risk for cardiac events 40-fold
process, is the most addictive form and is with a 25-fold increase in sudden death.9
smoked.5 The hydrochloride salt of cocaine Cocaine may also have delayed activity
decomposes while heated and is taken by remote from acute use, as the noncocaine
mouth, intranasally, or intravenously. metabolite is also active.10 The water-solu-
Regardless of the form, cocaine is ab- ble cocaine metabolites are present in the
sorbed quickly. Smoked cocaine has the urine for 72 hours afterward.11,12 Cocaine
most rapid onset of action, within 3 to 5 metabolites can also be detected by hair
seconds with a peak effect within 3 mi- analysis and detects 4 times as many co-
nutes yet a relatively short duration of caine users than identified through self-
action lasting up to 15 minutes. The intra- reporting.13
venous route also has rapid pharmacoki- To better understand the maternal
netics, with up to 60 seconds for the onset consequences of cocaine use, the effects in
of action, 5 minutes for the peak effect, the nonpregnant abuser must be realized.
and duration of action up to 60 minutes. Jenkins et al14 studied the cardiovascular
The intranasal (snorted) route is slower and emotional effects of smoked cocaine
with onset within 5 minutes, peak effect of on human subjects. Within 2 minutes of
20 minutes, and duration of action of 1½ use, systolic blood pressures (BPs) rose by
hours. Orally administered cocaine is the a mean of 25 mm Hg, whereas diastolic
slowest route, with on onset of action by BPs rose by a mean of 6 mm Hg. The
20 minutes, peak effect by 1½ hours, and mean increase in the heart rate was 20
total duration of action up to 3 hours. beats/min. Interestingly, the cardiovascu-
Once absorbed, the physiological lar parameters did not have a smooth
hallmark of cocaine is profound vaso- decline, and all were below the initial
constriction, through its sympathomimetic baseline within 2 hours of administration.
properties. Cocaine blocks the presynap- Aside from these changes, cocaine induces
tic reuptake of the sympathomimetic neu- other physiological responses that could
rotransmitter norepinephrine, serotonin, theoretically place a pregnant woman at
and dopamine. The norepinephrine ef- an increased risk for adverse outcomes.
fects lead to hypertension, tachycardia, Other effects of acute cocaine use include
and possible cardiac arrhythmias. The coronary vasospasm, possible ischemia
dopaminergic effects on the limbic system after reduced cardiac oxygen delivery, pla-
and cerebral cortex lead to the ‘‘high’’ or telet activation, increased platelet aggreg-
euphoria experienced with cocaine use.6–8 ability, and alteration of the thromboxane
Cocaine is metabolized through hepatic production leading to an increased risk of
and plasma cholinesterase to form the thrombosis.15–17 As a result, 25% of
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126 Cain et al
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Efficacy of Cocaine in Pregnanacy 127
cross over to the response in humans, this alter the uteroplacental blood flow with
information is helpful in providing under- resultant fetal and neonatal sequelae. Co-
standing of the human experience with caine crosses the placental barrier easily,
cocaine exposure. Animal data document owing to its low molecular weight, lipid
the BP fluctuations with cocaine are ex- solubility, and low ionization.36 Some
aggerated in comparison with the non- data suggest that aside from the exposure
pregnant animal. This may provide through the maternal blood, cocaine, ben-
insight into the etiologies of a preeclamp- zoylecgonine, and noncocaine are stored
sia-like picture and placental abruption in the placental membranes and myome-
with cocaine use. A dose-dependent in- trium, leading to a potential continuous
crease in BPs is observed after cocaine source of exposure after the acute use.37
administration in ewes, with pregnant The amniotic fluid also acts as a reservoir
ewes demonstrating a significantly in- for fetal cocaine exposure. The fetal se-
creased response in comparison with non- rum levels of cocaine and its metabolites
pregnant ewes.32 Woods and Plessinger33 are only 3% of the amniotic fluid levels in
documented maternal cocaine levels were ewes.38 Therefore, the fetus is exposed to 3
8 to 10 times higher in pregnant ewes routes of exposure, transplacental pas-
compared with nonpregnancy, with a sage, the placental membranes, and my-
concomitant increase in the systemic vas- ometrium and recycling through the
cular resistance and other vascular pa- amniotic fluid. The presumed etiology
rameters. Although the uterine blood for the adverse fetal outcomes is reduced
flow is unaffected in nonpregnant rabbits, uteroplacental blood flow secondary to
a dose-dependent reduction in blood flow the vasoconstrictive effects of cocaine ex-
was demonstrated in the uterine and pla- posure. As with any other substance, one
cental vasculature in pregnancy.34,35 of the most dangerous periods is during the
first trimester. Owing to the significant
vascoconstrictive effects, cocaine users ex-
perience a significant increase in first tri-
Fetal and Neonatal mester spontaneous abortion.27,39 An
Consequences of In Utero increased risk of congenital malformations
Cocaine Exposure especially of the CNS and cardiac system
A 23-year-old G1P0 presents to your la- has been suggested.39–41 The overall mal-
bor and delivery suite with no prenatal formation rate in these pregnancies is 10%
care and contractions, vaginal spotting, versus 2% for cocaine-negative controls.39
and decreased fetal movement. BP was Fetal brain growth is also adversely af-
170/100; urine has trace protein. A urine fected presumably due to fetal intracranial
drug screen is positive for cocaine. A bed- vasoconstriction, as Handler et al42 docu-
side ultrasound confirms a 34-week intra- mented that cocaine use was associated
uterine pregnancy with a fetal demise. She with a 16% incidence of microcephaly,
rapidly delivers a stillborn with no mor- which occurred in only 6% of nonusing
phologic abnormalities. The aftercoming controls. Other fetal vascular beds are at
placenta has a fresh clot adherent to it risk, as the cocaine-mediated vasoconstric-
consistent with a 70% placental abrupt- tion is the presumed etiology of various
ion. Her mother is wondering how this disruption patterns including bowel infarc-
happened and could the cocaine habit she tion, atresia or perforations, porencephalic
advised her daughter to quit have led to cysts, and nonsyndromic limb defects.43
this outcome? The effect of cocaine use on birth weight
The previously mentioned cardiovas- has been studied extensively. However,
cular effects of cocaine exposure directly because of the multitude of confounding
www.clinicalobgyn.com
128 Cain et al
variables, the changes in birth weight and However, whether the blood flow and
other parameters may be due to several BP fluctuations with cocaine, the fetal
other factors including the gestational age neuroendocrine environment, infection,
during which cocaine was used, overall or other factors are the culprit, these
socioeconomic status, maternal nutrition- pregnancies are at risk for spontaneous
al status, cigarette smoking, alcohol con- prematurity. Ischemic injuries not related
sumption during the pregnancy and to other medical factors have been docu-
concomitant polydrug abuse.44 mented in premature infants of cocaine
Earlier documentation of fetal growth abusers.49 The exposed infants also had
aberrations were published by Zuckerman significant increases in CNS symptoms
et al in 1989.45 Women with positive urine including jitters/tremors (adjusted OR
assays for cocaine had infants with a 93 g 2.17; 99% CI, 1.44-3.29), high pitched
lower in birth weight, a 0.7-cm reduction in cry (2.44:1.06-5.66) irritability (1.81; 1.1-
length, and a 0.43-cm reduction in head 2.80), excessive suck (3.58; 1.63-7.88),
circumference. Although the reduction in hyperalertness (7.78: 1.72-35.06), and
birth weight did not reach statistical sig- autonomic instability (2.64; 1.17-5.95). It
nificance, the change in length and head is uncertain whether these behavioral
circumference was significantly different manifestations are due to the cocaine ex-
with a P = 0.01. The Maternal Lifestyle posure or withdrawal. However, Chasn-
Study of 717 cocaine-exposed infants and off and colleagues document that these
7442 nonexposed controls evaluated the symptoms commonly occur within the
physical and behavioral findings during first 2 to 3 days of life, whereas the cocaine
the neonatal period.46 This multicenter metabolites remain in the neonatal urine
prospective study demonstrated an earlier for as long as the first week of life.
gestational age at delivery by 1.2 weeks, a A meta-analysis of 31 studies evaluat-
536 g reduction in birth weight, 2.6-cm ing the effects of cocaine use in pregnancy
reduction in birth length, and a 1.5-cm confirmed a significant increase in low
reduction in head circumference in com- birth weight (<2500 g) with an OR of
parison with nonexposed controls. All of 3.66 and 95% CI of 2.90-4.63. Antenatal
these parameters attained statistical signifi- exposure to cocaine was also associated
cance with P<0.001.47 Therefore, the with a significant increase in small for
growth restriction pattern associated with gestational age<10 percentile for the ges-
cocaine use may be symmetric or asymmet- tational age with OR 3.23 (2.43-4.30).The
ric. A meta-analysis of 31 studies evaluat- risk for preterm birth (<37 wk) was in-
ing the effects of cocaine use in pregnancy creased with OR 3.38 (2.72-4.21). Overall
included confirmed a significant increase in maternal cocaine use led to a mean reduc-
low birth weight (<2500 g) with an odds tion in birth weight by 492 g.48
ratio (OR) of 3.66 and 95% confidence In utero ‘‘stress’’ is thought to acceler-
interval (CI) of 2.90-4.63. Antenatal expo- ate fetal lung maturation. In 1996, Han-
sure to cocaine was also associated with a lon-Lundberg and colleagues compared
significant increase in small for gestational the lung maturation profiles by surfac-
age<10 percentile for the gestational age tant/albumin ratio in cocaine-exposed
with OR 3.23 (2.43-4.30). The risk for pregnancies to negative controls. Cocaine
preterm birth (<37 wk) was increased with doubled the odds of a mature lung pro-
OR 3.38 (2.72-4.21). Overall maternal co- file.50 Cocaine users with preterm prema-
caine use led to a mean reduction in birth ture ruptured membranes are also more
weight by 492 g.48 likely to present with advanced cervical
The etiology for preterm labor in dilatation and have a shorter latency peri-
the general population is uncertain. od to delivery than noncocaine users.51
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Efficacy of Cocaine in Pregnanacy 129
However, this study was done before the cocaine-abusing mother. She quickly real-
routine use of antenatal steroids and the ized that she was not ready to handle the
present-day group B strep coverage (pro- responsibility of a child and put the baby
tocols with antibiotics). This finding was up for adoption. Your local adoption
corroborated by Martinez et al in 1996,52 agency has found a wonderful couple
who also demonstrated a significant in- who know of the child’s rough entry into
creased risk of intrauterine fetal death in the world, but regardless they are pro-
these patients (18.2% vs. 0%). Bateman ceeding with the adoption process. They
et al53 demonstrated a doubled risk for have a few questions on what to expect, so
preterm labor and delivery in an inner city they can prepare to handle the physical
cocaine-positive population. Over the and emotional needs of the baby as he
past decades, the successful efforts to grows and develops. What information is
reduce the vertical transmission of human the nursery and adoption agency going to
immunodeficiency virus have been life- share?
saving. However, cocaine and other illicit The concept of fetal origins of adult
drugs are known to negatively impact disease was first described by Barker et al
overall immunity. In 1997, Bulterys in 198958 who documented that low birth
et al54 demonstrated a risk ratio of 4.0 weight placed the offspring at significant
(95% CI, 2.0-8.1) for vertical human im- risk for heart disease. Although the exact
munodeficiency virus transmission with pathophysiological etiology for this is
injected cocaine and heroin. uncertain, Hincliffe et al59 proposed that
There are no evidence-based data dem- low birth weight infants had a reduction
onstrating an optimal medical manage- in nephrons, which would lead to a risk
ment for infants with in utero exposure, for hypertension later in life. As the co-
and this is an area for potential future caine/crack epidemic of the 1980s, data
research as the cocaine epidemic contin- are now emerging on the long-term effects
ues.55 The etiology for the different of in utero exposure and the implications
neonatal neurological findings in co- for these children, especially as they reach
caine-exposed neonates is uncertain. In school age. A literature review by Messiah
adults, the association of cocaine expo- and colleagues highlights the issues of
sure with and resultant cerebrovascular long-term evaluation of these neonates.
insults is well documented. Frank et al56 For various reasons, including patients
performed a longitudinal evaluation of lost to follow-up, sample size, varying
head ultrasounds in infants with in utero documentation regarding actual expo-
exposure compared with nonexposed sure, and other confounding variables,
controls. Although there was no differ- little is known regarding the long-term
ence in the scans with light exposure to cardiovascular and metabolic effects of
cocaine, those infants exposed to heavy cocaine exposure.60
exposure had an increased incidence of A continuation of the Maternal Life-
subependymal hemorrhage in the caudo- style Study evaluated the body mass index
thalamic groove (covariate adjusted OR: and BPs of 9 year olds with in utero
3.88; 95% CI, 1.45-10.35).57 cocaine exposure. The parameters were
compared in 277 cocaine-exposed chil-
dren and 603 nonexposed controls with
regression analysis performed to rule out
Postnatal Consequences of In other lifestyle-related factors such as diet,
Utero Cocaine Exposure sedentary lifestyle as an etiology. Interest-
It is a rewarding day in the nursery. Baby ingly, children who were exposed to heavy
boy Doe was born at 28 weeks to a cocaine use in utero had significantly
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130 Cain et al
higher body mass index and BPs. The adverse outcomes. Maternal risks include
children delivered at the onset of the hypertensive disorders, cardiovascular
cocaine epidemic are now becoming fluctuations, and placental abruption.
adults. Little is known regarding the Prenatal exposure has a profound effect
long-term adult health effects associated on the unborn fetus, with known in-
with their in utero exposures. As their creased incidence of growth aberrations
cardiovascular system is primed to react and fetal loss. The exposed neonate must
differently than the rest of the population, endure a multitude of CNS aberrations
there is the possibility for increased hyper- and are at risk for intracranial events.
tension, heart disease, and other adverse Unlike in utero exposure to opiates, there
health conditions.61 Xiao and colleagues is no evidence-based treatment plan de-
evaluated the long-term risk of in utero veloped for the management of the neo-
cocaine exposure on vascular reactivity nate exposed to cocaine.
in rats. Cocaine exposure significantly Each jurisdiction has their own ruling
increased norepinephrine-induced vasocon- regarding which patients can have urine
striction while decreasing the phosphoryla- drug testing, and under which circumstan-
tion of nitric oxide synthase with a ces. A high index of suspicion for cocaine as
concomitant reduction in the baroreflex a possible factor for the patient scenario
sensitivity in the adult male rats.62 These must be held until confirmatory test results
physiological changes would increase the are obtained. However, the conversation
risk for hypertension. There is no evidence regarding drug use should not be delayed
that this is true in humans. until the acute event. Upon presentation for
The emotional response to stress is prenatal care, all pregnant women should
enhanced in children with in utero expo- be questioned. Although the May 2012
sure. Chaplin et al, using the Trier Social ACOG Committee Opinion is directed to-
Stress Test, evaluated emotional response ward opiate exposure, the basic principal of
to stress in 49 adolescents with prenatal nonjudgmental questioning, and informing
cocaine exposure and 33 nonexposed ado- the patient that this information is being
lescents. They compared salivary cortisol, requested so the health care team can best
BP, and heart rate. Exposed adolescents take care of her during the pregnancy and
demonstrated increased cortisol before afterward holds true for all illicit drugs.64
and after stress. Exposed girls also had Each location has their own requirements
an increased anxiety and anger response for consenting neonates for antenatal drug
to stress in comparison with nonexposed exposure, and therefore, consultation with
girls. Exposed boys had a reduced dia- the local authorities regarding this is
stolic BP response.63 The long-term recommended.
behavioral and social implications of As the initial group of children born
these results have yet to be determined. during the recent cocaine epidemic be-
come adults, the long-term medical effects
of their in utero exposure will become
Summary evidenced. The controversies abound.
The non–obstetric-related sequelae of the The potential long-term effects for the
cocaine epidemic are well documented in upcoming generations are beyond com-
the literature. Unfortunately, this epi- prehension. Certainly this would be asso-
demic also includes women of childbear- ciated with a significant personal and
ing age, with resultant risks for health care cost. All of these issues raise
pregnancy-related adverse outcomes. the need for means to reduce the use of
Mothers using cocaine during pregnancy illicit drugs in general, and specifically
place themselves and their fetus at risk for during the antepartum period.
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Efficacy of Cocaine in Pregnanacy 131
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132 Cain et al
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