Discussion:
Substance abuse during pregnancy is still an important health concern
and has several harmful impacts on both the mother and the fetus.
Pregnant women are frequently abusing polysubstance, which may aggravate
harmful effects on both the mother and the fetus.[3] Pregnancy is a
state where there are pharmacokinetic alterations affecting absorption,
distribution, metabolism and elimination. The type of the substance, its
dosage, period of pregnancy, and most importantly, the individual in
consideration all influence these effects.[4] This woman was
addicted to four psychological drugs which were Pregabalin, Chloral
hydrate, Methamphetamine, and Tramadol before pregnancy and continued
taking them during pregnancy. Psychological drugs have the potential to
be teratogenic, meaning they raise the possibility of birth defects and
poor cognitive outcomes.[4] Pregabalin is an alkylated derivative of
gamma aminobutyric acid (GABA) that is legally permitted by many
countries for the treatment of neuropathic syndromes, fibromyalgia,
partial onset seizures, and generalized anxiety disorder.
It works by binding to calcium channels, regulating calcium influx, and
affecting GABAergic neurotransmission; therefore, its analgesic,
anxiolytic, and antiepileptic properties are conferred by this method of
action.[5] Furthermore, Pregabalin has also been shown to cross the
placenta in mice, rats, and monkeys.[6] Its exposure was associated
with a higher incidence of significant abnormalities when compared to
nonexposed pregnancies with a rate of 5.9 per 100 live births, compared
to 3.3 per 100 for unexposed pregnancies.[7] Moreover, some animal
studies with antiepileptic drugs like pregabalin have reported skeletal
malformations, orofacial clefts, neural tube defects such as spina
bifida, increased rates of spontaneous abortions, growth retardation,
and behavioral anomalies.[8, 9]
Due to a lack of safety studies in pregnancy,
pregabalin is considered the last
treatment option for various neurological diseases for pregnant women
and more research is required to assess its safety for pregnant women as
well as its potential effects on the health of the fetus.[6]
On the other hand, Chloral hydrate (CH) was one of the most commonly
used sedatives for non-invasive diagnostic procedures in clinics, like
performing transthoracic echocardiography (TTE) and objective hearing
tests for children. However, it’s no longer in use except in
China.[10] It works by ameliorating GABAa receptor function; thus,
decelerating central nervous system performance.[11] Because it is
no longer used, the literature
hasn’t mentioned any previous study about the teratogenic effect of CH
on fetus due to mother intake. The third drug, which is Methamphetamine
(MA), is a central nervous system stimulant that causes high dopamine,
serotonin, and norepinephrine presynaptic concentrations. The use of
this substance is linked with high levels of energy and exhilaration. It
is the only illegal drug that can be made from everyday products like
decongestants and cough syrups sold over-the-counter. With a high
bioavailability, it may be smoked, snorted, injected, and used rectally.
MA raises the risk of myocardial infarction, hypertension,
cardiomyopathy, and stroke due to its alpha and beta adrenergic
effects.[12] It’s one of the most widely utilized illicit substances
during pregnancy is MA.[13] In addition, a study published in 2019
showed that the studies that have been released before couldn’t prove
that there is relevance between Mmethamphetamine and the congenital
malformations except cleft
palate.[12] Nevertheless, an environmental scan was published in
2021 to show the impact of MA use during pregnancy on the pregnant women
and on their fetuses, the study extracted data from 80 articles and
identified 463 results related to 210 outcomes and seven interventions.
The outcomes were distributed in 6 categories: 41% for general
neonatal/infant outcomes,16% for
cognitive outcomes, 15% for
neurological outcomes, 14% for
behavioral outcomes, 11% for maternal outcomes, and 3% for
interventions (maternal/neonatal).[14] In this case, multiple
outcomes from previous categories were found in the same fetus, compared
to other cases where the fetus suffered from few manifestations, except
the behavioral outcomes which we
couldn’t indicate because of the
fetus’s death.
Ultimately, tramadol is a common centrally acting atypical opioid
analgesic prescription. Even though this medication is used extensively,
not much is known about its potential teratogenicity.[15] Prescribed
opioid painkiller usage during pregnancy is a public health issue, since
it affects 2%–4% of pregnancies. Opioid analgesics have the potential
to damage fetuses since they can cross the placenta. There is
conflicting and incomplete data about the safety of opioid analgesics
for pain management during pregnancy.[16] A cohort study in Ontario
published in 2022 included a 599,579 pregnancies to study the
relationship between prescribed opioid analgesics in early pregnancy and
the risk of congenital anomalies, 11,903 were exposed to opioid
analgesics, 781 pregnant women were in contact with tramadol, 38 was the
number of fetuses with a congenital anomalies classified by organ
system: 11 for cardiovascular, 10 for gastrointestinal, 16 for
musculoskeletal. Urinary, neoplasms, and oral clefts share the same
number of anomalies from 5 to 6. The previous study indicates that
although the absolute incidence of anomalies is minimal, there may be a
little increased risk of congenital abnormalities with exposure to
opioid analgesics.[16] Another cohort study documented all
pregnancies in Denmark between 1997 and 2016 and was also published in
2022 to study the risk of spontaneous abortion or major congenital
malformations due to tramadol exposure during early pregnancy, the
result of this study presents that 4% of pregnancies with maternal
exposure to the drug experienced a significant congenital deformity
compared to pregnancies without maternal exposure at a rate of 3.8%,
according to this result the study suggested that taking tramadol does
not seem to be linked to severe congenital abnormalities.[17]
The fetus in our study presented with multiple anomalies including
anencephaly, exophthalmos of both eyes, cleft palate, absence of the
nose, gastroschisis, ectopia cordis, absence of the testes, a small
penis, absence of the spinal cord, imperforate anus, and clubfoot. We
attribute these multi-system anomalies to the multiple illicit drugs use
of the mother during pregnancy.
To our knowledge, this is the
first case that deals with multi-drug use during pregnancy since
previous cases were only about one drug.
Conclusion :
There are only a few studies in the medical literature about the
teratogenic effects of the addiction to each previously mentioned drug
individually; however, there isn’t any study about the combined effect
of two or more of them. Furthermore, the anomalies in the previous
studies weren’t similar to the anomalies in our case, which involved
many fetal body systems, so we attribute these multi-system
developmental abnormalities in the fetus to multiple drug use by the
mother. Therefore, further
research on addiction to more than one of these drugs is desirable to
extend our knowledge about their common impact on both the pregnant
woman and her fetus including its growth and possible anomalies.