REV.CHIM.(Bucharest)♦70♦No. 11 ♦2019 http://www.revistadechimie.ro 3818
The Chemical Pregnancy
MIHAI CRISTIAN DUMITRASCU1,2, MADALINA ILIESCU3, RAZVAN COSMIN PETCA1,4*, FLORICA SANDRU1,3*,
CLAUDIA MEHEDINTU1,5, PATRICIA DELIA FARCASANU1, NICOLETA MARU1, CALIN CHIBELEAN6, AIDA PETCA1,3
1Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Bvd., 050474, Bucharest, Romania
2University Emergency Hospital, Splaiul Independentei no.169, 050098, Bucharest, Romania
3Elias Emergency Hospital, 17 Marasti Blvd., 011461, Bucharest, Romania
4Prof. Th. Burghele Clinical Hospital, 20 Panduri Str., 050653, Bucharest, Romania
5Malaxa Clinical Hospital, 12 Vergului Str., 022441, Bucharest, Romania
6George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 38 Gheorghe Marinescu Str.,
540139, Targu Mures, Romania
The chemical pregnancy is an early pregnancy loss occurring shortly after implantation. 50-75% of all
miscarriages are considered to be chemical pregnancies. Although the pregnancy test is positive, the fetus
cannot be detected on ultrasounds; it can be asymptomatic or it can have menstrual-like cramping and
bleeding. There are numerous risk factors associated with miscarriage, such as: epidemiological, genetic,
anatomical, endometrial, endocrine and immune factors, infections, inherited thrombophilia and
antiphospholipid syndrome. Many drugs are related with spontaneous miscarriage, significant evidence
being found for nonsteroidal anti-inflammatory drugs, inhaled corticosteroids, antidepressant medication,
antiepileptic and antihypertensive drugs, the artemisinin-based combination therapy and for the diclofenac/
misoprostol combination. Besides the common diseases like asthma, chronic hypertension, chronic kidney
disease, thyroid disorders, diabetes mellitus, polycystic ovary syndrome and rheumatoid arthritis, there was
also found a higher correlation with the risk of miscarriage for the Zika Virus infection. In conclusion,
chemical pregnancy is a type of early pregnancy loss which usually doesn’t need prevention, associated
with multiple risk factors.
Keywords: miscarriage, risk factor, early pregnancy loss, exposure, environmental factors
A chemical pregnancy is defined as an early pregnancy
loss occurring shortly after implantation. It differs from other
miscarriages by the fact that these types of pregnancy loss
can occur at any time during a pregnancy, but more
frequently before the 6th week. Although there are found
high levels of human chorionic gonadotropin in the patient’s
blood, the fetus can not be detected on ultrasounds.
Chemical pregnancies account for 50-75 % of all
Although the exact cause of a chemical pregnancy
remains unknown, there are described some contributing
factors, such as: advanced maternal age, low body mass
index (BMI), uterine abnormalities, insufficient hormone
levels (progesterone), chromosomal abnormalities,
infections, implantation outside the uterus, thyroid disorders
A chemical pregnancy is usually indicated by a positive
pregnancy test, followed by a negative one. Studies
showed that up to 25% of pregnancies result in miscarriage
before a woman misses a period or has any pregnancy
symptoms. Sometimes, a chemical pregnancy can be
asymptomatic, but it can also be suggested by mild
abdominal cramping, mild spotting a week before an
expected period, vaginal bleeding within days of getting a
positive pregnancy result. These symptoms can also occur
during a healthy, ongoing pregnancy. At the same time,
considering that bleeding and menstrual-like cramping are
often the only symptoms, most women assume they are
having their menstrual cycle. Bleeding after a positive
pregnancy test can be also due to the implantation, spotting
often appearing in 10-14 days after conception, as a
brownish or pinkish discharge. The chemical pregnancy is
not associated with pregnancy-related symptoms like
fatigue or nausea [1,2].
* email: email@example.com; Phone: +40722224492 All the authors have equal contribution to this paper
firstname.lastname@example.org Phone: +40722276620
A chemical pregnancy doesn’t usually need medical
intervention or treatment. As soon as 2 weeks after an
early pregnancy loss, most women can attempt to get
pregnant again. A history of chemical pregnancy doesn’t
associate difficulties in conceiving again. On the contrary,
it is a positive sign that a woman could obtain a pregnancy
in the future .
A chemical pregnancy can also occur after in vitro
fertilization (IVF) , having a chemical pregnancy is the
first IVF cycle meaning that’s more likely to have a
successful pregnancy in a next IVF cycle .
Although there are not specific ways to prevent a
chemical pregnancy , metformin can be used in
pregnant women with polycystic ovary syndrome, being
associated with a significant decreasing in the rates of
early pregnancy loss . In order to solve the inadequate
secretion of progesterone, dydrogesterone was widely
used in preventing the recurrent and the threatened
miscarriage, but due to the high association with
congenital heart disease, it is not used anymore in many
countries now [4,5].
Risk factors for miscarriage
Recurrent spontaneous miscarriage is defined as three
or more consecutive pregnancy losses before 24 weeks of
gestation [5-8]. It affects 1-2% of women of reproductive
age trying to conceive [6,8].
A strong independent risk factor for pregnancy loss is
the maternal age at conception; the risk rising from 11% at
20-24 years of age to 93% at 45 years of age. Another risk
factor, but with a lower impact is the advanced paternal
age (over 40 years of age). The risk of miscarriage
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increases after each successive pregnancy loss, from 9%
after no losses, 12% after one, 20% after two and 40% after
three or more pregnancy losses [6,8]. Other risk factors
are: obesity, which is associated with early recurrent
miscarriage, heavy alcohol consumption of 5 or more units
per week, which leads to an increased risk of sporadic
miscarriage, maternal cigarette smoking and high caffeine
consumption of more than three cups of coffee per day,
which have dose-dependent relationships with the risk of
Regarding the chromosomal disorders, the most
important cause of miscarriage before ten weeks of
pregnancy is the fetal aneuploidy. The cytogenetic
abnormalities are described at least in 50-60% of all
miscarriages, trisomy being the most frequent, with a risk
of occurrence increasing with the maternal age. In 2-5%
of the recurrent miscarriages, one partner has a balanced
structural chromosomal anomaly, which can be either a
Robertsonian translocation, or a balanced reciprocal
translocation . Although they are phenotypically normal,
their meiosis consists in abnormal segregation, which leads
to 50-70% of their gametes and embryos to be unbalanced
, thus turning the pregnancy into miscarriage.
Between 1.8% and 37.6% of women presenting with
recurrent miscarriage are having congenital uterine
anomalies, such as bicornuate and septate uterus.
Miscarriages occurring in the context of an uterine septum
may be explained by the poor vascularization of
fibromuscular tissue composing the septum, this leading
to a bad development of the decidua and the placenta
It is considered that uterine fibroids, which are affecting
30% of women at conceiving age, impede the embryonic
implantation because of their space-occupying effect,
which leads to a lower expression of HOX 10, a gene
involved in implantation and differentiation [6,8].
Although inherited thrombophilia is associated more
with second-trimester miscarriage, it can also increase
the risk of recurrent miscarriage, the possible mechanism
being the thrombosis of the uteroplacental circulation. This
pathology includes protein S deficiency, activated protein
C resistance, prothrombin gene mutation and factor V
Antiphospholipid syndrome is an acquired autoimmune
disorder and one of the important treatable causes of
recurrent miscarriage. It is characterized by
antiphospholipid antibodies including anti-Beta-2-
glycoprotein 1 antibodies, lupus anticoagulant and
anticardiolipin antibodies. Antiphospholipid antibodies
appear in 15% of women with recurrent miscarriage, being
responsible of a 90%
risk of further pregnancy loss, in all
cases left untreated. The mechanisms by which these
antibodies lead to pregnancy morbidity are the inhibition
of trophoblastic function and differentiation and placental
injuries mediated by inflammation, as a response to the
activated complement. Also, in later pregnancy, these
antibodies are leading to thrombosis of the uteroplacental
Some cases of recurrent miscarriage are explained by
disorders of decidualisation, a phenomenon consisting in
changes of the stroma, endometrial glands and cellular
composition induced by progesterone, in order to support
the implantation of the embryo. Based on the observation
that the time of conception is significantly reduced in some
women with recurrent miscarriage, it was developed a
theory which suggests that the endometrium sometimes
allows an abnormal development of the embryos, which
will finally miscarry to implant. Another theory talks about
an inadequate secretion of progesterone, either in early
pregnancy or in the luteal phase of the menstrual cycle.
This second theory revealed the critical importance of
progesterone, which is essential for implantation of the
embryo, inducing secretory changes in the endometrium
Maternal endocrine disorders such as diabetes mellitus
and thyroid dysfunction have been associated with
spontaneous miscarriage [6,8,13-15]. A risk factor for
recurrent miscarriage is the poor controlled diabetes, with
high levels of haemoglobin A1c during the first trimester of
pregnancy. Also, the treated thyroid dysfunction doesn’t
increase the risk of spontaneous abortion. While the role
of antithyroid antibodies in the occurrence of miscarriage
remains unclear, hyperprolactinemia, which is linked with
thyroid disorders, has also been associated with pregnancy
loss. The risk of miscarriage is linked with polycystic ovary
syndrome (PCOS), the mechanism probably being based
on the insulin resistance, while the elevated free androgen
index is also associated with an increased risk of
subsequent miscarriage [6,8].
A sporadic miscarriage can be the consequence of a
severe infection with bacteremia or viremia, while the
recurrent miscarriage may need an infective agent which
can persist undetected in the genital tract [16,17]. For
example, Chlamydia trachomatis leads to a persistent and
asymptomatic infection, spreading to the endometrium or
to the fetal tissue [8,9].
Studies have found high levels of uterine Natural Killer
(NK) cells associated with high rates of miscarriage, NK
cells contributing to the cytokine response at the maternal-
fetal interface .
Periconceptional caffeine intake
Although several studies have shown no association
between preconception caffeine intake and fetal loss [18-
20], there are others which have concluded that a high
daily preconception caffeine consumption increases the
risk of spontaneous abortion [18,21-23]. Another study has
found that an intake of more than 300 mg per day caffeine
prior to pregnancy increased the risk of fetal loss by 31%
The risk of spontaneous abortion is also linked with
prenatal alcohol exposure, especially before or around the
time of conception [18,24,25].
Another harmful environmental factor in pregnant
women is the radiation exposure, which increases the risk
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of early miscarriage. The study which found this correlation
included mothers who were exposed to radiations in the
Medication related with spontaneous miscarriage
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs are widely used
by pregnant women, their periconception intake being
correlated with an increased risk of miscarriage, that being
a dose-response relationship [27-30]. The risk of
miscarriage is increased by 80% in case of using NSAIDs
during pregnancy, being much higher when this medication
was used for longer than a week, or it was taken around
The link between NSAIDs and the risk of miscarriage
may be explained by the main pharmacologic effect of
this drug class, which is the inhibition of the prostaglandin’s
production, finally leading to malimplantation. A successful
embryonic implantation depends on the prostaglandin’s
levels. Taking into account that the process of implantation
is affected during early pregnancy, the risk was especially
observed for early miscarriage [30,32,33]. This was also
proven by the stronger association of miscarriage and
women with a body mass index lower than 25 kg/m2, this
finding might be explained by the fact that obesity
stimulates the prostaglandin biosynthesis, that being
essential for the embryonic implantation . It was
observed that cyclo-oxygenase 2 inhibitors, which are the
newer selective NSAIDs are leading to an increased risk of
post-implantation and peri-implantation miscarriages,
being classified as pregnancy category C .
Although NSAIDs and aspirin are increasing the risk of
miscarriage, studies haven’t shown the same effect for
Paracetamol, which has a lot of the indications for use of
NSAIDs. That can be explained by the different
pharmacological effect of the Paracetamol [30,34].
Corticosteroids are globally used by 2% of pregnant
women in early pregnancy. Most studies have shown a
correlation between the use of inhaled corticosteroids and
a slightly increased risk of spontaneous abortion, the oral
use doesn’t associate the same risk .
Inhaled administration of corticosteroids is related only
to early miscarriage, a correlation with the late miscarriage
hasn’t been described yet. This reflects that intrauterine
exposure to this medication influences the fetal
environment, leading to an increased risk of early
pregnancy loss [35-37].
A common indication for inhaled corticosteroids is
asthma, which is considered itself a risk factor for
miscarriage. In addition, the risk of miscarriage is higher
among women with history of one or more asthma
exacerbations in the year before the pregnancy compared
with those without exacerbations [35,38,39]. This fact can
be explained by the abnormal smooth muscle activity of
the uterus, which is induced by hypoxia during the asthma
exacerbations [35,40,41]. So, it’s difficult to separate the
effect of inhaled corticosteroids from the effect of the
underlying asthma .
Although oral route of administration for corticosteroids
leads to increased degrees of fetal exposure because of
their higher concentrations in the maternal circulation
[35,42]; there are no reports of similar correlation with the
risk of pregnancy loss as it was found for the inhaled
medication . Furthermore, it was showed that high
doses of oral corticosteroids have a protective effect, thus
they are used in preventing the recurrent miscarriages,
although there are some disagreements about their
effectiveness [35,40,43-45]. This may be explained by the
anti-inflammatory properties of oral corticosteroids, which
inhibit in high doses the abnormal immune response, which
is frequently responsible for the miscarriages [35,41].
Studying the risk of spontaneous abortions associated
with maternal use of antiepileptic drugs (AEDs) has shown
that the maternal exposure to AED polytherapy is one of
the most important risk factor for intrauterine death among
the pregnant women with epilepsy. Still, the strongest
predictor of intrauterine death was the presence of major
congenital malformations in at least one of the parents,
suggesting that fetal loss is influenced more by intrinsec
and genetic parental or maternal transplacental factors
than by epilepsy or antiepileptic treatment .
There are numerous controversies about the role of the
antiepileptic medication in spontaneous abortions, some
studies showing a significantly increased risk of AEDs use
among women without epilepsy and no association
between spontaneous abortions and AEDs use during
pregnancy in women with epilepsy [46,47].
A prospective study which has included 7055
pregnancies in women with epilepsy found that the risk of
intrauterine death is significantly increased by some
parameters. It was revealed that the risk is increased by
maternal age, the older women being at a higher risk and
by the number of previous pregnancies with intrauterine
deaths, a greater risk corresponding to a greater number. It
was also found a decreasing risk of pregnancy loss with
increasing gestational week, the majority of miscarriages
occurring in early pregnancy . While some studies
reported higher rates of pregnancy losses in women with
localization-related epilepsy [46,48], this study has found
an increased risk among the women with undetermined
or unclassified epilepsy . Comparing 7 different
antiepileptic treatment categories including 6
monotherapies and a polytherapy, they found no
relationship between occurrence of pregnancy loss and
AED monotherapy, although this is the predominant
treatment regimen among the pregnant women with
epilepsy; this finding is consistent with other studies [46,49-
52]. Another observation refers to the fact that it was no
correlation between intrauterine death and the dose of
antiepileptic drugs, at least for lamotrigine, carbamazepine
and valproic acid. However, the polytherapy was
associated with a significantly higher risk of pregnancy
loss when compared with all monotherapies combined
. As regards the major convulsive seizures, these have
no influence on spontaneous abortions [46,49].
Approaching the folate supplementation during
pregnancy among the women with epilepsy, there are
some disagreements. While some studies showed that
periconceptional folate is related with a reduced rate of
spontaneous abortion, others found no relationship between
folate supplementation and intrauterine death [46,53].
Antidepressants use among pregnant women has
increased in the last decades, the recent prevalence being
between 3.2 and 7.6 %. The most common prescribed
antidepressants are the selective serotonin reuptake
inhibitors (SSRIs), which have been associated with an
increased risk of miscarriage .
Although there are conflicting results of the studies
regarding the association between antidepressants use
and miscarriage, more recent studies showed a greater
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risk of spontaneous abortion related to the antidepressants
use during the first trimester, when compared with
unexposed women, with and without depression [55,56].
It was found a particularly higher risk for the serotonin and
norepinephrine reuptake inhibitors monotherapy, but all
classes of antidepressant have been associated with
elevated risks of miscarriage .
Comparing the unexposed women diagnosed with
depression in the previous 4 years with unexposed women
without depression, it was revealed a slightly elevated risk
of miscarriage for the previous ones, suggesting that
depression itself is a risk factor for severe pregnancy
outcomes, such as miscarriages .
Moreover, it was proven an elevated risk of miscarriage
ranging from 1.5 to 1.7 among prenatal antidepressants
users. A study including women who took antidepressants
in the 3 months before pregnancy, but not in the first
trimester, showed a lower relative risk of spontaneous
abortion than first trimester antidepressants users. Also, it
was showed that stopping antidepressants use before
pregnancy leads to a decreased risk of miscarriage .
Another study based on the use of SSRIs found that
continuing the antidepressant medication during the first
trimester leads to a 20% higher risk of miscarriage than
stopping it .
The mechanism of miscarriage, suggested by some
studies, is that antidepressants may increase the risk of
pregnancy loss by acting directly on chromosomal or
placental development [57-59].
Chronic hypertension in pregnant women is associated
with severe complications, such as: miscarriage or fetal
death, placental abruption, eclampsia, preeclampsia,
HELLP syndrome, liver or renal failure, intrauterine growth
restriction and preterm birth [60-64]. In order to reduce the
incidence of these adverse outcomes, the mild and
moderate hypertension during pregnancy must be carefully
treated and supervised, decreasing the risk of severe
hypertension‘s occurrence .
The most used drugs for the treatment of hypertension
are angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin receptor blockers (ARBs), which are also used
for the treatment of chronic kidney disease (CKD) and heart
failure. Exposure to this medication in the second and third
trimesters of pregnancy is known to be harmful for the
Studying the effect of ACEI and ARB exposure in early
pregnancy proved that these classes of medication are
associated with increased rates of miscarriages. The higher
rate of spontaneous abortion was also observed for the
other antihypertensives, showing a non-specific effect of
the treatment in combination with the underlying disease
Another risk factor for early miscarriage is the chronic
kidney disease, which affects only 1 from 750 pregnancies,
because of the reduced fertility rates [26,65,68-70].
Artemisinin-based combination therapy (ACT) anti-
ACT is being used as a first-line treatment for falciparum
malaria in the endemic countries, ACT exposure being more
common than quinine exposure [71,72]. Because of the
limited data regarding the safety of this therapy in pregnant
women, treatment in the first trimester is not
recommended unless oral quinine is not available or the
life of the mother is at risk [57,73,74].
Animal studies have found an increased rate of fetal
loss based on the embryo-toxicity of artemisinin, which
affects the primitive erythroblasts. In humans, these cells
correspond to the primary form of red blood cells in
circulation between 4 and 10 weeks of gestation [57,75].
In addition, malaria itself can be responsible for severe
outcome, such as fetal loss, perinatal mortality, preterm
birth and even maternal death. A retrospective analysis
showed that both symptomatic and asymptomatic malaria
infection is an important risk factor for miscarriage.
However, the same study found no relationship between
the first trimester artemisinin exposure and pregnancy loss,
while other studies revealed a higher risk of miscarriage
among women treated with ACT in the first trimester
compared with the unexposed women. Also, the risk
associated with ACT was similar or lower compared to
oral quinine [57,76].
Misoprostol is a prostaglandin E1 analog usually used in
combination with diclofenac in many rheumatic diseases
and inflammatory disorders, in order to prevent gastric
ulcer, which is an adverse effect of NSAID. It decreases
the gastric acid secretion through its mechanism of
reducing the proton pump activity. In addition, misoprostol
stimulates the contraction of the smooth muscles of the
uterus, being related with an increased risk of miscarriage.
It can happen not only directly, but also indirectly, the uterine
contractions leading to vascular disruption and a
subsequent increased rate of malformations . Because
of this effect on the uterus, Misoprostol is administrated
vaginally for medically induced abortions in doses of 400-
800 mcg, in combination with Mifepristone or alternatively
Studying the women exposed at diclofenac/ misoprostol
three months prior pregnancy, it was found an increased
risk of miscarriage in the early pregnancy, even though the
medication was used in a lower dose than that
recommended for induced abortion and in oral, not vaginal
Although combination diclofenac/misoprostol is
contraindicated during pregnancy, it’s important to consider
that only 50% of pregnancies are planned, that leading to
an increased risk of exposure during the early pregnancy
Diseases related to spontaneous miscarriage
Polycystic ovary syndrome (PCOS)
PCOS is one of the main causes of anovulatory infertility.
Compared to the general population, this condition has
been associated with higher rates of early pregnancy loss
(30-60%) [3,79,80]. In addition, hyperinsulinemic
resistance is considered an independent risk factor for early
miscarriage, having a bad influence on the implantation
environment and on the endometrial function .
This condition is defined by a normal level of serum free
thyroxine and a raised level of serum thyroid-stimulating
hormone, which is above the upper limit of normal (TSH>=
4.15 mU/l). Although there are studies which demonstrated
a correlation between an increased risk of miscarriage and
subclinical hypothyroidism, others have shown no
significant difference in loss rate between euthyroid
women and women with subclinical hypothyroidism [81-
Recent studies have observed a significantly higher risk
of both early and late spontaneous abortion among women
REV.CHIM.(Bucharest)♦70♦No. 11 ♦2019 http://www.revistadechimie.ro 3822
with rheumatoid arthritis, compared to the general
population. It was found that women with rheumatoid
arthritis experience more often recurrent events of early
miscarriage. This can also be explained by the effect of
methotrexate, an antirheumatic treatment, which was
itself associated with an increased risk of spontaneous
abortion. So, it’s very important to establish if pregnancies
occurred under disease-modifying antirheumatic drugs
such as methotrexate, those being used around the time
of conception .
Zika Virus Infection
Another condition which has been associated with
miscarriage is Zika Virus infection. Although this correlation
wasn’t studied enough until now, some cases were
described in the literature [86-88].
A recent article reported the case of a 10 weeks pregnant
woman, which visited an outpatient clinic because of
headache, mild arthralgies and a pruritic, macular rash.
These symptoms had begun the day after her return from a
trip to Suriname, where she didn’t use personal protective
measures or malaria chemoprophylaxis. Although her
symptoms resolved spontaneously after 6 days, the
ultrasonography performed on day 14 after the onset of
symptoms revealed no fetal heartbeat, at an estimated
gestational age of 11 weeks and 4 days. 21 days after the
onset of the symptoms, it was performed amniocentesis,
followed by dilatation and curettage. Testing the amniotic
fluid, the fetal and the placental tissue, a positive result for
Zika Virus was obtained. Furthermore, the histopathological
analysis of the placental tissue specimens revealed that
the intrauterine fetal death occurred one week before the
curettage. Using in situ hybridization, evidence of Zika Virus
infection was proven in fetal mesenchymal cells,
particularly in the perichondrium and also in the amniotic
epithelial cells . This finding leads to the observation
that Zika Virus replicates in pluripotent cells (amniotic
cells), which are important for the early-stage embryo
development; that may be a possible explanation for the
association of the Zika Virus infection with the miscarriage
Another essential finding was the prolonged viremia of
the patient, until the day 21 from the onset of the symptoms,
which is not corresponding with the current assumption
that Zika Virus viremia can be detected only in the first 7
days from the onset of the symptoms [86,89].
Between 50 and 75% of all miscarriages are chemical
pregnancies, which are early pregnancy losses occurring
shortly after implantation. Although the gestational sac isn’t
visible on ultrasounds and the pregnancy-related symptoms
are not present yet, the chemical pregnancy can be early
detected by a positive pregnancy test. The chemical
pregnancy doesn’t usually need treatment and in many
cases there are no specific ways to prevent it, but taking to
consideration all the causes proved to be involved in early
miscarriage, eliminating the risk factors frequently turns
into favorable outcomes. Every practitioner should have in
mind that whenever women have a personal history of
early miscarriage, a close and careful look at the health
state and environmental details is capable to change for
the future the bad prognosis into a favorable one.
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Manuscript received: 23.09.2019