1.

Ectopic Pregnancy:

Ectopic pregnancy (EP) is the implantation of the zygote at a position other than the endometrial
cavity of the uterus. The implantation is followed by proliferative growth of the fetal tissue and
establishment of disrupted placenta, creating cancer like environs. Extrauterine pregnancy and eccysis
are synonym terms for EP {Tong, 2015 #6}. The maturing blastocyst erode and invade surrounding
tissues, followed by maternal vasculature hemorrhage and bleeding into the abdominal cavity {Seeber,
2006 #3}. It is also referred to as trophoblastic disease and is largely associated with placental invasion
and outgrowth {Roushani M,2016 # 38}. Ectopic pregnancy accounts for 6% of early pregnancy
maternal deaths {Seeber, 2006 #3}. It is one of those pregnancy related complications from the past
that were left undiagnosed and uncured. Most common sites reported for carrying EP are fallopian
tube, fimbriae, uterus interstitium, ovary, abdomen, and cervix {Seeber, 2006 #3}. Among these the
most prevalent is fallopian tube ectopic pregnancy, commonly referred to as tubal pregnancy,
accounting for 98% of Eps {Seeber, 2006 #3}. Heterotopic pregnancies are the rarest kind of EP where
the implantation occurs both extra-uterine and intrauterine{Chen, 2015 #4}.

Any condition that halts the passage of the zygote from fallopian tube to uterine cavity such as presence
of lymphocytes, macrophages, and anti-microbial peptides, is regarded as a potential risk factor in the
incidence of ectopic pregnancy. These include physiological obstructions, chemotactic failures,
imbalanced tubal motility such as ciliary dysfunctions, and abnormal conceptus {Seeber, 2006
#3;Tong, 2015 #6}. Previous tubal surgeries, pelvic infections, sexually transmitted diseases, induced
ovulation, assisted reproductive techniques, cigarette smoking that slows down zygote’s tubal
movements, high progesterone level that interrupts tubal contractility, and advancing age are some of
the controllable and uncontrollable risk factors leading to ectopic pregnancy {Seeber, 2006 #3;Tong,
2015 #6}. About 50% of the ectopic pregnancies occur without any pre-present risk factors{Chen,
2015 #4}.

Ectopic pregnancy has no distinguished set of symptoms; normally include abdominal pain, swelling,
and bleeding in first trimester, often misunderstood for normal pregnancies, miscarriages, and other
pregnancy complications {Mausner Geffen, 2017 #9;Mol, 1998 #8}. This fact becomes one reason for
its poor diagnosis, and delay in accurate and timely treatment. But world statistics show an increase in
the clinically reported cases of extrauterine pregnancies with 197 cases diagnosed per 100,000 persons
{Tong, 2015 #6}. The rise may be due to the development of successful assay procedures or prevalence
of risk factors {Mol, 1998 #8}. Treatment options for EP include ingestions of medicines designed to
block the pathology at various levels, surgery, and uterine artery embolization. All of which have their
own advantages and drawbacks.

Word ectopic comes from the Greek word ‘ektopos’ meaning ‘out of place’. The first case of ectopic
pregnancy was dealt by Albucasis in 963 ADS, who through evacuating the abdominal wall of patient
with swelling isolated a fetal skeleton. Tubal rupture was first observed by Jean Riolan in 1604 AD in
a four-month pregnant woman who passed away after the accident. The first scenario of ovarian ectopic
pregnancy was highlighted in 1682 AD, which was then unknown {Seeber, 2006 #3}.

Defects in ciliary beating movements and smooth muscle contractility are two major causes for tubal
retention of the conceptus as previously explained in risk factors. Intensification in nitric oxide
synthase affect the ciliary beat and muscle contractions. Influx of pro-inflammatory cytokines in early
pregnancy generate receptive indications for the conceptus. Leukemia Inhibitory Factor (LIF) is
enhanced in ectopic pregnancies as compared to both pregnant and non-pregnant women, which is a
cytokine in charge of promoting implantations. Vascular Endothelial Growth Factor (VEGF) creates
an oxygen rich environment endorsing embryo implantation; it has been observed raised in fallopian
tubes. Mucin-1 Expressing Cancer (MUC-1) is an anti-adhesive molecule is reported to be
significantly decrease in ectopic pregnancies. Trophinin protein associated with adhesive molecule
family is normally tightly regulated, but experiments reveal its increased concentrations in tubal
pregnancies {Seeber, 2006 #3}.

The aim of this review article is to highlight the limitations and shortcomings of various conventional
strategies and systems that have been developed for the diagnosis of ectopic pregnancy, the need for
nanoparticle mediated diagnostic systems and their management, and how they complement more
efficient and sensitive prognostic approaches for EP.

2. Current Strategies Pose an Un-efficient Diagnosis and Treatment:

2.1. Diagnosis:

a. Human Chorionic Gonadotropin (HCG):

With the rise in ectopic pregnancy complications, the need to design new diagnostic procedures for
determining EP with grave complexity became necessary. Various systems and procedures have been
prepense that meets the demand. Immunomagnetic Reduction Assays (IMR) of the Human Chorionic
Gonadotropin (HCG) hormone in the serum and urine of pregnant women is often done to detect
ectopic pregnancies {Mausner Geffen, 2017 #9}. HCG is a glycoprotein secreted by the placenta
detectable by 2 weeks of pregnancy to maintain the corpus luteum during pregnancy {Mausner Geffen,
2017 #9}. The diagnosis is based on the quantitative rise in HCG by 66% in 85% of normal
pregnancies, thus levels below 66% would indicate ectopic pregnancy and below 50% suggest high
chances of abortion {Mausner Geffen, 2017 #9}. The percentage values represent possibilities of
ectopic pregnancies calculated on basis of estimation protocols, and the fluctuations may in part due
to other pregnancy abnormalities such as other hormonic imbalances.

In addition, electrochemistry, mass spectrometry, resonance, fluorescence, and antibody-mediated

detection of HCG concentrations has played a vital, responsive, and cost-effective role {Barkalina,
2014 #32}. But these methods have their limitations including the qualitative assessments only, data
interpretation, religious washing, batch changes of antibodies, high cost of antibodies, and human
resource for equipment operation {Marion, 2012 #1}.

b. Transvaginal Ultrasonography

Transvaginal ultrasonography approach is accustomed to visualizing extrauterine pregnancies after the

3rd month. Whereas early diagnosis of ectopic pregnancies is vital to prevent tubal rupturing,
abdominal bleeding, fetal tissue cancerous growth, and death of patients, which cannot be achieved
through ultrasounds. Moreover, the ultrasonography techniques do not generate an accurate position
of the fetus in ectopic pregnancies {Fernandez, 1991 #10}. In only 70% of the cases of EP, diagnosis
at first clinical trial is accomplished through ultrasonography {Fernandez, 1991 #10}. Serial
estimations of HCG levels followed by ultrasounds and other imaging techniques consume time and
are expensive leading to severity of the condition and life-threatening hemorrhages {Fernandez, 1991
#10}.

c. Biomarkers

Serum and blood biomarkers have then been a focus for competent diagnosis of ectopic pregnancies.
However apart from HCG many biomarkers have been selected from literature based on their roles as
causative, pathogenic, and proliferative agents. Creatine Kinase (CK) is released when muscles of
fallopian tube get damaged {Fernandez, 1991 #10}. In a study incorporating its measurement in
ectopic pregnancies compared to normal pregnancies, the values overlapped between the two with
sensitivity of 57% and specificity of 67% {Duncan, 1995 #7}. In addition, markers of abnormal
embryo, abnormal corpus luteum function, inflammation, serum progesterone, abnormal implantation,
and abnormal angiogenic response are exploited as diagnostic factors in the struggle for designing a
prognosis regimen for ectopic pregnancy {Fernandez, 1991 #10}. Currently, majority of these markers
have failed to proceed further from phase II clinical trials. Problems with isolation of the markers pose
another challenge. These biomarkers cannot differentiate between ectopic pregnancies and
spontaneous miscarriages {Fernandez, 1991 #10}.

2.2. Treatments:

a. Medicines

Methotrexate is the commonly used medicine for treating ectopic pregnancy. Acting as competitive
inhibitor of folinic acid, it is a substrate for enzyme dihydrofolate reductase. The product incorporates
into the nucleic acids and halts DNA and RNA synthesis. Pretreatment serum levels of HCG less than
1500 IU/I makes methotrexate treatment preferential {Fernandez, 1991 #10}.

Trials of Nivolumab have stirred success in treating cancers but have been less likely associated with
gynecological complications. Adding on, its mode of action dampens the immune system. Hence,
nivolumab has not yet certified for gynecological disorders {Fernandez, 1991 #10}.

Mifepristone is used to medically terminate pregnancy by acting antagonist to progesterone receptor.

In combination with methotrexate, it increases the hit ratio by 13% but is unable to treat clinical trials
of ectopic pregnancies to these in-silico promised values.

Gefitinib has been used as a molecularly targeting drug interrupting EGFR signaling of placental
tissue. Endothelial Growth Factor Receptor (EGFR) is associated with tissue survival response and has
been reported the highest in placenta {Herbst, 2004 #21}. Gefitinib induces programmed cell death of
placental tissues when administered in ectopic pregnancies. Reports to FDA has mentioned strong side
effects such as skin rash, interstitial lung disease, and diarrhea {Cohen, 2004 #22}.

b. Surgery

Invasive surgeries are the last resort of treatment owing to the late diagnosis and clinical determination
of ectopic pregnancy. Injury of abdominal organs, general anesthesia, infection, damaging future
fertility, death from uncontrolled bleeding after conceptus removal, and risk of triggering
choriocarcinoma are few of the menaces associated with surgical removal of ectopic fetus {Fernandez,
1991 #10} {Chetty, 2009 #23}. Laparoscopy and laparotomy are the two surgical treatments
performed with ports of 10mm diameter {Ehrenberg-Buchner, 2009 #24}. For the safe management,
a pretherapeutic score has been formulated incorporating gestational age, human chorionic
gonadotrophin (HCG) level, progesterone level, abdominal pain, hemoperitoneum volume and
haematosalpinx diameter calculated through transvaginal ultrasonography {Chang, 2014 #5}. A score
of ≤ 12 suggests towards non-surgical treatment with success rate of 82%. However, these testings are
quite time-consuming, and surgeries need accurate validation before they are conducted.

c. Uterine Artery Embolization

It is the bilateral cannulation of uterine arteries followed by the injection of polyvinyl alcohol or tris-
acryl gelatin particles into the vessels for maintaining blood flow to uterus. UAE is advised only in
cases of excessive bleeding in the uterus because it is followed with preterm labor, post-partum
hemorrhage, fertility complications, and miscarriages {Glenn, 2018 #25}.

3. Nanoparticles in Reproductive Medicine:

Nanotechnology is multidisciplinary field integrating physics, mathematics, chemistry, natural,

computed, and statistical methods. To examine, diagnose, engineer, treat, and understand the physical
and biological world, nano-sized particles are engineered and exploited in a myriad of ways. They
were discovered in 1950s and were acknowledged as a hallmark by 2000s {Barkalina, 2014 #32}. In
the last decade they have been emerging in biomedical applications involved in targeted drug
deliveries, tissue mechanics, diagnostic imaging, drug designing, and assay formulations {Barkalina,
2014 #32}. Initially they were launched primarily in cancer diagnostics and treatment to break the
inseparable idea of targeting affected cell populations only.

Exploiting nanotechnology in reproductive medicine means the generation of nanoparticles (NPs) or

nanocarriers that can bare varieties of drugs, are tolerant of long distant circulations, and assess the
target tissue with precision and accuracy {Muoth, 2016 #26}. This goal can be achieved by
customizing their key features such as size, surface area, charge, shape, fluid dynamics, chemical
potential, magnetic, optical, catalytic properties, versatility, biocompatibility, stability, and targeted
action {Barkalina, 2014 #32;Muoth, 2016 #26}. In reproductive medicine, apart from offering novel
ways of pregnancy conception, nanotechnology is increasingly suggesting ways of non-invasive and
targeted diagnosis and therapeutics, early and accurate disease detection, minimization of side effects,
and development of systems that will detect disease and simultaneously deliver drugs to tissues or cells
based on molecular initiations {Barkalina, 2014 #32}. Nano-biosensors for reproductive oncology,
endometriosis, preeclampsia, fetal growth restriction, ectopic pregnancy, uterine fibroids, and
reproductive infections are few of the diseases within which efforts for nano-based biomedicines are
under way or are in clinical trials {Barkalina, 2014 #32}. Moreover, NPs are involved as research tools
in investigating the extent of gene expressions in offspring and understanding molecular pathways
associated with reproductive disease proliferation {Barkalina, 2014 #32}.
Small sizes of nanoparticles facilitate the cellular uptake, smooth placental transfer, intracellular
trafficking, and endogenous organelle targeting of diagnostic or therapeutic materials {Barkalina, 2014
#32;Muoth, 2016 #26}. In a study to analyze the accumulation rate of three sized gold nanoparticles,
it was concluded that AuNPs larger than 80nm could not cross the placenta in pregnant mice
{Semmler-Behnke,2014 #33}. In case of surface charge, charged NPs are less likely to cover long
distances due to irrelevant charge interactions with intracellular environment; especially negatively
charged NPs cross placenta with difficulty because of negative charge repulsion from placental
membrane {Muoth, 2016 #26}. In a study to comparatively estimate in-vivo toxic accumulation of
positively and negatively charged iron oxide NPs, the former NPs were found in large amount in fetal
liver of mice post-birth {Di Bona KR,2014 # 34}.

Stability, which is important for long distance travelling, systemic administration, and prevention of
off-target dose disposal, can be achieved by coating NPs with organic biocompatible coatings such as
polyethylene glycol (PEG) {Barkalina, 2014 #32}. The new forms of coatings enable NPs to simulate
according to micro-environments such as presence of ligand, certain pH, temperature {Barkalina, 2014
#32}. Talking about the customization for targeting, various ligands, antibodies, peptides, and
aptamers can be conjugated with NPs for active attack on receptors, proteins, nucleic acids, or other
molecules Barkalina,2014 # 26; Petros RA,2010 # 35}.

Nano-biosensors convert the biological events into electronic signals leading to proficient bio-
detection of ovarian, cervical, and prostate cancer. Biomarkers like epididymis secretory protein 4
(HE4) for ovarian cancer, and prostate-specific antigen (PSA) for prostate cancer have successfully
been made a hallmark for their diagnosis {Barkalina, 2014 #32}.

Endometriosis is a gynecological complication comprising of the growth of endometrial tissue outside

the uterine cavity. Invasive laparoscopy detection procedures are adopted for its diagnosis {Barkalina,
2014 #32}. In a study paramagnetic iron oxide NPs have been intravenously administered in a rat
model with induced endometriosis. Affinity of these NPs for macrophages allow them to act as MRI-
signal enhancers for diagnosis of the outgrown ectopic tissues {Lee HJ,2012 #36}.

4. Nanoparticle-mediated Systems Vows Beneficial Up gradation of Diagnostic and

Therapeutic Approaches:

As discussed, the location probabilities of ectopic pregnancies range from cervix to fimbriae of ovary,
advancing in complications of diagnosis, prognosis, and treatment. Medications and diagnosing
systems reaching such locations has posed a major challenge ever since the discovery of the first case.
The above-mentioned diagnosis and treatment options have their limitations when it comes to crossing
maternal-fetal placental barrier, complete and reduced dose transfer of medicines to targeted tissues,
avoiding injuries to maternal organs by large sized equipment, prevention of therapeutic agents to enter
maternal circulation and cause future pregnancy complexities {Figueroa-Espada, 2020 #27}, timely
and accurate transfer for efficient diagnosis and treatment, and dependence on biomarkers as specific
determinants of ectopic pregnancies.

In-silico and experimental models promise that nanoparticle mediated systems promise better
upgradation of diagnostic and therapeutic approaches for ectopic pregnancy. NPs have the potential to
cross the placental barrier and accumulate in the fetal organs without damaging maternal circulations
and systems {Muoth, 2016 #26}. Thus, they are exploited to be used as drug carriers for targeted
therapy depending upon their size, surface to volume ratio, charge distribution, and shape {Muoth,
2016 #26}. These NP dimensions can be customized to comply with case-to-case complications.

4.1. Nanotechnology Mediated EP Diagnostic Systems:

a) Gold Nano-particles.

As discussed earlier, fluctuations in HCG concentrations are associated with pregnancy related
complications, pre-natal down’s syndrome, and testicular cancer in men {Marion, 2012 #1}. Previous
HCG testing involved HCG-antibody mediated detection strategies that would cost high. Peptide
aptamer regulated gold nanoparticle assay is a new quantitative analysis of HCG concentrations for
early diagnosis of ectopic pregnancy {Marion, 2012 #1}. Aptamers are short single stranded RNA or
DNA with specificity and affinity for proteins, peptides, carbohydrates, ad toxins. Those that bind
strongly with proteins are called peptide aptamers. They have become increasingly popular due to their
easy generation, feasible cost, friendly handling, precise results, diverse configurational features, and
stability in spectrum of media and natural environ {Marion, 2012 #1}. AuNPs, due to their inert nature,
optical, and electrical properties are favored for the assay {Marion, 2012 #1}. The colorimetric
detection of HCG in serum and urine samples using catalytic gold nanoparticles and peptide aptamer
was successfully achieved through naked eye, also cutting down the manpower and cost for post-assay
interpretation methods {Marion, 2012 #1}.

HCG binding peptide aptamer has positive charge because of arginine. The comparative affinities of
peptide aptamer for HCG and AuNPs is the basic working principle of the assay. In absence of HCG,
AuNPs bind with peptide aptamer electrostatically (AuNPs are allotted negative charge during their
design). This disrupts the catalytic activity of AuNPs that convert a yellow-colored chemical
compound (4-NP) to a colorless substance (4-AP).
The higher the concentration of HCG, the more HCG- peptide aptamers will stay bound and freer
AuNPs will be available in solution that would increase catalysis of yellow 4NP to colorless 4-AP.
Consequent gradual decrease in the wavelength intensity of the solutions is calculated by statistically
tested values such as change in absorption rate and significantly associated with respective HCG
concentrations.

For determining sensitivity of the assay, serial concentrations of HCG were added that resulted in a
series of yellow to pale yellow and colorless solutions as defined by precise wavelength intensities.
For specificity analysis of the colorimetric assay, interfering molecules like glucose, uric acid, urea,
ascorbic acid, acetaminophen, and acetylsalicylic acid, interleukins were added along with HCG. Only
HCG caused a significant color change of the solution.

b) Magnetic Nanoparticles.

This diagnosis system incorporating magnetic nanoparticles is based on a complex of systems such as
immuno-magnetic separation, fluorescence detection, and Enzyme linked Immunosorbent Assay
(ELISA) {Huang X,2016 #37}. This system implies highly fluorescent glutathione-stabilized silver-
gold nano alloy (GSH-AgAuNA) with magnetic nanoparticles (MNPs). It works on the principle of
sandwich Enzyme Linked Immunosorbent Assay (ELISA). GSH-AgAuNA is conjugated with
monoclonal antibody-I (MAB-I) and MNPs with monoclonal antibody -II (MAB-II). Both MABs have
strong affinity against HCG antigens.

GSH-AgAuNA + MAB-I are added to the biological fluid sample. The alloy attaches to HCG and
imparts high intensity fluorescence. Following the fluorescence, the MNPs conjugated with MAB-II
are added to the sample. The MAB-II has higher affinity for HCG antigens. The detachment of HCG
from MAB-I of GSH-AgAuNA and attachment of MAB-II of MNPs causes a consecutive decrease in
the fluorescent intensity. This reversal in the fluorescence is detected quantitatively. The immunoassay
detects the minimum limit of 0.25 ng/mL for HCG concentrations

This procedure is environment friendly, shows outstanding fluorescence as compared to organic dyes
{Huang X,2016 #37}. Advantages of magnetic nanoparticles include their biocompatibility and ease
of modifying their surfaces with various antigens {Huang X,2016 #37}. This reverse immunoassay is
one of its kind that validates diagnosis by two-way biding confirmation of the presence of HCG
concentrations.
c) Platinum (Pt) Nanoparticles.

A diagnostic procedure for achieving selective, stable, reproducible, biocompatible, and ultra-sensitive
diagnosis of ectopic pregnancy is the electrochemical immunoassay system {Roushani M,2016 # 38}.
Platinum nanoparticles (PtNPs) are immobilized through covalent interactions onto the surface of a
nano-combination of graphene, chitosan, and ionic liquid; the nano-combination act as electrode.
PtNPs has affinity for HCG antibodies and immobilize them onto the nanocomposite surface. This
leads to PtNPs acting as linkers for detection of HCG antigens. As HCG molecule binds with the
PtNPs-attached antibody, an electronic current is passed from the constructed nanocomposite
electrode. Rutin is a compound with biological origin. In the electrochemical immuno assay, it is used
as a redox probe acting as immuno sensor for differential pulse voltammetry detection.

The novelty in this electrochemical immunoassay is that the developed nanocomposite gives off larger
electrode surface area and brisk electrons transfer. Graphene is well known for being the best electrical
conductor, lightest weight, easily foldable to various forms, and outstanding mechanical properties.
Chitin is a cellulose of natural membrane; it imparts greatest permeability for water and good adhesion.
Ionic liquids have low vapor pressures and diverse electrochemical window. The detection limits of
HCG hormone are as low as 0.00035mIU/mL with ultra-sensitivity for HCG {Roushani M,2016 # 38}.

D) Polyglycidyl methacrylate Nanoparticles (PGMA):

Multimodal Polyglycidyl methacrylate (PGMA) nanoparticles are made part of model systems for
analyzing their adsorption capacities by fetal and maternal tissues to incorporate them in diagnostic
systems. Fluorescently labelled and paramagnetic PGMA nanoparticles were administered in pregnant
mice {Ho, 2017 #29}. Relative fetal and maternal tissue uptake was quantified by confocal microscopy
because conventional fluorescence intensity and magnetic resonance lacked the required sensitivity.
Tissues with neoplastic growth will show more adsorption of PGMA as indicated by the higher
accumulation rates of PGMA seen in trophoblastic tissue of conceptuses {Ho, 2017 #29}.

Figure 1 shows a summary of all the types of diagnostic systems discussed.

Figure 1: Depiction of the mode of diagnosis of ectopic pregnancy through platinum, magnetic,
PGMA, and gold nanoparticles.
5. Conclusions:

Current world is racing with the nanotechnological advances in every field of natural and physical
domains from pharmaceutical industries to mathematics. Consequently, for early and correct diagnosis
of ectopic pregnancy and prevention of life-threatening stages nanotechnology has been interfered in
EP too. The discussed system of diagnosis are representative models for disease diagnosis. Present
systems have numerous short comings; efforts have been made to compensate few using
nanotechnology and nanoparticles. Still, the toxic aspects and controversaries regarding the human use
of nanotechnology need to be addressed for taking them step further into clinical trials.

6. Limitations:

The focus on literature was found more on the targeting tissues and biomarkers for diagnosis rather
than the extent of efficacies for different combinations of nanoparticles. Inclining the subject matter
more towards efficiencies would preferably give more applicative outcomes. Previous models for
diagnostic testing have demonstrated the use of small molecules for testing {Marion, 2012 #1}, thus,
more representative models need to be constructed for nano mediated testing of systems. Other
question rises on the safety of the nano particles for human use particularly on maternal organs.
Targeting nanoparticles on solid tumors or disease targets is correlated with increase in membrane
permeability of vessels of circularity systems {Pritchard N, 2021# 27}. The nanoparticles leak out of
the vessels after their prolonged retention and accumulate into the body tissues {Pritchard N, 2021#
27}. Such diagnostic systems should be constructed that simultaneously work for the removal of
nanoparticles as well. Clear configurations and mechanism of action of each type of nanoparticle
should be investigated for a better understanding of their biodistribution {Ho, 2017 #29}. Similar as
in the case study of a Japanese mouse model showed that nanoparticles of size 30nm crossed the
placenta, accumulated in fetal liver and brain, and exhibited in form of abnormal blood flow, fetal
death in utero {Whigham, 2019 #28}.
References:

1. Tong, S., et al. (2015). "Molecular diagnostics and therapeutics for ectopic pregnancy." MHR:
Basic science of reproductive medicine 21(2): 126-135.
2. Seeber, B. E. and K. T. Barnhart (2006). "Suspected ectopic pregnancy." Obstetrics & Gynecology
107(2 Part 1): 399-413.
3. Mol, B., et al. (1998). "The accuracy of single serum progesterone measurement in the diagnosis
of ectopic pregnancy: a meta-analysis." Human reproduction (Oxford, England) 13(11): 3220-3227.
4. Mausner Geffen, E., et al. (2017). "Pitfalls and tips in the diagnosis of ectopic pregnancy."
Abdominal Radiology 42(5): 1524-1542.
5. Marion, L. L. and G. R. Meeks (2012). "Ectopic pregnancy: history, incidence, epidemiology, and
risk factors." Clinical obstetrics and gynecology 55(2): 376-386.
6. Fernandez, H., et al. (1991). "The use of a pretherapeutic, predictive score to determine inclusion
criteria for the non-surgical treatment of ectopic pregnancy." Human Reproduction 6(7): 995-998.
7. Duncan, W., et al. (1995). "Measurement of creatine kinase activity and diagnosis of ectopic
pregnancy." BJOG: An International Journal of Obstetrics & Gynaecology 102(3): 233-237.
8. Control, C. f. D. and Prevention (1995). "Ectopic pregnancy--United States, 1990-1992." MMWR.
Morbidity and mortality weekly report 44(3): 46-48.
9. Chen, C.-Y., et al. (2015). "Quantitative analysis of total β-subunit of human chorionic
gonadotropin concentration in urine by immunomagnetic reduction to assist in the diagnosis of
ectopic pregnancy." International Journal of Nanomedicine 10: 2475.
10. Chang, C.-C., et al. (2014). "Colorimetric detection of human chorionic gonadotropin using
catalytic gold nanoparticles and a peptide aptamer." Chemical Communications 50(92): 14443-
14446.
11. Herbst, R. S., et al. (2004). "Gefitinib—a novel targeted approach to treating cancer." Nature
Reviews Cancer 4(12): 956-965.
12. Cohen, M. H., et al. (2004). "United States Food and Drug Administration drug approval
summary: gefitinib (ZD1839; Iressa) tablets." Clinical Cancer Research 10(4): 1212-1218.
13. Chetty, M. and J. Elson (2009). "Treating non-tubal ectopic pregnancy." Best Practice &
Research Clinical Obstetrics & Gynaecology 23(4): 529-538.
14. Ehrenberg-Buchner, S., et al. (2009). "Ectopic Pregnancy: Role of Laparoscopic Treatment."
Clinical obstetrics and gynecology 52(3): 372-379.
15. Glenn, T. L., et al. (2018). "Cesarean scar ectopic pregnancy: current management strategies."
Obstetrical & gynecological survey 73(5): 293-302.
16. Muoth, C., et al. (2016). "Nanoparticle transport across the placental barrier: pushing the field
forward!" Nanomedicine 11(8): 941-957.
17. Figueroa-Espada, C. G., et al. (2020). "Exploiting the placenta for nanoparticle-mediated drug
delivery during pregnancy." Advanced Drug Delivery Reviews 160: 244-261.
18. Whigham, C.-A., et al. (2019). "The untapped potential of placenta-enriched molecules for
diagnostic and therapeutic development." Placenta 84: 28-31.
19. Ho, D., et al. (2017). "Maternal-placental-fetal biodistribution of multimodal polymeric
nanoparticles in a pregnant rat model in mid and late gestation." Scientific reports 7(1): 1-11.
20. Barkalina, N., et al. (2014). "Nanotechnology in reproductive medicine: emerging applications of
nanomaterials." Nanomedicine: Nanotechnology, Biology and Medicine 10(5): e921-e938.
21. Pritchard N, Kaitu’u-Lino TU, Harris L, Tong S, Hannan N. Nanoparticles in pregnancy: the next
frontier in reproductive therapeutics. Human reproduction update. 2021 Mar;27(2):280-304.
22. Semmler-Behnke M, Lipka J, Wenk A, Hirn S, Schäffler M, Tian F, Schmid G, Oberdörster G,
Kreylin WG. Size dependent translocation and fetal accumulation of gold nanoparticles from
maternal blood in the rat. Particle and fiber toxicology. 2014 Dec;11(1):1-2.
23. Di Bona KR, Xu Y, Ramirez PA, DeLaine J, Parker C, Bao Y, Rasco JF. Surface charge and
dosage dependent potential developmental toxicity and biodistribution of iron oxide
nanoparticles in pregnant CD-1 mice. Reproductive Toxicology. 2014 Dec 1; 50:36-42.
24. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications.
Nature reviews Drug discovery. 2010 Aug;9(8):615-27.
25. Lee HJ, Lee HJ, Lee JM, Chang Y, Woo ST. Ultrasmall superparamagnetic iron oxides enhanced
MR imaging in rats with experimentally induced endometriosis. Magnetic resonance
imaging. 2012 Jul 1;30(6):860-8.
26. Huang X, Li Y, Huang X, Xie X, Xu Y, Chen Y, Gao W. A novel reverse fluorescent
immunoassay approach for sensing human chorionic gonadotropin based on silver-gold nano-
alloy and magnetic nanoparticles. Analytical and bioanalytical chemistry. 2016
Jan;408(2):619-27.
27. Roushani M, Valipour A. Using electrochemical oxidation of Rutin in modeling a novel and
sensitive immunosensor based on Pt nanoparticle and graphene–ionic liquid–chitosan
nanocomposite to detect human chorionic gonadotropin. Sensors and Actuators B: Chemical.
2016 Jan 1; 222:1103-11.
Plagiarism: