Ectopic Pregnancy
Diseases

Definition

An ectopic pregnancy (EP) is a condition in which a fertilized egg settles and grows in any location other than the inner lining of the uterus. An ectopic pregnancy occurs in about one in 50 pregnancies and is a potentially life-threatening condition, due to the risk of severe internal bleeding and shock, caused by the rupture of the organ on which it is implanted. It is most likely to be found at between five weeks and ten weeks of the pregnancy.

How does it happen?

After conception, the fertilized egg travels down the fallopian tubes on its way to the uterus. If the tube is damaged or blocked and fails to propel the egg toward the womb, the egg may become implanted in the tube and continue to develop there.
Because the vast majority of ectopic pregnancies occur in a fallopian tube, they're often called tubal pregnancies. Much less often, an egg implants in an ovary, in the cervix, directly in the abdomen, or even in a c-section scar.
It's also possible for a woman to have one embryo normally implanted in her uterus and another implanted in her tube or elsewhere. This is called a heterotopic pregnancy, and it's pretty rare, occurring in only 1 in 4,000 pregnancies.
If an ectopic pregnancy isn't recognized and treated, the embryo will grow until the fallopian tube ruptures, resulting in severe abdominal pain and bleeding. This can cause permanent damage to the tube or loss of the tube, and if it involves very heavy internal bleeding that's not treated promptly, it can even lead to death. That's why early diagnosis, treatment, and follow-up care are so important.

Ectopic pregnancy

Classification

• Tubal pregnancy(95%) : The vast majority of ectopic pregnancies implant in the Fallopian tube. Pregnancies can grow in the fimbrial end (5% of all ectopic pregnancies), the ampullary section (80%), the isthmus (12%), and the cornual and interstitial part of the tube (2%).
• Non tubal ectopic pregnancy: Two percent of ectopic pregnancies occur in the ovary, cervix, or are intraabdominal.
• Heterotopic pregnancy: In rare cases of ectopic pregnancy, there may be two fertilized eggs, one outside the uterus and the other inside. Although rare, heterotopic pregnancies are becoming more common. The survival rate of the uterine fetus of an ectopic pregnancy is around 70%.

Epidemiology

The number of ectopic pregnancies has increased dramatically in the past few decades. Based on hospital discharge data, the incidence of ectopic pregnancy has risen from 4.5 cases per 1,000 pregnancies in 1970 to 19.7 cases per 1,000 pregnancies in 1992. This rising incidence is strongly associated with an increased incidence of pelvic inflammatory disease(which is a risk factor).
The case-fatality rate has declined from 35.5 maternal deaths per 10,000 ectopic pregnancies in 1970 to only 3.8 maternal deaths per 10,000 ectopic pregnancies in 1989.

ectopic pregnancy,2000

Symptoms

Ectopic pregnancy can be difficult to diagnose because symptoms often mirror those of a normal early pregnancy. These can include missed periods, breast tenderness, nausea, vomiting, fatigue, or frequent urination.
Symptoms typically develop around the sixth week of pregnancy. They include one or more of the following:

• Pain on one side of the lower tummy (abdomen). It may develop sharply, or may slowly get worse over several days. It can become severe.
• Vaginal bleeding often occurs, but not always. It is often different to the bleeding of a period. The blood may look darker.
• Other symptoms may occur such as diarrhoea, feeling faint, or pain on passing poo (faeces).
• Shoulder-tip pain may develop. This is due to some blood leaking into the abdomen and irritating the diaphragm.
• If the Fallopian tube ruptures and causes internal bleeding, can be present severe pain or collapse.
• Sometimes there are no warning symptoms (such as pain) before the tube ruptures.

Ectopic pregnancy,2013

Risk factors

An ectopic pregnancy can happen to any woman, even if she has no known risk factors. Certain women are at a higher risk than others, though. One of the most important risk factor is a damage of the Hair-like cilia located on the internal surface of the Fallopian tubes that carry the fertilized egg to the uterus. In fact the fertilized egg travels through the fallopian tube to the womb (uterus). Anything that blocks or slows the movement of this egg through these tubes can lead to ectopic pregnancy:

• Surgery on the fallopian tubes to correct a problem or to reverse a tubal ligation (surgical sterilization).
• A previous ectopic pregnancy. After one ectopic pregnancy, the chance of having another one is about 1 in 10.With one previous ectopic pregnancy treated by linear salpingostomy, the recurrence rate ranges from 15 to 20 percent, depending on the integrity of the contralateral tube.Two previous ectopic pregnancies increase the risk of recurrence to 32 percent.
• An infection in the upper reproductive tract (this is called pelvic inflammatory disease, or PID). PID is often caused by untreated sexually transmitted infections (STIs), such as gonorrhea or chlamydia.
• Fertility issues. (Approximately 50% of pregnancies in women using intrauterine devices (IUDs)will be located outside of the uterus. However, the total number of women becoming pregnant while using IUDs is extremely low. Therefore, the number of ectopic pregnancies related to IUDs is very low.One explanation for the mistaken association of IUDs with ectopic pregnancy may be that when an IUD is present, ectopic pregnancy occurs more often than intrauterine pregnancy.Simply because IUDs are more effective in preventing intrauterine pregnancy than ectopic pregnancy, implantation is more likely to occur in an ectopic location.
• A mother who took the drug DES while pregnant.
• A gynecological condition called endometriosis may cause scarring that affects your fallopian tubes, increasing the risk of having an ectopic pregnancy.
• Smoking:Cigarette smoking has an independent and dose-related effect on the risk of ectopic pregnancy. Cigarette smoking is known to affect ciliary action in the nasopharynx and respiratory tract. A similar effect may occur within the fallopian tubes.
• Multiple sexual partners, early age at first intercourse and vaginal douching are often considered risk factors for ectopic pregnancy. The mechanism of action for these risk factors is indirect, in that they are markers for the development of sexually transmitted disease, ascending infection, or both.

ectopic pregnancy

Diagnosis

Once the patient arrives at the hospital, a pregnancy test, a pelvic exam, and an ultrasound test may be performed to view the uterus’ condition and fallopian tubes..

• The blood test to check your level of the beta subunit pregnancy hormone human chorionic gonadotropin hCG. If it's high enough to suggest pregnancy, but not as high as it should be at your stage, the pregnancy may be ectopic. In fact, in a normal pregnancy, the β-HCG level doubles every 48-72 hours until it reaches 10,000-20,000mIU/mL. In ectopic pregnancies, β-HCG levels usually increase less. Mean serum β-HCG levels are lower in ectopic pregnancies than in healthy pregnancies. Serial serum β-HCG levels are necessary to differentiate between normal and abnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has been initiated.
• Pelvic ultrasound: in this test, an ultrasound probe is inserted into the vagina, and pelvic images are visible on a monitor. Transvaginal ultrasound can reveal the gestational sac in either a normal (intrauterine) pregnancy or an ectopic pregnancy. Ultrasonography is probably the most important tool for diagnosing an extrauterine pregnancy.Transvaginal ultrasonography, or endovaginal ultrasonography, can be used to visualize an intrauterine pregnancy by 24 days postovulation or 38 days after the last menstrual period.An empty uterus on endovaginal ultrasonographic images in patients with a serum β-HCG level greater than the discriminatory cut-off value means an ectopic pregnancy.
• In rare cases, laparascopy may be needed to ultimately confirm a diagnosis of ectopic pregnancy. Its routine use on all patients suspected of ectopic pregnancy may lead to unnecessary risks, morbidity, and costs.

If an ectopic pregnancy has been confirmed, the health care provider will decide on the best treatment based on the medical condition.

"Best modality for diagnosing ectopic pregnancy,2013":
http://emedicine.medscape.com/article/2041923-overview
ectopic pregnancy,2013

Pathogenesis

Role of Adrenomedullin

Ectopic pregnancy seems to be related to the peptide ADRENOMEDULLIN.
Human adrenomedullin is a 52-amino acid peptide with a single disulfide bridge between residues 16 and 21 and with an amidated tyrosine at the carboxy terminus . It shows some homology with calcitonin gene-related peptide (CGRP) and has therefore been added to the calcitonin/CGRP/amylin peptide family.
Adrenomedullin is synthesized as part of a larger precursor molecule, termed preproadrenomedullin. Preproadrenomedullin contains a 21-amino acid N-terminal signal peptide that immediately precedes a 20-amino acid amidated peptide, designated proadrenomedullin N-terminal 20 peptide or PAMP. The gene encoding has been mapped and localized to a single locus of chromosome 11 and is expressed in a wide range of tissues.
Pregnancy is associated with increased circulating adrenomedullin concentrations in both rats and women. The plasma concentration of adrenomedullin has been reported to increase progressively from the first to third trimester, with a further increase postpartum.

It was first discovered as a potent vasodilator and has subsequently been found to exert a diverse spectrum of pathophysiological actions.
In the female, the expression of ADM in the endometrial glands is higher than that in the uterine stroma and myometrium. It had been proposed that ADM may be involved in EP.
ADM acts through a CGRP or ADM receptor, which consists of a calcitonin receptor-like receptor (CRLR) in association with one of the three receptor activity-modifying proteins (RAMP) .
A study has been done to compare the location and the levels of expression of ADM and their receptor components and to study the effects of ADM on ciliary beat frequency (CBF) and muscular contraction in human oviductal tissue from simulated normal pregnancy and tEP.
The study observed a significantly lower CBF in the tEP oviduct than the control oviduct. There was a reduction in ciliary beating, which would slow down the transport of the fertilized egg to the uterus,that may be the result of a decrease in the ADM level in tEP because the administration of ADM restores it toward the normal value. As a consequence there was a consistently lower smooth muscle contraction frequency in tEP compared with controls. In fact the treatment with ADM in tEP was able to restore the contraction frequency to a significantly higher level, approximating that of controls. In a university teaching hospital were studied the tracings of the smooth muscle contraction of oviductal tissue from control (n=5) and tEP (n = 4) treated with ADM .The pattern of change was consistent among all the samples in each group. In both tEP and controls, treatment with ADM 100 nm significantly increased the basal tone and the frequency of contraction but decreased the amplitude.
The results suggest that the lower ADM level in the oviducts of tEP may lead to the decrease in ciliary beating and muscle contraction, with the result that the embryo is retained and implanted in the oviduct. The findings explain for the first time the etiology of tubal pregnancy on the basis of an impairment of the transport of the fertilized ovum resulting from an ADM deficiency and raise the possibility of using the plasma ADM level as a predictor for tubal ectopic pregnancy.

(Modulation of CBF by ADM and its receptor antagonists in oviductal tissue of tubal ectopic pregnancy (n = 4) and controls (n = 4). )

Possible role of adrenomedullin in the pathogenesis of tubal ectopic pregnancy,2012
adrenomedullin,a multifunctional regulatory peptide,2013

Role of smoking

Epidemiological studies have shown that cigarette smoking is a risk factor for tubal ectopic pregnancy. Animal and human studies have demonstrated effects on oviductal function resulting from smoke exposure. Inhalation of smoke has been reported to affect the electrical activity of the rabbit oviduct and to temporarily influence patency of human Fallopian tube. Despite these findings, the exact mechanism by which smoking leads to tubal ectopic pregnancy remains unknown.
A recent study reported down-regulated transcription of two G-protein–coupled receptors, prokineticin receptor 1 (PROKR1) and PROKR2, in Fallopian tube from women with tubal ectopic pregnancy, where implantation had already occurred.Ligands for these receptors, the prokineticins (PROK) 1 and PROK2, are proangiogenic. Placental PROK expression has been shown to be up-regulated in hypoxic conditions and, in the endometrium, PROK1 is reported to increase the expression of proangiogenic cytokines. PROKs are also known for regulating genes that are important in implantation. PROK1 has been shown to induce expression of leukemia inhibitory factor (LIF) in the human endometrium, and LIF is known to play a crucial role in successful intrauterine implantation in mice. The study hypothesized that cigarette smoking attenuates tubal PROKR expression resulting in changes in Fallopian tube function, providing a possible explanation for the link between smoking and tubal ectopic pregnancy.

A Potential Mechanism Explaining the Link between Smoking

and Tubal Ectopic Pregnancy,2010

Role of Progesterone

Data about the effects of hormones on the tubal muscles and ciliary function are conflicting, but it has been proposed that progesterone regulates ciliary beat frequency (CBF) in several mammalian species. In guinea pigs injected in vivo with progesterone, the beat frequency of the fimbria of the fallopian tube were decreased 1.5 days after the onset of treatment . In humans, a reduction of CBF by 40-50% was observed 24 hour after treatment with 10 μM progesterone in vitro, suggesting a direct effect of the hormone [. In cows, progesterone caused a rapid reduction of CBF within 30 minutes after exposure to 20 μM progesterone [. These in vitro studies have used rather high concentrations of the steroid, and it was therefore not clear if physiological levels of progesterone could evoke similar effects. Recent studies in our lab on mice have, however, demonstrated that the CBF is reduced within 30 minutes by 100 nM progesterone This concentration can be found in blood serum of cycling women.This quite rapid response suggests that progesterone might regulate CBF in the fallopian tube via another pathway than the classical genomic mechanism.
Previous studies indicate that at least two different classes of progesterone receptors are expressed in the ciliated cells of mice and humans, i.e. membrane PRs, (mPRs) together with the classical PR (PR) , and both types of receptors are therefore candidates for mediating rapid effects of progesterone in the fallopian tube .
It is important to reveal the mechanisms regulating transport of gametes and ciliary motility since dysfunction of the fallopian tube and cilia can lead to ectopic pregnancies and other forms of infertility . Furthermore, interference with gamete transport is a possible target for novel contraceptive treatment strategies.

Using a method that detects variations in light intensity has been studied the effect of ovarian steroids on human Fallopian tube epithelia) ciliary beat frequency in vitro.The scientists have found that baseline ciliary beat frequency averages between 5-6 Hz. Cilia from ampullary segments of the Fallopian tube beat significantly faster (5.4 Hz +- 0.2) than those from fimbrial segments (4.8 Hz +- 0.2). There was no significant difference in baseline ciliary beat frequency at any other anatomical site in the Fallopian tube. Incubation with progesterone (10 mumol/l) suppresses human Fallopian tube epithelial ciliary beat frequency by 40-50%. This inhibition was observed at similar magnitudes in all Fallopian tubes studied irrespective of anatomical site. Progesterone-induced reductions in ciliary beat frequency were concentration dependent and prevented by the progesterone receptor antagonist mifepristone (RU486). Oestradiol alone (10 mumol/l) had no effect on ciliary beat frequency at any anatomical site in the Fallopian tube but did prevent the reduction in ciliary beat frequency seen with progesterone when tissues were incubated with these two steroids together.

High Progesterone Levels and Ciliary Dysfunction—A Possible Cause of Ectopic Pregnancy
rapid effects of progesterone on ciliary beat frequency in mouse fallopian tube,2000

MTHFR polymorphism

Ectopic pregnancy seems also to be related to the polymorphism of MTHFR, (methylenetetrahydrofolate reductase).

Recurrent pregnancy loss (RPL)is defined by American Society of Reproductive Medicine (ASRM) as two or more failed pregnancies.Several etiological factors like endocrinological problems, uterine structural or chromosomal anomalies and prothrombotic conditions can be the cause in some of these cases. It has been a very common practice to blame the hereditary thrombophilias which include methylenetetrahydrofolate reductase (MTHFR) mutations in the pathogenesis of RPL.
Thrombophilia disorders can lead to disordered placental perfusion because of thrombosis in the spiral arteries and intervillous space which can lead to problems of late pregnancy like late fetal loss and preeclampsia. But the association of hereditary thrombophilia's with early pregnancy loss is not clarified yet. The roles of hereditary thrombophilia's in RPL's have been extensively studied and a large amount of contradictory literature about this issue has accumulated.
A case-control retrospective study was performed between February 2007 and December 2011. The study population consisted of 495 couples, who had two or more consecutive pregnancy losses before 20 weeks' gestation. MTHFR C677T gene polymorphisms were analyzed .Parental chromosomal abnormalities are detected in about 2–8% of couples with recurrent miscarriages.In the study, among 495 women tested for polymorphisms in these genes, an abnormality was detected in 81 cases, the most frequent of which was MTHFR heterozygote mutation. The frequency of MTHFR heterozygote mutation in the normal control subjects was found to be 38.1%.
So this study found that a significant difference between the incidence of RPL in cases and controls existed only for the homozygous and heterozygous mutations of MTHFR C677T mutations. So it seemed to have an association with RPL.
The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution.The mutation consists of a C→T transition at position 677 in the methylene tetrahydrofolate reductase (MTHFR) gene, which is associated with elevated plasma homocysteine levels in the presence of concomitant folate deficiency. Elevated plasma homocysteine is a risk factor for venous thromboembolism.

Association of recurrent pregnancy loss with chromosomal abnormalities and hereditary thrombophilias,2013

Therapy

An ectopic pregnancy may be treated in any of the following ways:

• Methotrexate may be given, which allows the body to absorb the pregnancy tissue and may save the fallopian tube, depending on how far the pregnancy has developed. Methotrexate is an antineoplastic agent that inhibits cell proliferation by destroying rapidly dividing cells. It acts as a folate antagonist. Contraindications to methotrexate therapy are existence of an intrauterine pregnancy, immunodeficiency,evidence of tubal rupture and clinically important hepatic or renale disfunction.
• If the tube has become stretched or it has ruptured and started bleeding, all or part of the fallopian tube may have to be removed. Bleeding needs to be stopped promptly, and emergency surgery is needed.
• Laparoscopic surgery under general anesthesia may be performed. This procedure involves a surgeon using a laparoscope to remove the ectopic pregnancy and repair or remove the affected fallopian tube. If the ectopic pregnancy cannot be removed by a laparoscope procedure, then another surgical procedure called a laparotomy may be done.

Historically, the treatment of ectopic pregnancy was limited to surgery. With evolving experience with methotrexate, the treatment of selected ectopic pregnancies has been revolutionized. Medical therapy of ectopic pregnancy is appealing over surgical options for a number of reasons, including eliminating morbidity from surgery and general anesthesia, potentially less tubal damage, and less cost and need for hospitalization.

Measures of current trends in the management of ectopic pregnancy in the United States from 2002 to 2007 indicated that the percentage of patients treated with methotrexate increased from 11.1% to 35.1%, whereas surgical management decreased from approximately 90% to 65%.

Ectopic pregnancy medication,2013
ectopic pregnancy,medlineplus,2013