Seminar on ectopic pregnancy prepared by 2 medical students in Sulaimani university/Iraq

1. AREZ ESMAIL QADR SHAMAL M. AZIZ ECTOPIC PREGNANCY

2. Normal pregnancy implantation Pregnancy is the period during which a woman carries a developing fetus normally in the uterus, starting from conception (fertilization of ova) until the baby born. After ovulation the ovum is picked up by the fimbria of fallopian tubes and then swept by ciliary action towards the ampulla where fertilization occurs. As soon as the zygote develops it begins dividing very rapidly, it remains in the fallopian tube for 3 -4 days untill reaches morula stage (8-32 cell stage)

3. Normal pregnancy implantation The embryo proceeds through the isthmus to the uterine cavity for up to 72 hours, by the sixth day it enters the uterus and begins to penetrate the decidua (endometrium) this is called implantation which takes place within the uterine cavity in normal positioned pregnancy . Then hCG is produced by trophoblast, which can be detected in the serum of the mother in the first week after implantation, its level doubles every 36-48 hours in normal healthy pregnancy starting from 5 to 50 ,100, till reaching 1000 IU/L Delay or obstruction of the passage of fertilized egg down the fallopian tube to the uterus may result in implantation in the fallopian tube or ovary or peritoneal cavity, this known as ectopic pregnancywhich eventually most fails to develop , and the hCG fails to raise dramatically as happens in the normal intra uterine pregnancy.

4. Normal pregnancy implantation

5. Ectopic pregnancy ?

6. Ectopic pregnancy Definition: An ectopic pregnancy, or eccysis , is a complication of pregnancy Occurs when the site of implantation is outside of the womb (uterine cavity) either in the tubes,ovaries or abdominal cavity, With rare exceptions, ectopic pregnancies are not viable, Pregnancy can even occur in both the womb and the tube at the same time (heterotopic pregnancy). Classification: 1- tubal pregnancy: The vast majority of ectopic pregnancies 95-98 % implant in the Fallopian tube, among these: 80% in the ampulla 10% in isthmus 5 % in fimbria 2% interstitial 2% in a rudimentary horn of a bicornuate uterus

7. classification 2-Nontubal ectopic pregnancy Rare sites (2-5%) are; The ovaries, broad ligaments, Abdominal cavity and peritoneum cervix. 3-Heterotopic pregnancy in rare cases of ectopic pregnancy 1/1000, there may be two fertilized eggs, one outside the uterus and the other inside. This is called a heterotopic pregnancy. Often the intrauterine pregnancy is discovered later than the ectopic, mainly because of the painful emergency nature of ectopic pregnancies.

8. classification Since ectopic pregnancies are normally discovered and removed very early in the pregnancy, an ultrasound may not find the additional pregnancy inside the uterus. When hCG levels continue to rise after the removal of the ectopic pregnancy, there is the chance that a pregnancy inside the uterus is still viable. This is normally discovered through an ultrasound Although rare, heterotopic pregnancies are becoming more common, likely due to increased use of IVF.

9. Common sites for ectopic pregnancy

10. epidemiology Incidence; 22/1000 live births 16/1000 pregnancies In USA from 1970 – 1992 , the risk 5x increased from 4 to 19 / 1000 pregnancies fatality rate : fatality rate from ectopic pregnancies dropped almost 90% (from 35.5 per 1000 ectopics to 3.8 per 1000 ectopics). Despite the sharp improvement in the fatality rate by the end of this period of time, ectopics were still the second leading cause of maternal mortality in the USA (accounting for 12% of all maternal deaths in 1987).

11. Why? The reason for the increase in ectopic pregnancy during this time period is not entirely clear, but it was thought that the increase of risk factors were responsible for a significant portion of the increased number of cases of ectopic pregnancy.

12. Risk factors Any mechanism that interferes with the normal function of fallopian tube increases the risk of ectopic pregnancy The mechanism canbe: Anatomical; scarring that blocks transport of the egg Functional; impaired tubal mobility

14. Risk factors 1-History of pelvic infection PID is the most common risk factor for ectopic pregnancy 8 folds increases the risk, due to destruction of the fallopian tubes. Chlamydia (a common sexually transmitted disease) and Gonorrhea are both able to grow within the fallopian tubes and cause; 1-tremendous damage to the endosalpinx (lining of the inner tubal lumen), 2-agglutination (sticking together) of the mucosal folds in the tube 3-peritubal adhesions (scar tissue). . the risk of an ectopic pregnancy is greater when the woman with the infection is younger Other pelvic or lower abdominal infections can also result in pelvic adhesions and an increase in the ectopic pregnancy rate (such as appendicitis). The chances of another ectopic in the same fallopian tube also in the other tube are increased 5x

15. Risk factors 2-History of surgery on the fallopian tubes or within the pelvis: Tubal ligation in the past 2 years,When a bilateral tubal ligation (tubes tied) is followed by either an unexpected pregnancy (failed tubal ligation) or is "reversed" with a tubal reanastomosis (tubal reconstruction) there is an increased risk of a tubal ectopic pregnancy. When a woman has a history of pelvic surgery that is associated with significant adhesion formation (such as myomectomy) there is also an increased risk of an ectopic pregnancy.

16. Risk factors 3- Prior history of ectopic pregnancy. When an ectopic pregnancy in the fallopian tube is treated conservatively (by preserving the tube), there is a roughly 10 fold increase the risk of recurrence in the same tube 4-History of IUD use. The use of an IUD is a classic "risk factor" for ectopic pregnancy. Actually, all but the progesterone containing IUDs are relatively protective against ectopic pregnancy while the IUD is in place. That is, the number of ectopic pregnancies in women using an IUD for contraception is about one half that of women using no contraception. However, of IUD pregnancies there is a greater chance of an ectopic location (3-4%) since the number of intrauterine pregnancies with an IUD in place is markedly reduced.

17. Risk factors Additionally, IUDs can be associated with infections of the uterine cavity and fallopian tubes (especially just after insertion) which can independently increase the chance for an ectopic pregnancy.. The reason for this increase in the nomber of EPs with progesterone IUD is not clear. A theory is that somehow the progesterone enhances tubal implantation.

18. Risk factors 5-History of Diethylstilbestrol (DES )exposure in utero. This drug is a is a synthetic nonsteroidal estrogen that was used for certain conditions, including breast and prostate cancers ,From about 1940 to 1970, DES was given to pregnant women under the mistaken belief it would reduce the risk of pregnancy complications and losses Later researches has shown that this drug has many bad medical effects and female babies of women who used it were at risk of developmental abnormalities of the genital system Their tubes are more likely to be abnormal and predispose to ectopic pregnancy, these females were known as DES daughters

19. Risk factors 6-History of destruction of the uterine cavity or lining. Such as history of uterine synechiae (scar tissue) from previous surgery (like endometrial ablation for dysfunctional bleeding ) or presence of multiple submucosal fibroid tumors this cause a larger percentage of the pregnancies to implant in a space other than the uterine cavity. Similar to the situation with IUDs, the total ectopic pregnancy rate may not be increased but when a pregnancy does occur the reduced likelihood of an intrauterine pregnancy increases the relative percentage of ectopic pregnancies.

20. Risk factors 7-History of non-infectious pelvic inflammation (endometriosis, foreign body). Inflammation of the delicate tubal structures can result in adhesion formation (scar tissue), which will then increase the risk of an ectopic pregnancy. This inflammation may be due to endometriosis or the presence of a foreign body, either of which are strongly associated with scar tissue formation.

21. Risk factors 8-Use of assisted reproductive technology (such as IVF (in vetro fertilization) and GIFT (gamete intrafallopiantransfere). When multiple embryos or gametes are placed into the uterus or the fallopian tubes, the risk for multiple pregnancy rises significantly. The risk of twins and heterotopic pregnancy is generally thought to be about 1 / 30,000 pregnancies . with ARTs the rates of ectopics and dizygotic twins have increased to 1/10,000 . the incidence of heterotopic pregnancy may increase to as frequently as 1 /100 pregnancies.

22. Tubal pregnancy

23. Pathophysiology The trophoblast develops in the fertilized ovum and invades deeply into the tubal wall. Following implantation, the trophoblast produces hCG which maintains the corpus luteum. The corpus luteumproduces oestrogen and progesterone which change the secretoryendometrium into decidua. The uterus enlarges up to 8 weeks and becomes soft. The tubal pregnancy does not usually proceed beyond 8-10weeks due to: > lack of decidual reaction in the tube, > the thin wall of the tube, > the inadequacy of tubal lumen, > bleeding in the site of implantation as trophoblast invades.

24. Pathophysiology Separation of the gestational sac from the tubal wall leads to its degeneration, and fall of hCG level, regression of the corpus luteum and subsequent drop in the oestrogen and progesterone level. This leads to separation of the uterine decidua with uterine bleeding. Fate of tubal pregnancy Tubal mole Tubal abortion Tubal rupture

25. Fate of tubal pregnancy 1- Tubal mole: The gestational sac is surrounded by a blood clot and retained in the tube. This may remain for long period in the tube and forms so called (chronic ectopic pregnancy),or they may be gradually absorbed (involution) 2-Tubal abortion: This occurs more if ovum had been implanted in the ampullary portion of the tube. Separation of the gestational sac is followed by its expulsion into the peritoneal cavity through the tubal ostium. Rarely, reimplantation of the conceptus occurs in another abdominal structure leads to secondary abdominal pregnancy.

26. Fate of tubal pregnancy If expulsion was complete the bleeding usually ceases but it may continue due to incomplete separation or bleeding from the implantation site.

27. Fate of tubal pregnancy 3-Tubal rupture: More common if implantation occurs in the narrower portion of the tube which is the isthmus. Rupture may occur in the anti-mesenteric border of the tube. Usually profuse bleeding occurs -> intraperitonealhaemorrhage. If rupture occurs in the mesenteric border of the tube, broad ligament haematoma will occur.

28. presentation Early symptoms are either absent or subtle. Clinical presentation of ectopic pregnancy occurs at a mean of 7.2 weeks after the last normal menstrual period, with a range of 5 to 8 weeks The most common presenting symptoms that are suggestive for EP are:

29. Clinical traid (3As) Amenorhea ectopic pregnancy Abdominal pain Abnormal vaginal bleeding

30. symptoms Pain and discomfort In the Lower back , abdomin, or pelvis. Usually unilateral Pain may be confused with a strong stomach pain, it may also feel like a strong cramp Shoulder pain. This is caused by free blood tracking up the abdominal cavity and irritating the diaphragm, and is an ominous sign. Pain while urinating Pain while having a bowel movement

31. symptoms Bleeding Vaginal (external)bleeding usually mild. An ectopic pregnancy is usually a failing pregnancy and falling levels of progesterone from the corpus luteum on the ovary cause withdrawal bleeding. Internal bleeding (hematoperitoneum) is due to hemorrhage from the affected tube. Dizziness, headache, weakness, fainting all may happen due to bleeding

32. signs General examination: signs of early pregnancy (Breast tenderness, nausea and vomitig, change of apettite …) Weakness, pallor, hypotension and tachycardia, tachypnoea due to bleeding Abdominal examination: Lower abdominal tenderness and rigidity especially on one side may be present.

33. signs Vaginal examination: Vaginal spotting Bluish vagina and bluish soft cervix. Uterus is slightly enlarged and soft. Marked pain in one iliac fossa on moving the cervix from side to side. Ill defined tender mass may be detected in one adnexa in which arterial pulsation may be felt. Speculum or bimanual examination should not be performed unless facilities for resuscitation are available, as this may induce rupture of the tube

34. diagnosis The diagnosis can be difficult Your doctor may perform some tests to help confirm suspected ectopic pregnancy including; Detailed history of (cycle, pregnancy, PID,infertility, gynaecological surgery, contraception…) Proper general, abdominal, vaginal examination and vital signs Investigations: including

35. Diagnosis 1.hormonal assay Serum β-hCG Urine pregnancy tests are positive in only 50-60% of ectopic. Detection of β-hCG in the serum by ELISA or radioimmunoassay are more sensitive and can detect very early pregnancy about 10 days after fertilization i.e. before the missed period. If the test is negative (generally less than 5 IU/L), normal and abnormal pregnancy including ectopic are excluded. If the test is positive , and doubles every 36-48 hour till reaching 1500 IU/L which is The threshold of discrimination for intrauterine pregnancy, this indicates a normal intrauterine pregnancy, An abnormal rise in blood β-hCG levels may indicate an ectopic pregnancy and ultrasonography is indicated.

36. Diagnosis Progesterone The second most common hormone after hCG in pregnancy is progesterone. Generally, a progesterone concentration of greater than 25 ng/mLis highly correlated with a normal intrauterine pregnancy while a concentration of less than 5 ng/mLis highly correlated with an abnormal and nonviable pregnancy

37. Diagnosis 2-Ultrasound In general, a positive β-hCG test with empty uterus by sonar ± adnexial mass indicates ectopic pregnancy. Discriminatory hCG zones: Diagnosis of ectopic pregnancy is made if there is: An empty uterine cavity by abdominal sonography with b -hCG value above 6000 mIU/ml. An empty uterine cavity by vaginal sonography with b -hCG value above 2000 mIU/ml.

38. Ultrasound

39. Diagnosis 3-Culdocentesis in this test, a needle is inserted into the space at the top of the vagina, behind the uterus and in front of the rectum to aspirate fluid and Determines if there is blood in the space behind the uterus If non-clotting blood is aspirated from the Douglas pouch , intraperitonealhaemorrhage is diagnosed. But if not, ectopic pregnancy cannot be excluded.

40. Diagnosis 4-laparoscopy or laparotomycan also be performed to visually confirm an ectopic pregnancy. Often if a tubal abortion or tubal rupture has occurred. Laparoscopy: an endoscope is inserted through a small incision in the woman’s abdomen This allows you to see the fallopian tubes and other organs This takes place in an operating room with anaesthesia

41. Uncommon Sites of Ectopic Pregnancy 1-Cornual angular pregnancy 2-Pregnancy occurs in the blind rudimentary horn of a bicornuate uterus. 3-Cervical pregnancy 4-Ovarian pregnancy 5-Abdominal (peritoneal) pregnancy

42. Cornual angular pregnancy It is implantation in the interstitial portion of the tube. It is uncommon but dangerous because when rupture occurs bleeding is severe and disruption is extensive that needs hysterectomy. In some cases, the pregnancy is expelled into the uterus and rupture does not occur. www.freelivedoctor.com

43. Pregnancy in a rudimentary horn Pregnancy occurs in the blind rudimentary horn of a bicornuate uterus. As such a horn is capable of some hypertrophy and distension, rupture usually does not occur before 16-20 weeks.

44. Cervical pregnancy Implantation in the substance of the cervix below the level of uterine vessels. May cause severe vaginal bleeding. Can be diagnosed by trans vaginal ultrasound

45. Ovarian pregnancy Aetiology: * Pelvic adhesions. * Favourable ovarian surface for implantation as in ovarian endometriosis. Pathogenesis: * Fertilization of the ovum inside the ovary or, * implantation of the fertilized ovum in the ovary.

46. Ovarian pregnancy Spiegelberg criteria for diagnosis of ovarian pregnancy: * The gestational sac is located in the region of the ovary, * the ectopic pregnancy is attached to the uterus by the ovarian ligament, * ovarian tissue in the wall of the gestational sac is proved histologically, * the tube on the involved side is intact. www.freelivedoctor.com

47. Abdominal (peritoneal) pregnancy Types: Primary: implantation occurs in the peritoneal cavity from the start. Secondary: usually after tubal rupture or abbortion. Intraligamentous pregnancy: is a type of abdominal but extraperitoneal pregnancy. It develops between the anterior and posterior leaves of the broad ligament after rupture of tubal pregnancy in the mesosalpingeal border or lateral rupture of intramural (in the myometrium) pregnancy.

48. Abdominal (peritoneal) pregnancy Diagnosis: History: of amenorrhoea followed by an attack of lower abdominal pain and slight vaginal bleeding which subsided spontaneously. Abdominal examination: Unusual transverse or oblique lie. Foetal parts are felt very superficial with no uterine muscle wall around. Vaginal examination: The uterus is soft, about 8 weeks and separate from the foetus. No presenting part in the pelvis.

49. Abdominal (peritoneal) pregnancy Special investigations: Plain X-ray: shows abnormal lie. In lateral view, the foetus overshadows the maternal spines . Ultrasound: shows no uterine wall around the foetus Magnetic resonance imaging (MRI): has a particular importance in preoperative detection of placental anatomic relationships. www.freelivedoctor.com

50. DIFFERENTIAL DDX DIAGNOSIS

51. (1) NON GYNECOLOGICAL

52. (2) Gynecologic disorders

53. TREATMENT Rx Ectopic

54. Treatment options

55. EXPECTANT MANAGEMENT

56. Criteria for selection asymptomatic women no evidence of rupture or hemodynamic instability less than 100 ml fluid in the pouch of Douglas hCG less than 1000 iu/l at initial presentation Adnexalmass less than 3cm they should objective evidence of resolution, such as decliningbhCG levels. They must be fully compliant and must be willing to accept the potential risks of tubal rupture.

57. MONITORING Initial follow up twice weekly with serial hCGmeasurements weekly by transvaginal examinations By the first week drop in HCG level Adnexal mass size Otherwise reassess the options (Medical/Surgical) If the fall of HCG & reduction in size of adnexal mass satisfatory weekly hCG and transvaginal ultrasound examinations Till the HCG falls less than <20 IU

58. 45–70% of pregnancies of unknown location resolve spontaneously with expectant management Ectopic pregnancy was subsequently diagnosed in 14–28% of cases of pregnancy of unknown location Intervention has been shown to be required in 23–29% of cases.

59. MEDICAL 2 MANAGEMENT

60. CRITERIA for MEDICAL MANAGEMENT Selection criteria Minimal symptoms & The patient must be hemodynamicallystable no signs or symptoms of active bleeding or haemoperitoneum. Absence of foetal heart beat Normal FBC,U&E(urea & electrolytes),LFT(liver function tests) Exclusion criteria Any hepatic dysfunction, thrombocytopenia (platelet count <100,000), blood dyscrasia(WCC <2000 cells cm3). Difficulty or unwillingness of patient for prolonged follow-up (average follow-up 35days). Ectopic mass >3.5cm The presence of cardiac activity in an ectopic pregnancy

63. Rest up to one hour after the injection.

65. ADVICES Patient should be given information on(preferably written) Need for further treatment Adverse effects Women should be able to return easily for assessment at any time during follow-up Advice avoid sexual intercourse during treatment to maintain fluid intake use reliable contraception for three months after methotrexate has been given, barrier or hormonal) Avoid exposure to sunlight. “- Avoid alcohol and vitamin preparations containing folic acid until the hormone level is back to zero. - Avoid aspirin or drugs such as Ibuprofen for one week after treatment.

66. OUTCOME 90% successful treatment with single dose regime. Recurrent ectopic pregnancy rate 10 – 20%. Tubal patency approximately 80%. 14 % of medical management second dose of methotrexate 75% would experience abdominal pain-separation pain. This usually occurs between day 3-7 10% would finally require surgical management

68. but considering the cost of follow up & the loss of work time for patient & carers

70. Indications for surgical treatment The patient is not a suitable candidate for medical therapy. Medical therapy has failed. The patient has a heterotopic pregnancy with a viable intrauterine pregnancy. The patient is hemodynamically unstable and needs immediate treatment.

71. EMERGENCY

72. RUPTURED ECTOPIC PREGNANCY

73. Get help- call senior /Consultant on call ABC of resuscitation give facial oxygen Site two IV lines , commence IV fluids (crystalloid) Send blood for FBC, Clotting screen and cross-match at least 4 units of blood. insert indwelling catheter arrange theatre for laparotomy whilst awaiting transfer to theatre continue fluid resuscitation and ensure intensive monitoring of haemodynamic state do not wait for BP and pulse to normalise prior to transfer-resuscitation and surgery need to go hand in hand. Pfannensteilincision, salpingectomy and wash out of abdomen assess bloods /consider CVP record operative findings including the state of the remaining tube/pelvis Anti – D immunoglobulin (250 IU)to be given to Rhesus negative women

75. patients with cornual ectopic pregnancies.

79. in a patient with a history of an ectopic pregnancy in the same tube.

81. Persistent trophoblast When salpingotomy is done, protocols should be in place for the identification and treatment of women with persistent trophoblast. Monitoring serum HCG levels would help to identify the persistent trophoblast. Most Easily Treated With MTX

82. Other Types Mx Cervical Ovarian Heterotropic Abdominal

83. Cervical pregnancy

84. Ovarian pregnancy Laparotomy and inoculation of the ectopic pregnancy and reconstruction of the ovary if possible. Otherwise, removal of the affected ovary is indicated. Ovarian cystectomy is the preferred treatment Treatment with MTX and prostaglandin injection has also been reported

85. Abdominal (peritoneal) pregnancy The condition should be terminated surgically through Laparotomy once diagnosed MTX treatment appears to be contraindicated because of the high rate of complications due to rapid tissue necrosis

86. Heterotropic pregnancy Depends upon the state of the woman and the skill of the doctor. .Surgical

87. Laparoscopy is the ideal surgical method to remove an ectopic pregnancy before it ruptures without interrupting the viable pregnancy. Although the intrauterine pregnancy can still survive if the ectopic pregnancy ruptures, there is an increased danger of miscarriage. The surgery must be done with great skill and it is important that bleeding be addressed quickly. Medical therapies include injecting the ectopic pregnancy in order to terminate the gestation.

88. Anti D Non sensitized women who are rhesus negative with a confirmed or suspected ectopic pregnancy should receive anti-D immunoglobulin. In accordance with RCOG Guideline it is recommended that anti-D immunoglobulin at a dose of 250 IU (50 micrograms) be given to all non sensitized women who are rhesus negative and who have an ectopic pregnancy.

89. ADVICE Not using IUCD Not using progesterone only pills Treatment for any PID Follow up by HCG that should disappear after 1 month Do HSG after 40 day to see patency of the tube Use barrier method of contraception Timing of pregnancy, visit specialist in any missed period

90. Recurrence of ectopic Infertility Shock & death Tubal rupture & organ damage Psychological Surgical Rx Medical Rx COMPLICATION

91. Prognosis Fertility following ectopic pregnancy depends upon several factors, the most important of which is a prior of infertility. The treatment choice history , whether surgical or nonsurgical, also plays a role. For example, the rate of intrauterine pregnancy may be higher following methotrexate compared to surgical treatment. Rate of fertility may be better following salpingostomy than salpingectomy.

92. Reference 1.Gynecology & obstetrci by Ten teachers 19th edition 2.RCOG guidelines (Royal college of obstetric & gynecology) 3.ACOG(American college of obstetric & gynecology) 4.ASRM(American society of reproductive medicine) 5.Wikipedia .com 6.Livemedicine.com 7.Dr.Abraham ( laparascopy Video)