19 Prior pelvic inflammatory disease, endometriosis and ectopic

Joyanto Choudhury and Saikat Banerjee

The aim of pre-pregnancy counseling is to PRIOR PELVIC INFLAMMATORY address issues regarding women’s concerns DISEASE about their ability to fall pregnant and to give birth to a healthy baby at the end of pregnancy. PID is defined as an infection of the endo- Pelvic inflammatory disease (PID)1 and metrium, fallopian tubes and/or contiguous endometriosis2 are both risk factors associated structures caused by the ascent of microorgan- with subfertility and thus could potentially isms from the lower genital tract1. The major- lead to failure to become pregnant. In the ity of cases in young women are associated event of a successful conception, tubal dam- with sexually transmitted infections (STIs), age secondary to these pre-existing disease the most prevalent being Chlamydia trachoma- processes increases the risk of an ectopic preg- tis and Neisseria gonorrhoeae. These organisms nancy. Of great importance, a prior history of often initiate an inflammatory process and an is a possible indicator of then are replaced by opportunistic bacteria existing tubal damage and hence a strong risk including aerobes, anaerobes and Mycoplasma factor for reoccurrence3. Such an event will not sp8. Special consideration should be given to only be associated with an unsuccessful preg- tuberculosis which is discussed separately in nancy, but also with maternal morbidity at the this book. very least, if not mortality. Even in the pres- The Department of Health and Human Ser- ence of first-world medical facilities, ectopic vices in the USA9 and the Department of Health pregnancy still remains the leading cause of in the UK10 have expressed concerns that with maternal mortality in the first trimester, with changes in lifestyle, STIs represent a growing three women dying in the UK4 and 45 in USA every year5. problem with nearly 333 million curable cases 9 With the development of early pregnancy occurring worldwide annually . This concern assessment units, screening for risk of ectopic is not only based on increasing numbers of pregnancy, one of WHO’s primary objectives6, new STIs diagnosed in genitourinary clinics, not only is possible, but also has been shown but also on the fact that these rates are highest to be cost effective7. It is therefore imperative in women who are young and in the reproduc- to use the opportunity, when meeting a poten- tive age range. Young women aged 16–25 years tial mother to be, to identify risk factors for account for nearly half of all STIs diagnosed in ectopic pregnancy and to decide upon a man- genitourinary clinics, and it is this same group agement plan in advance for possible compli- that will potentially be considering a preg- cations that may arise. nancy post-infection. Of further concern is the

251 PRECONCEPTIONAL MEDICINE fact that 15% of women rarely or never use a infection in pregnancy are identical to those condom with a new sexual partner9. outside pregnancy, with development of repeat Prior infection (symptomatic or asymp- PID, increased risks of subfertility and ecto- tomatic) is a risk factor for current infection, pic pregnancy. Approximately 70% of preg- which may be associated with vaginal dis- nant and non-pregnant women infected with charge, irregular or pelvic chlamydia are asymptomatic; a small propor- pain, all of which direct women to seek medi- tion may present with non-specific symptoms cal advice. Unfortunately, such infections can including , , lower also be asymptomatic and thus undetected , or arthri- at the time of consultation in the absence of tis. The vaginal discharge may be mild, irritat- routine screening procedures. Pre-pregnancy ing, usually yellow, and often goes unnoticed. counseling sessions may provide one of the Therefore, in the presence of these symptoms, few times that an otherwise healthy woman women in the clinic should be offered a test voluntarily accesses medical attention, and, as to exclude the possibility, with appropriate such, becomes an ideal chance to opportunisti- treatment and counseling if the result proves cally screen for STIs. positive. For women with no prior history of infec- Asymptomatic chlamydia infection during tion, the current UK national antenatal care pregnancy is associated with adverse preg- guidelines published by the National Institute nancy outcomes (low birth weight, preterm of Clinical Excellence (NICE)11 state that there delivery and preterm rupture of membranes) is no good evidence to suggest that routine as well as with postpartum and antenatal screening for STIs (other than HIV, neonatal morbidity, including respiratory tract syphilis and hepatitis B) is indicated. Previ- infection and conjunctivitis15. Up to two-thirds ously, however, with the advent of the National of women affected with chlamydia during Chlamydia Screening Programme12, NICE had labor may transmit the organism to the infant envisaged that based on current expert opin- during vaginal delivery. The infection clearly is ion, women who are pregnant or seeking pre- treatable and therefore is not an indication for pregnancy counseling at the age of 25 years or cesarean section; no evidence links chlamydia younger, should be advised on the availability with chorioamnionitis. of the screening program and that screening Microbiological detection is by vaginal, urine could be undertaken as part of this program. In or blood tests (Tables 1 and 2). Nucleic acid the USA routine antenatal screening is recom- amplification tests (NAAT) have a higher sen- mended for chlamydia along with gonorrhea, sitivity (90–95%) than enzyme immunoassays the latter if the pregnant woman comes from (40–70%) and therefore are the recommended an area of high prevalence13. Referral screen- laboratory test for diagnosing chlamydia ing programs also have the additional benefit infection from endocervical and vulvovaginal of contact tracing. swabs16. The vulvovaginal swabs have a sen- sitivity similar to endocervical swabs (90– 95%) and can be taken by either the patient Chlamydia or health-care worker. Variable sensitivities (65–100%) have been reported using the first Chlamydia trachomatis is currently the most catch urine (FCU) specimen. culture common curable STI in the western world. In can be used on all specimen types, but has current screening programs, 8.5% of women low sensitivity (60–80%); because it requires below 25 years of age test positive for chla- expertise and is costly, it is not recommended mydia14. The clinical implications of chlamydia for routine purposes. On the other hand, the

252 Prior pelvic inflammatory disease, endometriosis and ectopic pregnancy

Table 1 Tests in asymptomatic women. (Modified from UK National Screening and Testing Guidelines, 200616)

Site or specimen Gonorrhea Chlamydia Syphilis HIV Urethra Culture NAAT NAAT Oropharynx Urine NAAT Blood EIA/TPPA/TPHA+VDRL EIA

NAAT, nucleic acid amplification test; EIA, enzyme immunoassay; TPPA, Treponema pallidum particle assay; TPHA, Treponema pallidum hemagglutination assay; VDRL, Venereal Disease Research Laboratory

Table 2 Tests in symptomatic women. (Modified from UK National Screening and Testing Guidelines, 200616)

Site or specimen Gonorrhea Chlamydia Syphilis HIV Urethra M+C DGM Cervix M+C NAAT Vagina NAAT NAAT Rectum Culture culture Oropharynx Culture Tissue culture PCR Urine NAAT Blood EIA IgM EIA/LIA M+C, microscopy + culture; DGM, dark ground microscopy; PCR, polymerase chain reaction; EIA, enzyme immunoassay; LIA, line immunoassay direct fluorescent antibody test is applicable to can be identified on transvaginal ultrasonog- all specimens, including rectal and pharyngeal raphy appearing as elongated paraovarian swabs, but its widespread use is hampered by a cysts containing multiple partial septae and an low sensitivity (80%) and the need for techni- irregular inner luminal wall giving an appear- cal expertise; it is therefore not recommended ance described as ‘cog wheeling’. The cog for routine diagnosis. wheels are a result of aggregation of the tubal Diagnosis may also be made at surgical luminal cilia (Figure 2). The fallopian tubes inspection of the pelvic and abdominal cavities are usually bilaterally affected. At , with the demonstration of classical peritubular the pathognomonic feature of prior chlamydial adhesions (Figure 1a) as compared to the cen- tral midline adhesive disease more commonly pelvic infection is that of perihepatic adhesions associated with endometriosis (Figure 1b). named Fitz-Hugh-Curtis syndrome which is The tubal fimbrial ends are often damaged, also seen with prior gonorrheal infection and giving rise to distal occlusion with clubbing less commonly with tuberculosis associated and mild . Such hydrosalpinges PID.

253 PRECONCEPTIONAL MEDICINE

a b

Figure 1 (a) Fine filmy peritubular adhesions associated with pelvic inflammatory disease. (b) Dense central adhesions of the posterior cul de sac associated with endometriosis (note the tubal sparing)

re-exposure is suspected. It should be deferred for 5 weeks (6 weeks if azithromycin is given) after treatment is completed in order to avoid false positive results16. Pre-pregnancy treatment of the tubal damage is by to divide adhesions and possibly open up the distal blocked end of the by a cuff salpingostomy. An anti-adhesive barrier may be employed as recurrence of dis- ease and tubal re-occlusion is high (25–50%)18, forcing couples to later resort to in vitro fertil- Figure 2 Hydrosalpinx on transvaginal ultra- ization (IVF) therapies. sound (cog wheel) The evidence is limited regarding treatment of chlamydia around pregnancy as well as its effectiveness in reducing the incidence of pre- The recommended antibiotic therapy for term rupture of membranes, preterm delivery genital chlamydia infection (Table 3) in non- and low birth weight babies. Current studies pregnant women is doxycycline (100 mg twice are of poor quality19–23. Cohen et al.20 compared daily for 7 days) or azithromycin (1 g single the clinical outcomes in pregnant women with dose). Alternative agents are erythromycin proven cervical chlamydia infection success- (500 mg four times a day for 7 days) or ofloxa- fully treated with erythromycin 500 mg four cin (200 mg twice daily for 7 days). Doxycy- times a day for 7 days (n = 244) against those cline and ofloxacin are contraindicated in preg- who remained chlamydia positive through- nancy. The safety of azithromycin in pregnancy out pregnancy (n= 79) and chlamydia-free and lactating mothers has not yet been fully matched controls (n = 244) in a low-income assessed, although available data indicate that indigenous urban pregnant population con- it is safe17. Recommended therapeutic alterna- sidered at high risk. The successfully treated tives in pregnancy and breastfeeding are eryth- group had a significantly lower frequency of romycin or possibly amoxicillin (500 mg three preterm rupture of membranes (7.4% versus times a day for 7 days). A test of cure is not 20.3%), preterm contractions (4.1% versus routinely recommended but should be per- 24.1%) and small for gestational age babies formed in pregnancy or if non-compliance or (13.1% versus 25.3%) when compared with

254 Prior pelvic inflammatory disease, endometriosis and ectopic pregnancy

Table 3 Treatment and follow-up. (Modified from UK National Screening and Testing Guidelines, 200616)

Treatment in non- Treatment Test of Follow-up pregnant patient in pregnancy cure period Chlamydia Doxycycline 100 mg Erythromycin 500 mg In pregnancy only: Asymptomatic: oral twice daily for 7 oral four times a 5 weeks after 6 months; days; or azithromycin day for 7 days completing Symptomatic: 1 g single oral dose therapy 4 weeks Gonorrhea Single dose: ceftriaxone Same as non-pregnant 3 months 250 mg IM; or cefixime 400 mg oral; or spectinomycin 2 g IM Syphilis Early: single dose of First and second Early: 1, 2, 3, benzathine penicillin trimester: Single 6, 12 months G 2.4 MU IM; dose of benzathine then 6 monthly Late: 3x weekly doses penicillin G; until serofast; Third trimester: 2x Late: 3 monthly weekly doses until serofast Bacterial Metronidazole 400– Same as non-pregnant vaginosis 500 mg oral twice daily for 5–7 days; or 2 g single oral dose the chlamydia persistent group. There was The evidence remains difficult to evaluate in no such difference, however, when the suc- terms of neonatal effects. In situations where cessfully treated group outcomes were com- the link is obvious, such as in vertical infec- pared to the chlamydia negative group. The tion transmission, rapid identification and frequency of preterm birth was lower in the proper management of the neonate is consid- treated group compared to both the untreated ered a clinical and cost effective alternative group (2.9% versus 13.9%) and matched to screening. This is still considered an area controls (2.9% versus 11.9%). There was no of debate and research, especially for studies difference between the three groups regard- looking into treatment effects that reduce the ing other pregnancy outcomes, including fre- potential harms of preterm birth and neona- quency of vaginal deliveries, cesarean section, tal complications. If, however, the patient is postpartum endometritis, antepartum hemor- symptomatic, then the outlook is altered in rhage or stillbirth. These authors concluded favor of treatment. that in a high risk group for chlamydia infec- tion there are potential benefits with repeated prenatal chlamydia testing plus successful Gonorrhea erythromycin treatment. However, three large studies in the general female pregnant popu- Genital infection with Chlamydia trachomatis lation in 198521, 199022 and 199723, screened accompanies genital gonococcal infection in by rapid immunoassay antigen detection and up to 40% of women24. Undetected, untreated treated with erythromycin failed to show any or inadequately treated gonorrhea is another effect on pregnancy outcome, except when car- important cause of upper genital tract infec- ried out in the third trimester. tion in addition to facilitating the transmission

255 PRECONCEPTIONAL MEDICINE of HIV. Not unlike chlamydia, infection of the lead to serious adverse outcomes of pregnancy endocervix is often asymptomatic (in up to (80%) including spontaneous miscarriage, low 50%). Symptomatic infection may present birth weight babies, stillbirth and an increased with altered vaginal discharge, lower abdomi- risk of perinatal death27. nal pain, dysuria, menorrhagia or intermen- Based on the recent increase in cases of infec- strual bleeding. Hematogenous dissemination tious syphilis in the UK and USA, screening is may cause lesions, arthralgia, arthritis recommended for all asymptomatic patients and tenosynovitis. Diagnosis is based upon attending genitourinary clinics. Attendance at identification of Gram-negative Neisseria gon- a pre-pregnancy clinic also provides an excel- orrhoeae by culture of specimen obtained from lent screening opportunity. Furthermore, the endocervix and urethra (Tables 1 and 2). screening for syphilis should be offered to all Culture offers a readily available, specific, sen- pregnant women at an early stage in antenatal sitive and cheap diagnostic test that allows care because treatment of syphilis is beneficial confirmatory identification and antimicro- to the mother and baby9,11. bial susceptibility testing. It is currently the method of first choice for use in genitourinary The diagnosis is based upon serological tests and direct detection of Treponema pallidum by medicine clinics. Treatment comprises a trio of simultaneous activities: patient treatment, dark ground microscopy in primary and sec- contact finding and treatment, and avoidance ondary syphilis (Tables 1 and 2). Treponema pal- of unprotected until both lidum enzyme immunoassays (EIA) that detect partners have completed treatment. Recom- both IgG and IgM tend to be more sensitive mended antibiotics (Table 3) include ceftri- in primary infection. The Treponema pallidum axone (250 mg IM single dose), cefixime particle assay (TPPA) is recommended in pref- (400 mg oral single dose) and spectinomycin erence to the Treponema pallidum hemaggluti- (2 g IM single dose). Pregnant women should nation assay (TPHA). TPHA can be used in not be treated with quinolone or tetracycline combination with a cardiolipin antigen/reagin antimicrobials. A microbiological test of cure test, such as Venereal Disease Research Labo- is not routinely necessary. Pregnancy does not ratory (VDRL) or rapid plasma regain (RPR), diminish treatment efficacy. There is no evi- to maximize the detection of primary infection dence base to support widespread unselected on screening28. or selective community screening for gonor- The first line of treatment for infected indi- 25 26 rhea in the USA and UK . viduals is benzathine penicillin G 2.4 MU intramuscularly. A single dose is adequate for early syphilis, whereas three weekly doses are Syphilis recommended for late syphilis. In pregnancy, a single dose is optimum treatment in the first This is caused by infection with Treponema pallidum and is an uncommon cause of pelvic and second trimester, but two weekly doses infection per se, but in pregnancy the causative are required in third trimester. Alternative agent can cross the placenta to infect the fetus, treatment agents include azithromycin, cef- thus resulting in congenital disease. Untreated triaxone and doxycycline. Follow-up is essen- babies can display physical deformities (sad- tial to monitor cases of re-infection or relapse dle nose, frontal bossing, dental deformities, (Table 3). As is the case with most STIs, con- bowed legs), delays in development and sei- tact tracing and treatment is imperative not zures, along with many other problems. Of only for prevention of reinfection, but also for equal importance, maternal syphilis can also the health of the general population.

256 Prior pelvic inflammatory disease, endometriosis and ectopic pregnancy

Bacterial vaginosis finding is recent and, if verified, may be impor- tant to future research efforts to understand The etiology of is unknown. the etiology of the condition. At present, the It commonly causes asymptomatic disease most popular theory, that is, retrograde men- which can increase the risk of PID as well as struation and implantation35, originally pro- adverse pregnancy outcomes including pre- posed over a century ago by John Albertson term rupture of membranes, preterm delivery Sampson, tends to be repeated in textbooks, and low birth weight babies29. It has been sug- albeit with very little evidence, as it fails to gested that bacterial vaginosis is also linked to account for the presence of distal metasta- increased risk of acquisition of HIV, but further sis except for implantation at operative scar studies are required for accurate evaluation30. sites after cesarean section, a well described Diagnosis is based on the appearance of a but rare complication of this mode of deliv- Gram-stained smear according to the modi- ery. Another theory with growing popularity fied Ison-Hay scoring system. There is insuf- is that of tissue metaplasia36, but this is yet to ficient evidence regarding routine screening be confirmed. or treatment of asymptomatic pregnant and Endometriosis is said to involve 5% of the non-pregnant women to improve outcome. female population37, with higher incidence The recommended antibiotic for treatment in found at laparoscopy when investigating for symptomatic bacterial vaginosis is oral metro- causes of subfertility (25–40%)38 or nidazole 400–500 mg twice daily for 5–7 days (45–50%)39. Except in severe forms where or 2 g single dose31 (Table 3). resultant adhesions cause tubal damage, the A past history of unexplained late miscar- causal link with subfertility is not well defined. riage and/or preterm birth has been linked to It is thought that endometrial deposits may bacterial vaginosis in early pregnancy32, and secrete within the pelvic cavity that hence may be considered as an indicator for may be cytotoxic to sperm and/or the embryo screening in subsequent pregnancies33. immediately or shortly after fertilization. The Serological screening for hepatitis B virus possibility of subfertility is the main concern and HIV infection should be offered to all preg- in a pre-pregnancy clinic. During pregnancy nant women early in antenatal care because there are few issues, and rarely endometriosis appropriate antenatal interventions can reduce may be associated with worsening of pain due mother-to-child transmission of infection9,11. to stretching. More commonly, preg- This is discussed elsewhere in this book. nancy leads to an improvement of endometrio- sis associated pelvic pain40, and pregnancy was advised as a therapeutic methodology in the PRIOR ENDOMETRIOSIS era before modern treatment modes. Having said this, becoming pregnant should not be Endometriosis is defined as the presence of considered as a long-term treatment option, as -like tissue outside the uterine the effects usually are short term and confined cavity, the presence of which induces a chronic to the length of the associated amenorrhea41. inflammatory reaction2. Common locations Evidence to date suggests endometriosis to for such tissue include the , uterosacral be a complex trait influenced by both genetic and posterior cul de sac . and environmental factors. It has long been Although endometriosis is a chronic condi- considered that endometriosis carries a genetic tion thought to be potentially present at least predisposition in many families, but despite from the time of , it also has been extensive research no specific genes have been identified in the female embryo34. This latter identified. Encoding genes for detoxification

257 PRECONCEPTIONAL MEDICINE enzymes GST (glutathione-S-transferase) and medically and/or surgically is fraught with NAT2 (N-acetyltransferase 2) are thought limitations. In a study by Mahmood and Tem- to be responsible, but further studies are pleton50, women with suspected endometrio- required to confirm such an association42. sis underwent a diagnostic laparoscopy and Higher levels of dioxin, an exogenous toxin, staging. A repeat laparoscopic assessment at a have been detected in the blood of women mean interval of 12 months revealed that 27% with endometriosis43. The peritoneal environ- of women had disease regression, whilst the ment promoted by hormones, growth factors disease was static in 9%, and 64% had wors- and cytokines, along with existing damage to ening of the disease severity as defined by the peritoneal surface by trauma, infection or the rAFS (revised American Fertility Society) inflammation, can contribute to an increased score. Treatment is therefore based on current risk of disease development. Factors thought symptomatology and not disease identifica- to be protective against development of endo- tion or suspicion. Although it may be thought metriosis include current use of combined oral that early stage treatment will protect against contraceptive pills, smoking and exercise44. future disease progression and thus reduce the The gold standard of diagnosis is surgical risk of future sub- or , no evidence inspection2, at either laparoscopy or laparot- substantiates this theory, as the disease pro- omy. Endometriosis is characterized by a vari- gression rate is unknown (it would require ety of appearances which range from superfi- repeated surgical observation assessment), cial transparent sago grain lesions, red or black and the limited available data clearly identify lesions to deep fibrotic lesions of the perito- spontaneous disease regression. Interven- neum. Endometriotic cysts of the ovaries, tional treatment is not without risks which occurring in up to 20% of cases45, can reliably can result in a reduction in fertility with a risk be diagnosed by community based transvagi- of and adhesion formation51. nal ultrasonography46. Using this technique, Medical management of this estrogen the positive likelihood ratio ranges from 7.6 to dependent condition involves estrogen sup- 29.8 and the negative likelihood ratio ranges pression and thus ovulation suppression. from 0.1 to 0.4, thus establishing sonography Benefits only last for the duration of therapy, as a good diagnostic test to either confirm or are limited by the adverse side-effects of the exclude this condition. Endometriotic cysts drugs, and are short lived following cessation are colloquially known as chocolate cysts due of therapy52. The main indication for medical to their hemoglobin content. therapy, therefore, is pain management rather More recently, in highly specialist tertiary than subfertility. clinics, it has been possible to identify peri- Laparoscopic surgical management by exci- toneal disease on transvaginal ultrasound47, sion or is currently considered opti- transrectal ultrasound48 and magnetic reso- mal management with concurrent treatment nance imaging49. These are, however, not for subfertility2,53. In the presence of severe widely available in the community and most deep nodular disease careful prior counseling hospital based practices. is required, as treatment is not without associ- Despite the variable macroscopic appear- ated morbidity that can in itself adversely affect ances of endometriosis, the common linking and delay pregnancy. In these circumstances, feature of these lesions is that all display his- surgical treatment should be carried out by tological features of endometrial and specialist centers of excellence. In the UK cur- stroma. rently the British Society for Gynaecological Expectant management is the first line treat- Endoscopy (BSGE) has set out to identify such ment, as the ability to manage the condition units (www.bsge.org.uk). In cases of severe

258 Prior pelvic inflammatory disease, endometriosis and ectopic pregnancy disease with tubal occlusion treatment may be 19.7 per 1000 maternities) are reported annu- by IVF. However, many IVF specialists require ally. In Northern Europe the incidence of ecto- removal of of 4 cm or more in pic pregnancy is 18.8 per 1000 maternities55. diameter prior to treatment to improve ovar- In the last triennium (2003–05)4 in the UK, ian drug response and reduce the complication 14 reported maternal deaths resulted from of peritonitis by inadvertent puncture of the early pregnancy complications; ruptured ecto- cyst during egg collection53. pic and subsequent hemorrhage There are no known problems that can affect accounted for ten of these deaths. In the USA the fetus once conceived, except the risk of ectopic pregnancy accounts for 9% of all preg- future susceptibility of female offspring if a nancy related deaths each year55. This outlines genetic link is believed, as discussed earlier. the serious implications of the condition. Endometriosis support groups available Women with a prior ectopic pregnancy or worldwide (www.endometriosis.org) play a those who are aware of its potential risk, pos- vital role in improving awareness about the sibly directed by the presence of predisposing 3 disease process and its common sequelae, par- risk factors (Table 4), should be alert to its ticularly in relation to future fertility. possibility in a future pregnancy and require both counseling and support at any preconcep- tion visit. Prior ECTOPIC PREGNANCY Classically, ectopic pregnancy presents with a triad of associated symptoms: (1) amenor- Ectopic pregnancy is defined as implantation rhea of 6 weeks, (2) abdominal pain (69.3%) 57 of a fertilized ovum anywhere other than the and (3) vaginal bleeding (45.3%) . However, endometrial lining of the . Extrauterine implantation occurs most commonly in the Table 4 Risk factors for occurrence of an ectopic fallopian tube accounting for 98.3% of all ecto- pregnancy3 pic locations. Tubal implantation can be in the ampular region (79.6% of tubal pregnancies), High risk the isthmic region (12.3%), at the fimbrial Tubal surgery end (6.2%) or rarely in the interstitial region Sterilization (1.9%)3. The less common sites of ectopic Previous ectopic pregnancy pregnancy are ovarian, cervical, cesarean scar and intra-abdominal. Heterotopic pregnancy, In utero DES exposure when an intrauterine and an extrauterine preg- Intrauterine device use nancy occur simultaneously, is a rare condition Documented tubal pathology with an incidence in spontaneous conception Moderate risk cycles of 1:30,000. However, this incidence has been slowly rising in recent years with the Infertility advent of assisted reproduction techniques Previous genital infections and could range from 1:500 to 1:100 in IVF Multiple sexual partners pregnancies54. Low risk There is a global rise in the incidence of Previous pelvic or abdominal surgery ectopic pregnancy which is mainly attributed to the increasing incidence of PID55. In the Cigarette smoking UK around 11,000 cases are diagnosed per Vaginal douching year (incidence 11.5 per 1000 maternities)56, Early age of intercourse (<18 years) while in the USA 108,800 cases (incidence DES,

259 PRECONCEPTIONAL MEDICINE diagnosis can be difficult, as clinical presenta- nancy59, but should be assessed individually to tion is exceedingly variable, and some women ascertain the presence of personal risk factors. (as many as one-third) are completely asymp- The diagnosis of ectopic pregnancy using tomatic with absent risk factors. Hence the ultrasonography is often by exclusion with only way of ensuring that this potentially the identification of an intrauterine pregnancy. lethal diagnosis is never missed is that the cli- This can usually be achieved as early as 4 nician should always be aware of the probabil- weeks and 3 days of gestation by transvaginal ity and act to exclude the possibility, if there is ultrasonography (Figure 3) and a week later by any suspicion. transabdominal ultrasonography. Direct iden- Early diagnosis is important to minimize tification of the ectopic pregnancy by ultra- sonography has an overall sensitivity of more morbidity, allow for different treatment than 90%60 (Figure 4); in good units this is options and maximize scope for future fertil- now considered the norm. ity. For these reasons, there exists a valid argu- If the identification of an intrauterine sac is uncer- ment for offering ectopic pregnancy screening tain, the woman should be offered a serial trans- to women with known risk factors as soon as vaginal ultrasound assessment in 2–3 days, ide- conception is confirmed with a positive urine ally by the same ultrasonographer. At this time pregnancy test. In view of the unpredictability the images should become more conclusive and significant implications of the condition, with the development of an intrauterine well it may even be considered that there could be defined hypoechoic cystic structure within one a role for screening the entire pregnant popu- endometrial leaflet rather than the midline. It lation. In many ways awareness is one of the should also be spherical in outline and in one- main objectives of early pregnancy assess- third of cases may have a hyperechoic tropho- ment units in the form of secondary screen- blastic ring (Figure 3). ing. However, although routine screening for In women where a pregnancy cannot be ectopic pregnancy in the high risk population identified, a diagnostic laparoscopy may be is not cost effective58, it is undeniably good proposed if they are clinically compromised. practice to offer women with a prior ectopic Fortunately, the majority of such women, pregnancy an early pregnancy scan to confirm defined by Banerjee et al.61 as women with the location of the gestational sac. It is axiom- atic that ultrasonic findings of an empty uterus in a woman with a positive pregnancy test and clini- cal signs that might even remotely indicate ectopic pregnancy, receive follow-up by care-givers with suf- ficient understanding of the potential gravity of the situation to all concerned. Moreover, the clinician has a duty to inform the woman attending the pre-pregnancy clinic of his/her concerns and the availability (or lack) of such resources locally, so that there is no unnecessary delay when the woman discovers she is pregnant. Women with a family history of ectopic Figure 3 Transvaginal image of the sagittal sec- pregnancy may express concern regarding the tion through an anteverted uterus along the mid- chance of their having an ectopic pregnancy. line. The hypoechoic cyst seen at the center of the They can be assured that there is no genetic endometrial cavity is consistent with an intrauter- predisposition to occurrence of ectopic preg- ine pregnancy of 4–5 weeks’ gestation

260 Prior pelvic inflammatory disease, endometriosis and ectopic pregnancy

‘pregnancies of unknown location’, are clini- for pre-pregnancy counseling, the therapeutic cally stable with minimal symptoms. In such options include expectant, medical and surgi- women, serum hormone level estimation of cal management. human chorionic gonadotropin (hCG) and Expectant management has the obvious ben- progesterone is a useful tool to identify and efit of avoiding the risks associated with sur- monitor for spontaneous resolution of the gery. The success rate for spontaneous resolu- pregnancy, thus allowing attention to focus on tion varies between 25% and 88%, depending those women with a potentially problematic on the initial serum hCG level62. The subse- diagnosis of ectopic pregnancy. Subsequent quent intrauterine pregnancy rate following follow-up should be logical and individualized. expectant management is 89%, whereas the The authors’ current practice is to follow the risk of a recurrent ectopic pregnancy is 5%56. protocol described in Table 5, which aims to It is the authors’ current practice to consider reach a conclusive diagnosis in the safest pos- expectant management with initial serial hCG sible way with minimum number of hospital assays 48 hours apart and then at weekly visits. intervals until serum levels are less than 20 If ectopic pregnancy is identified in a woman IU/l63 in women with a pregnancy that is not who is clinically stable and presenting initially considered viable on ultrasound (absence of embryonic heart action or features not com- parable to menstrual dates). As a predictor of success, one would expect a drop in serial hCG levels of greater than 66% within the first 48 hours and then more than 50% within 7 days, ideally with an initial hCG of less than 1000– 1500 IU/l56. In a district general hospital set- ting, approximately 60% of ectopic pregnan- cies are successfully managed conservatively with no significant morbidity64. A reasonable alternative in clinically sta- ble women with an initial hCG of less than Figure 4 Transvaginal ultrasound image of an 3000 IU/l is medical management. In the ectopic pregnancy western world, this is increasingly becoming

Table 5 Protocol for management of ‘pregnancy of unknown location’ as defined by the absence of an intrauterine or extrauterine pregnancy on transvaginal ultrasound examination

Progesterone (nmol/l) hCG (IU/l) Likely diagnosis Management <20 >25 Resolving pregnancy Repeat urine pregnancy test or serum hCG in 7 days 20–60 >25 Ectopic pregnancy or miscarriage Repeat serum hCG in 2 days requiring intervention >60 <1000 Normal intrauterine pregnancy Repeat scan when hCG expected >1000 IU/l >60 >1000 Ectopic pregnancy Repeat scan same day by a senior examiner ± laparoscopy hCG, human chorionic gonadotropin

261 PRECONCEPTIONAL MEDICINE Surgical management of ectopic pregnancy an attractive treatment option and has been is still widely considered the first line of man- found to be cost-effective65. agement in most countries worldwide. Sur- Medical management of ectopic pregnancy gery involves laparoscopy or laparotomy (if comprises a single dose methotrexate injec- hemodynamically unstable) to perform either tion (systemic or local) at a dose of 50 mg/m2. a salpingectomy (Figure 5) or salpingotomy A small group of these women (14%) may (Figure 6). A meta-analysis of four cohort 63 require more than one dose of methotrexate, studies suggested that there might be a while around 10% will fail treatment, need- higher subsequent intrauterine pregnancy rate associated with salpingotomy (Table 6), but ing subsequent surgical intervention56. The the magnitude of benefit is small. This would success rate (defined as not requiring- sur need to be taken into consideration with the gery) varies between 74% and 97% depend- woman’s desire for future fertility, the state of ing on the initial level of serum hCG rather the unaffected contralateral fallopian tube, the than the size of the ectopic pregnancy66. After additional morbidity associated with salpin- methotrexate therapy, 62–70% of women have gotomy (small risk of tubal bleeding in the ini- a subsequent intrauterine pregnancy and 8% tial postoperative period), the potential need have recurrent ectopic pregnancy62. These val- for further monitoring, and any treatment for ues are almost identical to those obtained for persistent trophoblast (10%) as well as a risk expectant management. of repeat ectopic pregnancy in future. Also In order to offer either non-surgical option, under consideration would be the woman’s it is essential that the woman fully under- wishes and availability of IVF services. After stands the risks discussed, particularly that of partial or total salpingectomy the rate of recur- pregnancy rupture leading to hematoperito- rent ectopic pregnancy is 7–10% as compared neum and the need for emergency surgery. It to 15% after salpingotomy62. is essential when offering such treatment regi- The results of these studies have prompted mens that there be appropriate local protocols the recommendation by the Royal College of with a 24/7/365 immediate access for medical Obstetricians and Gynaecologists (RCOG) in reappraisal, should the clinical situation alter. the UK63 to consider laparoscopic salpingot- If this is not possible or there is even a doubt omy as the primary treatment when managing about patient compliance, a surgical approach a tubal ectopic pregnancy in the presence of should be adopted as the first line treatment contralateral tubal disease, whilst the evidence option. is not so clear when the contralateral tube is

a b

Figure 5 Laparoscopic salpingectomy ((a) before and (b) after)

262 Prior pelvic inflammatory disease, endometriosis and ectopic pregnancy

a b

Figure 6 Laparoscopic salpingotomy ((a) before and (b) after)

Table 6 Intrauterine pregnancy rates following surgical treatment of tubal ectopic pregnancy63

Salpingectomy (%) Salpingotomy (%) Silva et al. 54 60 Job-Spira et al. 56.3 72.4 Mol et al. 38 62 Bangsgaard et al. 66 89 healthy and future pregnancy is desired. In the aware that with IVF there is an increased risk latter circumstance the current accepted prac- of recurrence of ectopic pregnancy and hetero- tice is towards that of salpingectomy. topic pregnancy and that ovulation induction Laparoscopy is superior to laparotomy irre- techniques can also lead to an increased risk of spective of the type of tubal surgery, result- ectopic pregnancy (2.2% from IVF and 1.9% ing in a higher rate of intrauterine pregnancy from intracytoplasmic sperm injection)67. Pro- (77% versus 66%) and a lower rate of recur- phylactic salpingectomy after salpingotomy rent ectopic pregnancy (7% versus 17%). The could be considered if there is evidence of cumulative pregnancy rate is also influenced hydrosalpinx in the affected fallopian tube, as by a history of infertility with an overall con- it has been shown to increase the cumulative ception rate of 77% for all methods of treat- success rate of IVF 68. ment and a recurrence rate of 10%62. In heterotopic pregnancies, the tubal ectopic Age of the woman and prior history of infer- is usually managed by salpingectomy as it is tility rather than a prior history of ectopic impossible to monitor for persistent tubal tro- pregnancy should be the determining factor phoblast implants with a simultaneous ongo- for considering IVF. Referral to an assisted ing intrauterine pregnancy. The management conception unit may be considered in women of non-tubal ectopic pregnancies is outside the with a history of recurrent ectopic pregnancies scope of this chapter. because of the concern of tubal subfertility. Finally, all non-sensitized women who are Screening for evidence of tubal patency may rhesus negative with a confirmed or sus- be performed either radiologically or at lapa- pected ectopic pregnancy should receive anti- roscopy. However, patients should be made D immunoglobulin if managed medically or

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