What you should know about heterotopic With increasing use of ART and a rising incidence of , the phenomenon of coexisting intrauterine and extra- uterine gestations is becoming much less rare

Daniel M. Avery, MD Pelvic pain and few signs® of intrauterine pregnancy Dowden Health MediaDr. Avery is Associate Professor A 24-year-old woman, para 1-0-0-1, visits the hospital emer- and Chair, Department of gency department complaining of pelvic pain. She says the and Gynecology, University of Alabama School of painCopyright arose suddenlyFor and personal reports that she use had a positiveonly Medicine, Tuscaloosa, Ala. IN THIS urine earlier in the week. When asked about ARTICLE Marion D. Reed, MD her obstetric history, she reports vaginal delivery of an 8 lb, Dr. Reed is Assistant Professor, Ovarian “cyst” turns 8 oz infant at 38 weeks’ gestation 2 years earlier. Her human Department of Obstetrics and chorionic gonadotropin (hCG) level is 3,000 mIU/mL, but Gynecology, University out to be a gestation of Alabama School of Medicine, page 32 ultrasonography (US) reveals no evidence of pregnancy. She Tuscaloosa, Ala. is discharged with instructions to follow up with her physi- William L. Lenahan, MD cian in 2 days. When a pregnancy Dr. Lenahan is Adjunct Assistant When her abdominal pain worsens, she returns to Professor of Obstetrics and wanders, there are Gynecology, University of the emergency department. Physical examination reveals Alabama School of Medicine, many possibilities signifi cant tenderness of the abdomen and moderate to Tuscaloosa, Ala. He also practices ObGyn in Winfi eld, Ala. for where severe tenderness of the cervix upon motion. Transvaginal page 33 US shows a of normal size with a 5-mm endometrial The authors report no fi nancial relationships lining and no gestational sac. The patient’s abdomen is full relevant to this article. Hold off on curettage of fl uid, with large, hypodense areas adjacent to the uterus page 34 bilaterally but larger on the right. The preoperative diagno- sis: ruptured ectopic pregnancy. During the diagnostic laparoscopy that follows, approx- imately 500 mL of blood is discovered in the abdomen and pelvis, and a gestational sac is found to be densely adherent to the right pelvic sidewall, where the ureter nears the uter- ine vessels. The sac, which has partially separated from the ›› SHARE YOUR EXPERIENCES sidewall, is bleeding. Have you diagnosed a The surgeon peels the sac off the sidewall and controls heterotopic pregnancy? bleeding with electrocautery and liquid thrombin. The fi nal E-MAIL [email protected] FAX 201-391-2778 pathology report describes the tissue as an organizing blood clot with trophoblasts, consistent with ectopic pregnancy.

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30_OBGM1009 30 9/21/09 8:08:41 AM At a follow-up visit 3 weeks later, the patient reports persistent symptoms of preg- The literature on heterotopic pregnancy is slight nancy. Repeat US reveals a intrauterine pregnancy with two sacs, only one of which Duverney was the fi rst to report heterotopic pregnancy, in 1708, after fi nd- has a heartbeat. One week later, US shows ing an intrauterine pregnancy during the autopsy of a woman who had 1 confl uence of the sacs, with a single viable died from a ruptured ectopic pregnancy. It was 165 years, however, be- 2 at 8 weeks and 2 days of gestation. fore the fi rst review of the phenomenon was written. By 1970, only 479 such cases had been reported.20 Could heterotopic pregnancy have been

diagnosed earlier? Determining incidence remains a challenge—except that it is rising In 1948, DeVoe and Pratt calculated the incidence of heterotopic pregnan- his case illustrates challenges inherent cy by multiplying the incidence of two-ovum pregnancy by the incidence in the diagnosis of heterotopic preg- T of ectopic pregnancy, reaching an estimate of 1 in 30,000 nancy, which is much more common today annually.2 than it was when it was fi rst described 300 In 1965, Rothman and Shapiro found that only about 500 cases years ago. Incidence has increased from ap- of heterotopic pregnancy had been reported cumulatively.7 They rea- proximately 1 in 30,000 pregnancies to 1 in soned that, if the incidence of fraternal is 1 in 110 and the inci- 2,600 pregnancies annually. When assisted dence of ectopic pregnancy is 1 in 250, heterotopic pregnancy should reproductive technologies (ART) are used, occur at a rate of 1 in 27,500 gestations.7 They also speculated that the incidence may be as high as 1 in 100 many heterotopic pregnancies go undiagnosed because of early preg- pregnancies.1 nancy loss.7 Th e rising incidence suggests that the In 1971, Payne and colleagues hypothesized that ovulation- diagnosis of intrauterine pregnancy can no induction agents increase the incidence of heterotopic pregnancy, longer be used to exclude the presence of and McLain and associates reached a similar conclusion in 1987.9 ectopic pregnancy, and vice versa. Instead, The incidence of multiple pregnancy after oral ovulation induc- 9 steps must be taken to rule out both when tion is 8% to 10%, and it is 20% to 50% with injectable agents. In 1994, Crabtree and associates reported that both abdominal and het- a woman exhibits pain and signs of preg- erotopic pregnancies appear to be increasing in incidence.17 nancy. Today, the incidence of heterotopic pregnancy is thought to be In this article, we discuss the causes, about 1 in 2,600 pregnancies annually—primarily because of assisted diagnosis, and treatment of heterotopic reproduction.2 The calculated risk of heterotopic pregnancy is 1 in 119, pregnancy, including the necessity of a high and it rises to 1 in 45 with .8 index of suspicion, the unreliability of US imaging in 50% of cases, and the need to avoid curettage in the treatment of ectopic pregnancy until an empty uterus can be pregnancy during surgery for ectopic confi rmed. pregnancy • pregnancy termination • history of surgery to treat infertility, ec- Why is heterotopic pregnancy topic pregnancy, or tubal adhesions on the increase? • improvement in the assay used to mea- One reason may be the increase in ectopic sure gonadotropin pregnancy. Among the factors contributing • improvement in ultrasonography.2–4 to the rising incidence of ectopic pregnancy A previous ectopic pregnancy is a risk are: factor for ectopic pregnancy as well as for • pelvic adhesive disease heterotopic pregnancy.5 • eff ects of diethylstilbestrol (DES) on the Pelvic infection, antibiotic-induced genital tract tubal disease, previous ectopic pregnancy, • antibiotic-induced tubal disease pelvic adhesions, and tubal surgery with • use of an intrauterine device (IUD) cauterization of the tubes and subsequent • voluntary restriction of family size bowel adhesions distort the fallopian tubes • iatrogenic curettage of intrauterine and may render them unable to propel a

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TABLE Signs and symptoms How does heterotopic of heterotopic pregnancy pregnancy develop? Possibilities include the following, according Pain after spontaneous or induced to Wolf and colleagues: Two corpora lutea detected during ultrasonography • fertilization of two ova from a single or laparotomy coitus • superimposition of an intrauterine preg- Persistent Hegar’s sign or Chadwick’s sign after nancy over an existing ectopic pregnan- laparotomy for ectopic pregnancy cy (also known as superfetation).13 Absence of vaginal bleeding after laparotomy for Th e appearance of cardiac activity may ectopic pregnancy be discordant in heterotopic pregnancy, ac- Lateral location of a gestational sac identifi ed via cording to Hirsh and associates, suggesting ultrasonography that superfetation is indeed a mechanism in Fluid in the uterus its development, with one pregnancy con- ceived earlier than the other.14 Discordant appearance of fetal cardiac activity

Unpredictable quantitative human chorionic gonadotropin levels Diagnosis requires a high index of suspicion Th e timely detection of heterotopic preg- migrated embryo into the uterine cavity.2,6 nancy necessitates vigilance.10,15 Th e TABLE Ectopic pregnancy may result from internal lists signs and symptoms of this condition, migration of a fertilized ovum or transperito- which include abdominal pain, an adnexal neal migration of sperm.7 mass, peritoneal irritation, an enlarged DES exposure can distort the uterine uterus, and absence of vaginal bleeding.6 In cavity.8 Congenital and acquired uterine contrast to ectopic pregnancy, there is no The greatest malformations increase the risk of ectopic vaginal bleeding with heterotopic pregnan- 3 increase in the pregnancy. cy because an intact intrauterine pregnancy 8 incidence of hetero- In addition, ovulation-inducing drugs is present. topic pregnancy has and ovarian stimulation increase the num- been seen with GIFT ber of eggs available for conception, with a greater risk of multiple gestation and hetero- Ovarian “cyst” turns out to be a gestation and ART involving topic pregnancy.3,9,10 A 28-year-old woman, para 2-0-0-2, visits the multiple embryos Th e greatest increase in heterotopic emergency department complaining of acute pregnancy has been seen with ART involv- abdominal pain, and is given two diagnoses: ing the transfer of multiple embryos into urinary tract infection and incomplete abor- the uterus, as well as gamete intrafallopian tion at 5 weeks’ gestation. She is treated for transfer, also known as GIFT.10,11 When fi ve the infection and discharged, to be followed or more embryos are transferred, the risk of up with treatment by her private ObGyn for the heterotopic pregnancy increases to 1 in 45 incomplete abortion. pregnancies annually.11 Inadvertent place- Three days later she returns, reporting ment of the catheter tip near the tube, ex- cramping and increased pain. Ultrasonography cessive force or volume during transfer, and reveals intrauterine fetal demise at 8 weeks and retrograde migration of an embryo because 6 days of gestation, along with a hemorrhagic of uterine contraction may also increase the mass in the cul-de-sac—most likely a ruptured risk of heterotopic pregnancy.8 hemorrhagic ovarian cyst. Her history includes A heterotopic pregnancy in spontaneous two cesarean deliveries and treatment with conceptual cycles without ART is relatively clonidine for hypertension. Her blood pressure rare, even in a woman who has risk factors is normal, and her abdomen is diffusely tender, for ectopic pregnancy.12 with bowel sounds present. The preoperative

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32_OBGM1009 32 9/21/09 8:08:50 AM diagnosis: incomplete abortion and a ruptured FIGURE When a pregnancy wanders, hemorrhagic cyst. there are many possibilities for where During exploratory laparotomy, left sal- pingo-oophorectomy is performed, and a hemorrhagic ovarian cyst is removed, with evacuation of hemoperitoneum, followed by suction curettage. Almost no tissue is pres- ent in the uterine cavity at the time of surgery. The fi nal pathology report determines that the hemorrhagic cyst contained organizing clotted blood with trophoblasts, consistent with ecto- pic pregnancy. In addition, the uterine contents included scant tissue with hypersecretory endometrium. The physician theorizes that the collapsed gestational sac may have passed out of the patient’s uterus after US or during preoperative preparation. The patient does well postoperatively and is discharged home. Should ectopic pregnancy have been sus- pected earlier?

When a patient experiences pain after spon- Ectopic pregnancy can arise as a result of internal migration of a fertilized ovum or taneous or induced abortion, ectopic preg- transperitoneal migration of sperm. It may be observed at a number of possible sites nancy should be suspected.2 In addition, within the pelvis. ROB FLEWELL FOR OBG MANAGEMENT women who exhibit signs or symptoms of ectopic pregnancy or continuing pregnancy after an inconclusive or negative US should Don’t assume that the presence of an in- be assessed thoroughly to exclude ectopic trauterine gestation excludes the possibility pregnancy.5 of ectopic pregnancy when the patient expe- Conversely, if symptoms of pregnancy riences abdominal pain.16 persist or worsen after laparotomy for ecto- pic pregnancy, the surgeon should suspect Imaging is helpful but not foolproof another pregnancy.7 Even when a patient Identifying a heterotopic pregnancy before who is being treated for infertility exhibits surgery is an imaging challenge. Even when signs and symptoms of ectopic pregnancy, US is employed, the diagnosis is missed in concurrent intrauterine pregnancy must be 50% of cases—and even transvaginal US has ruled out.9 low sensitivity.17,18 One reason may be the A persistent Hegar’s sign or Chadwick’s discordant appearance of fetal cardiac ac- sign means that a pregnancy is still present.7 tivity in coexisting intrauterine and ectopic In addition, the absence of vaginal bleeding pregnancies. Alternatively, the gestational after surgery for ectopic pregnancy may indi- sac may be anembryonic.19 cate the presence of gestation.6 A gestational sac is a sonolucent struc- ture with a double decidual sac sign—i.e., Few heterotopic pregnancies an echogenic ring surrounding the sac. A are identifi ed before surgery pseudogestational sac containing fl uid or Only 10% of heterotopic pregnancies are blood can mimic a gestational sac.5 One detected preoperatively.3 One third of intra- helpful diagnostic sign of heterotopic preg- uterine gestations in a heterotopic pregnan- nancy during US examination is a lateral cy spontaneously abort.11 location of one of the gestational sacs.16 CONTINUED ON PAGE 34

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If two corpora lutea are present on US— Serial beta-hCG levels aren’t helpful or even at laparotomy or laparoscopy—sus- In heterotopic pregnancy, both gestations pro- pect heterotopic pregnancy.7 duce hCG, so the assessment of serial serum quantitative beta-hCG levels is not informative.11 Obstetric imaging should include views of the adnexae Th e adnexa and surrounding structures are When treating ectopic usually not imaged during obstetric US be- pregnancy, hold off on curettage cause the focus is on the intrauterine ges- Ectopic pregnancy and extrauterine gesta- tation.5 In addition, ultrasonographers are tion are life-threatening emergencies that frequently misled by the presence of fl uid in require timely diagnosis and treatment.5,19 the uterus. Th e traditional treatment for ectopic preg- It is important for the ultrasonographer nancy is laparotomy or laparoscopy with re- to examine the entire pelvic region for preg- moval of the ectopic pregnancy, followed by nancy (FIGURE, page 33), especially in wom- dilation and curettage (D&C). Th e curettage en who have been treated with ART or who removes the decidual cast and clots and is have pelvic infl ammatory disease or a his- intended to prevent postoperative bleeding. tory of pelvic surgery.11 Th e adnexae should However, curettage could destroy any intra- be assessed during every obstetric US, es- uterine pregnancy that is not yet diagnosed. pecially in women who are at risk of ectopic Th erefore, D&C should be withheld until the pregnancy.5 uterus is confi rmed to be empty.10

References

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