
HP is very rare in the general population, in everyday clinical practice. In 1948 its incidence was theoretically calculated around 1:30000 deliveries from natural conceptions [11]. The HP rate was estimated 1:27500, 1:7963 and 1:3889 deliveries in 1965 [12], 1983 [11], and 1986 [2], respectively. Over the years HP has been gradually rising; recently, its prevalence has increased up to 1-3% [13,14], due to the emergence of ART such as ovulation induction [2], IVF-ET and the rate of tubal and pelvic inflammatory disease (PID) [3]. The incidence of HP thus strongly depends on the incidence of both EP and multiple pregnancies in a certain population. Accordingly, the HP rate can be calculated from annually published reproductive health reports. In the case of ART, with unreasonable transfer of more than 4 embryos, the risk of HP has been reported as high as 1:45 [9]. When more than 3 embryos are transferred, the odds ratio for HP versus EP increases 10-fold [15].
HP is a very dangerous life threatening mixture and carries a significant mortality and morbidity, similar to that of EP. To a lesser extent, also the development of the IUP is jeopardized. Actually, maternal and fetal prognosis is tightly linked to early diagnosis, preventing unexpected rupture of the ectopic component and avoiding maternal hemorrhage, shock, blood transfusions and miscarriage of the IUP. Very often, the IUP ultrasound visualization and description by the unaware sonographer may produce a false reassurance for the clinician, even in symptomatic women. In such case the missed detection of the ectopic component is the determinant factor for its unexpected rupture. Nevertheless, successful obstetrical outcome of the IUP is still possible even in the case of tubal rupture [28,29]. The most commonly observed signs and symptoms of HP are the following: abdominal pain, adnexal mass, peritoneal irritation and uterine enlargement [3,22]. Symptoms can be also those of IUP or EP or something between them. The clinical findings are therefore unspecific, being common in other normal or abnormal kind of pregnancy. The identification of risk factors such as ART [2] or tubal damage [3], the history of previous EP or the use of intrauterine device are the clue to heighten diagnostic vigilance for an early detection [30].
Simultaneous visualization of both embryos with heart activity is the easiest diagnosis of HP, when the mirror artifact is ruled out [33,34]. This effect can very rarely occur when multiple echo reflections of the product of conception are determined by posteriorly flat anatomical surfaces acting as a mirror (colon distended by gas, psoas muscle). However the gestational sacs and embryos of HP are usually of different size, and also heart rate can appear at a different time minimizing the danger of a misdiagnosis [23,28]. In addition, the “one frame”, simply recognizable pattern of progressive HP is a rare ultrasound finding, which occurs in less than 10% of cases [34]. The most common differential diagnosis for HP is IUP with hemorrhagic corpus luteum and EP with intrauterine pseudo gestational sac [36,37]. Bicornuate uterus with pregnancies in both horns may rarely occur, mimicking HP [38]. Indeed HP in non-communicating horn of bicornuate uterus has also been described [39].
1. inhomogeneous adnexal mass or “blob sign” adjacent to the ovary, that the sonographer can move separately from it or observe spontaneously sliding,
2. empty sac with hyper echoic ring “bagel sign”,
3. sac containing a yolk sac and/or a fetal pole with or without pulsations [43,44]. The implantation of the ectopic component is most commonly tubal though it has also been described as interstitial, cervical, scar pregnancy [45], intramural and cornual. Cornual pregnancies are often diagnosed later than other forms of EP with life-threatening rupture and hemorrhage, due to the rich blood supply derived both from branches of the ovarian and uterine arteries. Therefore scan of adnexa, interstitium, cornua and cervix is recommended whenever pelvic fluid with a “ground glass” appearance (hemoperitoneum) is occasionally found in a first-trimester scan showing a normal IUP.
In spite of the introduction of ultrasound since 1970-1980 and of the increasingly extensive medical knowledge, early diagnosis of HP was not provided for long, and the majority of cases resulted only at laparoscopy or at laparotomy [30]. Most probably, in the first decades of TVU and ART, the presence of an IUP was giving a false sense of security to clinicians disregarding signs or symptoms of the coexistent EP. The French aphorism “think ectopic” was therefore easily forgotten whenever a well-implanted, normal gestational sac was found, despite the presence of acute abdomen in a pregnant woman. Many case reports of early ultrasound diagnosis including our [46] represented an exception rather than the rule. This unexpected low detection rate of TVU is the critical finding in the review article concerning all HPs reported from 1971 to 1993 [47], with only 46 out of 112 (41%) being diagnosed with TVU before surgery. Even the introduction and wide diffusion of TVU in clinical practice from 1994 to 2004 [30] did not produce any diagnostic improvement, as only 21 out of 80 cases (0,26%) of HP were diagnosed before surgery. Most cases were unexpectedly seen at by laparoscopy or laparotomy performed in emergency, mostly because of severe symptoms related to the rupture of the ectopic component. The diagnostic efficiency of ultrasound changed significantly in recent years as reviewed by Talbot., et al. [48], who reports 82 cases of HP 66% of which was conclusively diagnosed by TVU. In a recent huge retrospective series from China [22], the progress of ultrasound diagnosis has been strongly confirmed (Table I). The study includes 16483 women after IVF-ET examined by means of TVU; here 174 cases of HP were correctly diagnosed and only 10 were missed. This study also demonstrates that failure of early TVU diagnosis of HP not only may favor unexpected tubal rupture and severe hemorrhagic complications, but also determine the miscarriage of the IUP.
GA at UD | (1971-93) 112 cases 46 UD |
(1994-2004) 80 cases 21 UD |
(2005-2010) 82 cases 54 UD |
(2005-2011) 132 cases 122 UD |
5-8 weeks |
76% | 86% | 70% | 72% (5-6 weeks) 16% (7-8 weeks) |
9-10 weeks |
11% | 14% | 20% | 4,5 % (> 9 weeks) |
> 11 weeks |
6% | 0% | 10% |
Table 1: Gestational age (GA) at ultrasound diagnosis (UD) of heterotopic pregnancy (HP).
Tal et al. 1996 | Barenetxea et al. 2007 | Talbot et al. 2011 | Li et al. 2013 |
112 cases | 80 cases | 82 cases | 132 cases |
46 UD (41%) | 21 UD (26%) | 54 UD (66%) | 122 UD (92%) |
66 SD (59%) | 59 SD (74%) | 24 SD (29%) | 10 SD (7%) |
Table 2: Diagnostic efficiency of ultrasound diagnosis (UD) of HP [ultrasound versus surgical diagnosis (SD)].
Treatment of HP has a twofold therapeutic goal for the gynecologist. The former is to avoid the risk of life threatening hemorrhage from the EP, and the latter is to allow uneventful development of the IUP until viability. Even after escaping a potentially fatal condition, the good outcome of IUP is a clear expectation for a patient who is only concerned about becoming mother. Due to the rarity and variability of the clinical presentation of HP, no standard guidelines for management options are available, each case being treated according to surgical skill and expertise, side effects, resource availability and individual patient’s preference.
Favorable outcome of intrauterine component has been reported in most studies. Nguyen-Tran and Toy [71] demonstrated that 70% of IUPs in HP can proceed normally with early diagnosis and treatment, confirming a previous study by Han., et al [51] who reported that ART may led to a prognostic improvement in HP versus spontaneously occurring cases. In HP the risk of miscarriage seems to be increased for the intrauterine component [72]. Parallel to the increase of early ultrasound diagnosis, the survival rate for the IUP has been improved with time, rising from the rate of 48-51% reported in early studies [73] to 69% in 2007 [30] and 88% in 2014 [54], respectively. In addition, the risk of low birth weight or preterm delivery is not increased in pregnancies progressing to live birth [72].
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