Heterotopic pregnancy: Five case reports diagnosed in 2021

For comparative approach of the cases, we aim to resume our cases in tables ( Table 1 , Table 2 , Table 3 , Table 4 ). Fig. A Suspubic and transvaginal pelvic ultrasound showing and heterotopic pregnancy. A1: Intrauterine pregnancy with embryo associated with a heterogenous left uterine adnexal mass without any embryological structures corresponding to hematosalpinx measuring 60 mm. A2: Large hemoperitonum with floating intestines. A3: Sagittal view of the pelvis showing an intra uterine pregnancy and retrouterine heterogenous mass with a large hematoma taking all the Douglas pouch. Pelvic organs floating on the hemoperitoneum. A4: Axial view of the pelvis showing a left hematosalpinx. Fig. A Table 1 Summary of clinical features of the five cases. Table 1 Profile Case 1 Case 2 Case 3 Case 4 Case 5 Age (years) 40 38 36 28 32 Parity 5 2 0 0 3 Pathological medical or surgical history No 2 cesarean sections 2 spontaneous miscarriage Repeated genital infections No Contraception Micro-progestative pills Intra-uterine contraceptive device No No No Smoking exposition No Passive exposition Active exposition Active exposition Passive exposition History of ectopic pregnancy No No No Right ectopic pregnancy 6 months ago treated with methotrexate No Induced or spontaneous pregnancy Spontaneous Spontaneous Citrate clomiphene induced pregnancy Spontaneous Spontaneous Interval between beginning of symptoms and diagnostic (days) 10 23 7 12 15 

 Symptoms at the admission Acute pelvic pain Yes (left iliac fossa) Yes (left iliac fossa) Yes (left iliac fossa) Yes (right iliac fossa) Yes (left iliac fossa) Menstruation's delay (days) 66 60 70 52 72 Hemodynamic perturbations Vascular collapse Vascular collapse Vascular collapse Vascular collapse Vascular collapse Cutaneous-mucosal paleness Yes Yes Yes Yes Yes Peritoneal irritation signs Yes Yes Yes Yes Yes Uterin bleeding No Minimal No Minimal Minimal Table 2 Summary of sonographic (suspubic and transvaginal) and biological features of the five cases. Table 2 Profile Case 1 Case 2 Case 3 Case 4 Case 5 Sonographic parameters Intrauterine pregnancy Active intrauterine pregnancy of 7 weeks and 5 days of gestation according to Crown-rump length (CRL) ( Fig. A ) Active intrauterine pregnancy of 7 weeks and 6 days of gestation according to CRL Active intra uterine pregnancy of 9 weeks of gestation according to CRL ( Fig. B ) Intrauterine gestational sac without any embryological structure according to 5 weeks of gestation. Active intrauterine pregnancy of 9 weeks and 2 days of gestation according to CRL. Ectopic pregnancy Left uterine hematosalpinx measuring 45 mm without any embryo structure ( Fig. A ) Left uterine hematosalpinx measuring 60 mm without any embryo structure Left uterine Ectopic pregnancy with an embryo of 9 weeks according to CRL with heart beating. ( Fig. B ) Right uterine heterogenous adnexal mass measuring 6 cm corresponding to hematosalpinx Left uterine adnexal mass with an ectopic pregnancy of 8 weeks according to CRL. Cardiac activity was presented. Hemoperitoneum Large Large Large Large Large 

 Biological parameters Hemoglobin (g/dl) 6.9 8.1 5.4 5,2 8,7 Platelets (ele/mm 3 ) 308,000 156,000 203,000 120,000 150,000 Hematocrit (%) 20 28 29.1 18 25 Prothrombin level (%) 60 90 79 52 71 Creatinine (g/dl) 4,8 5,6 14 17 12 Table 3 Summary of management features of the five cases. Table 3 Profile Case 1 Case 2 Case 3 Case 4 Case 5 Anesthetic management  Anesthesia mode General ALR General General General  Red blood cells 2 No 3 3 1  Transfusion (unit)  ICU admission No No Yes (1 day) Yes (3 days) No Surgical approach Laparotomy (vascular collapse) Laparotomy (vascular collapse) Laparotomy (vascular collapse) Laparotomy (hemorrhagic choc) Laparotomy (vascular collapse) Intra-operative finding  Hemoperitoneum (ml) 1000 ml 600 ml 1000 ml 1500 ml 700 ml  Localisation of the ectopic pregnancy Ruptured ectopic pregnancy in left ampular fallopian tube ( Fig. D 1) Ruptured ectopic pregnancy in left ampular fallopian tube Abdominal ectopic pregnancy with trophoblastic implantation in the abdominal side of the left ampular fallopian tube an intact gestational sac with embryo floating in intraperitoneal cavity. ( Fig. C ) Ruptured ectopic pregnancy in right isthmic fallopian tube Ruptured ectopic pregnancy in left ampular fallopian tube ( Fig. D 2)  Anatomical conditions of the fallopian tube Damaged Damaged Trophoblastic invasion of the fallopian tube (hemorrhagic dissection) Damaged Damaged  Predisposing anatomical cause No Multiple peritoneal adhesions No Multiple peritoneal adhesions (chlamydia infection sequels). No Treatment Left salpingectomy Left salpingectomy Left salpingectomy Right salpingectomy Left salpingectomy Table 4 Summary of post-operative management and evolution features of the five cases. Table 4 Profile Case 1 Case 2 Case 3 Case 4 Case 5 Post-operative management Vaginal progesterone 800 mg/day Vaginal progesterone 800 mg/day Vaginal progesterone 800 mg/day No vaginal progesterone Systematic vaginal progesterone 800 mg/day (4 weeks) Evolution Normal evolution of the IUP Abortion 1 week later Normal evolution of the IUP Spontaneous miscarriage 2 days later Normal evolution of the IUP. Fig. B Transvaginal (B1) and suspubic (B2) pelvic ultrasound: Heterotopic pregnancy, double gestational sac in the uterus and fallopian tube, with embryo in each one. We can see the hemoperitoneum around the ectopic pregnancy. Fig. B Fig. C Intra operative finding of the heterotopic abdominal pregnancy: the localisation of the ectopic pregnancy in the abdominal side of the fallopian tube with the presence of a gestational sac with embryo floating in the peritoneal cavity (C2). Fig. C Fig. D Intraoperative finding of ectopic pregnancy in the left ampular tube associated with large hemoperitoneum. Fig. D Suspubic and transvaginal pelvic ultrasound showing and heterotopic pregnancy. A1: Intrauterine pregnancy with embryo associated with a heterogenous left uterine adnexal mass without any embryological structures corresponding to hematosalpinx measuring 60 mm. A2: Large hemoperitonum with floating intestines. A3: Sagittal view of the pelvis showing an intra uterine pregnancy and retrouterine heterogenous mass with a large hematoma taking all the Douglas pouch. Pelvic organs floating on the hemoperitoneum. A4: Axial view of the pelvis showing a left hematosalpinx. Summary of clinical features of the five cases. Summary of sonographic (suspubic and transvaginal) and biological features of the five cases. Summary of management features of the five cases. Summary of post-operative management and evolution features of the five cases. Transvaginal (B1) and suspubic (B2) pelvic ultrasound: Heterotopic pregnancy, double gestational sac in the uterus and fallopian tube, with embryo in each one. We can see the hemoperitoneum around the ectopic pregnancy. Intra operative finding of the heterotopic abdominal pregnancy: the localisation of the ectopic pregnancy in the abdominal side of the fallopian tube with the presence of a gestational sac with embryo floating in the peritoneal cavity (C2). Intraoperative finding of ectopic pregnancy in the left ampular tube associated with large hemoperitoneum.

Lamrissi Amine: Corresponding author writing the paper and operating surgeon Antaky Redouane: writing the paper and operating surgeon Mourabbih mariam: writing the paper Jalal Mohamed: study concept Fichtali Karima: study concept Bouhya Said: correction of the paper and operating surgeon.

I declare on my honor that the ethical approval has been exempted by my establishment.

None.

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patients.

Heterotopic pregnancy is a rare form of twin pregnancy, defined by the coexistence of an ectopic and intrauterine pregnancy. It was described for the first time by DUVERNET at 1708 [4] . The frequency was increased with the avenement of assisted reproductive techniques (ART), especially the frequency of use of ovulation inducer. The incidence is estimated at 1/30000 when associated with spontaneous pregnancy, above 1/100 when associated with in vitro fertilization, and 1/900 when using clomiphene citrate [5] , [6] , [7] . In 2021, the frequency of this pathology in our maternity was about 10% of all ectopic pregnancies (52 cases). One of them was induced with clomiphene citrate. The mechanical or functional fallopian tube factors are the same ones for the ectopic pregnancies (endometriosis, peritoneal adhesions, infections, pelvic inflammation…). Multiple embryo transfers in ART techniques are also associated with high risk of heterotopic pregnancies [8] . The diagnosis of heterotopic pregnancy remains one of the greatest challenges of the gynecological emergencies. It is often delayed due to the early visualization of an intrauterine sac, that confused the physician, with late detection of adnexal abnormalities. Also the clinical symptoms are often related to an ongoing abortion. The most common symptoms include abdominal pain, vaginal bleeding, peritoneal irritation and uterine enlargement, making the diagnostic easier [9] , [10] . Otherwise, the symptoms can be misleading when we had isolated abdominal pain associated with intrauterine pregnancy. This situation is very dangerous, and the evolution can be towards to rupture of the ectopic pregnancy or even maternal shock. In our five cases, diagnosis was delayed at minimal 7 days, after symptoms declaration, going to 23 days. All of them was diagnosed at advanced stage with vascular collapse. The diagnostic is based on suprapubic and transvaginal ultrasound by specifying the presence and the vitality of the intrauterine pregnancy and the site of the ectopic pregnancy. Although, the sensitivity of ultrasound can vary from 26.3% to 92.4% [11] . Often, the presence of an intrauterine pregnancy leads to difficulties of interpretation, especially in the youngest pregnancies that can make confusion to inexperimented physician. In 2 cases the adnexal mass was interpreted as an ruptured hemorrhagic cyst. The echographic signs that allow to confirm the diagnosis are the presence of intrauterine gestational sac associated with heterogenous adnexal mass corresponding to hematosalpinx or the visualization of latero-uterine mass surrounded by an echogenic trophoblastic halo, sometimes containing an embryon. The presence of hemoperitoneum supports the diagnostic [12] , [13] . In the above reported clinical cases, both intrauterine and ectopic pregnancies were visualized by ultrasound, 3 with hematosalpinx and 2 with evolutive ectopic pregnancies with embryo outside the uterine cavity. Hemoperitoneum was large in 4 cases. The treatment of heterotopic pregnancies consists of interventing as early as possible on the ectopic pregnancy, respect the intrauterine one, preserve patient fertility, and avoid the recurrence. Laparoscopy should be performed as the first line treatment, especially in case of uncertain diagnosis [14] . It has the advantage of avoiding the risk of uterine manipulation to preserve the intrauterine pregnancy, compared to laparotomy, which can cause uterine irritability and postoperative spontaneous abortion. Urgent Laparotomy is recommended in cases of hemodynamic instability or large hemoperitoneum like in our cases. Manipulation of the uterus should be minimal [15] . Salpingectomy was performed in all our cases because of anatomical damage following the rupture in 4 of them and the deep implantation of the trophoblast in the case of the abdominal pregnancy. For asymptomatic, hemodynamically stable patients and no evolutive ectopic pregnancy, expectant management can be suggested Intra-muscular injection of Methotrexate maybe an alternative only if the intrauterine pregnancy is not progressive [16] . A progestin therapy can be associated to avoid post-operative abortion. A 800 mg of Micronized progesterone was administered to four of our patients with intrauterine active pregnancies. One of them had spontaneous abortion 1 week later versus 3 with evolutive pregnancies. We report a second spontaneous abortion in our series without any hormonal treatment, but the evolution of the pregnancy was uncertain. The prognosis of the Heterotopic pregnancy depends on the early diagnoses and treatment [17] . Precisely treated, 30 to 75% of intrauterine pregnancies progress to term [18] . The complications are the result of late diagnosis, they are often hemorrhagic. In our cases, all of our patients had a severe anemia, 4 of them was transfused with red cell blood, 2 had elevated creatinine level and was admitted in intensive care unit. Take away points: 1- The exam of adnexa must be systematic in the first sonographic exam for pregnancy in all patients. 2- Detailed history and physical examination are importance to explore all risk factors related to heterotopic pregnancy 3- The presence of intra uterine pregnancy doesn't make optional the exam of adnex, especially if the patient reports symptoms or ectopic pregnancy risk factors. 4- The delayed diagnoses limit the possibility of conservative treatment and can be responsible of secondary infertility. The exam of adnexa must be systematic in the first sonographic exam for pregnancy in all patients. Detailed history and physical examination are importance to explore all risk factors related to heterotopic pregnancy The presence of intra uterine pregnancy doesn't make optional the exam of adnex, especially if the patient reports symptoms or ectopic pregnancy risk factors. The delayed diagnoses limit the possibility of conservative treatment and can be responsible of secondary infertility.

Dr. Lamrissi Amine.

The frequency of heterotopic pregnancy has increased in recent years, with the emergence of medically assisted procreation. The diagnosis is often difficult. The presence of any symptoms or ectopic pregnancies risk factors, associated with intrauterine pregnancy must lead the physician to miniciously screen of the adnexa to research any abnormalities. The standard treatment is conservative surgery, preferably by laparoscopy. However, treatment by laparotomy is not uncommon. Through these case reports, we brought to light the importance correlation of the clinical symptoms, and all risk factors in order to make the diagnosis as early as possible.

Heterotopic pregnancy (HP) is the occurrence of an intrafallopian pregnancy and an ectopic pregnancy (EP) simultaneously, whatever its location [1] . The most common ectopic pregnancies are located in the fallopian tubes. Abdominal location increases the risk of maternal mortality up to 90 times higher than a normal IUP [2] . The diagnosis of a heterotopic pregnancy is still underdiagnosed and difficult. The presence of the intrauterine pregnancy at the sonographic exam can make confusion to the physician. The main treatment consists of removing the ectopic pregnancy, while preserving the IUP, that make the second challenge after diagnoses. We report 5 cases of heterotopic pregnancy, diagnosed all of them in our maternity service, hospital mother and child Abderrahim Harrouchi, university hospital of Casablanca between January and December 2021. All of them were complicated by a large hemoperitoneum with vascular collapse. This pathology constitutes in this year 10% of all ectopic pregnancies (52 cases). Those cases reports have been reported in line with the SCARE 2020 criteria [3] .

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The authors declare having no conflicts of interest for this article.