Ectopic Pregnancy: Risk Factors and Sites of Ectopic Gestation

Ectopic pregnancy is a medical condition in which blastocyst, a 5-6-day-old cystic structure surrounded by embryonic cells, implants outside the uterine cavity accounting for 2% of all pregnancies. This condition is alarming due to the restricted growth opportunities for the embryo and, depending on the location, may lead to a medical emergency. Ectopic pregnancy accounts for 2.7% of pregnancy-related deaths.

To better understand the nature of ectopic pregnancy, let's explore how intrauterine pregnancy happens. Typically, an egg (ovum) encounters sperm in uterine (fallopian) tubes, a pair of tubal organs connecting ovaries with the uterine cavity. Here, generally, a sperm fertilizes the ovum and a zygote forms. After fertilization, the zygote travels via the uterine tube towards the uterine cavity, and eventually, it implants into the uterus by attaching it to its wall. If an embryo faces any obstacle preventing it from reaching the uterine cavity, it will stop in the tubes. Thus, fallopian tubes are the most common site of ectopic pregnancy, accounting for 96% of all ectopic pregnancies.

Risk Factors

Despite advanced diagnosis methods, 50% of women with ectopic pregnancies do not have a history or diagnosis of any known risk factors.

• Previous history of ectopic pregnancy: The history of one and more than one ectopic pregnancy in subsequent pregnancies would increase the risk up to 10% and 25%, respectively.
• Distorted tubal anatomy: The major causes of distorted tubal anatomy are congenital anomalies, infection, surgery, and tumors. Tubal reconstructive surgeries were concerning for ectopic pregnancy risk for a long time. Advancements in surgical settings and correct identification of eligible patients may affect the risk rates. According to the report, the use of microsurgical techniques reduced ectopic pregnancy rates. Moreover, mild tubal pathology is associated with a 1-10% risk of ectopic pregnancy, while severe tubal pathologies may increase this risk up to 20-40%.
• Pelvic inflammatory diseases (PID), including chlamydia, gonorrhea, and nonspecific salpingitis, cause recurrent infections and increase ectopic pregnancy risk. A population-based study reports 2.1 times increased ectopic pregnancy risk in patients with PID.
• Contraceptives and Intrauterine devices (IUD): According to the report by the CHOICE Project, the use of levonorgestrel-containing IUD, copper IUD, implants, oral contraceptives, contraceptive patches, or vaginal rings significantly reduces the risk of ectopic pregnancy compared to no contraception or barrier methods of contraception.
• Endometriosis is an inflammatory condition with the occurrence of uterine inner layer tissue outside of the uterus. It may lead to intra-abdominal scarring and subsequent challenges for fertility. In addition to this, endometriosis increases ectopic pregnancy risk up to 1.6 folds.
• Assisted Reproductive Technology (ART): The use of ART historically was associated with an increased risk of ectopic pregnancy, although rates of ectopic gestations are within ranges of 0.8% - 8.6% [8]. Significant risk factors increasing ectopic pregnancy during ART include excessive ovarian response, prior Cesarean section, and GnRH agonist use. The use of IVF was found to be linked with a higher risk than ISCI. Moreover, fresh embryo transfers show a 65% increased chance of ectopic pregnancy compared to frozen embryo transfers, which could be related to the use of hormonal stimulation.
• Cigarette smoking: Studies investigating human participants' smoking habits concluded that current smoking and smoking history during the lifetime is associated with 1.3 and 1.5 fold increased ectopic pregnancy risk. Later, molecular studies proved that cigarette smoking introduces genetic regulation changes decreasing epithelial cell turnover and ciliogenesis in fallopian tubes, eventually impairing tubal anatomy and motility.
• Maternal Age: Increasing age is linked with several challenges in achieving successful childbirth, such as decreased ovarian reserve and risk for spontaneous abortion. Moreover, abnormal localization of pregnancy is also associated with increased maternal age; women conceived at the age of 21 carry a 1.4% risk of ectopic pregnancy, while this number steadily increases by age and reaches 6.9% by the age of 44.

Extratubal Ectopic Pregnancies

Although fallopian tubes are the most common sites of ectopic implantation, several other locations may also host the pregnancy.

Abdominal pregnancy is defined as a pregnancy in the peritoneal cavity representing approximately 1-1.5% of all pregnancies. Pregnancy could be located primarily in the peritoneal cavity or may grow after tubal rupture or tubal abortion. Given the high vascularization of the peritoneum and abdominal organs, the abdominal cavity may be employed as a nourishing environment for fetal growth. However, this condition increases the risk of intraabdominal bleeding during the placental detachment, leading to 90-fold increased maternal mortality compared to an intrauterine pregnancy. Despite increased perinatal risks, there are reports of successfully terminated abdominal pregnancies in the literature.

The most common implantation location in the abdomen is a pouch of Douglas due to the gravitational force. However, other abdominal organs also may host the pregnancy.

Splenic pregnancy: Spleen is one of the rarest sites of ectopic pregnancy, with only 31 reported cases worldwide. Since the spleen cannot accommodate pregnancy, symptoms, including sudden-onset abdominal or epigastric pain irradiating to the left shoulder, may present earlier than abdominal pregnancies. Hence, no mortality has been reported in association with splenic pregnancies. Treatment of the condition may involve splenectomy or medical treatment using methotrexate.

Hepatic pregnancy is extremely rare yet occurs in less than 1% of ectopic cases. Authors from China report a case of a 23-year-old woman using oral contraceptives and presenting without amenorrhea who was diagnosed with hepatic pregnancy after a misdiagnosis of a liver tumor. Another study from India reports a case of a 25-year-old woman diagnosed with 18-week hepatic pregnancy. Pregnancy was terminated surgically; sadly, the patient did not survive bleeding from the liver surface after surgery.

Ovarian pregnancies are another rare form of ectopic pregnancy with an incidence of 0.5-1% of all ectopic gestations. In addition to traditional risk factors for ectopic pregnancies use of an IUD is associated with a drastic increase in occurrence. Moreover, literature reports the incidence of ovarian pregnancy after ART implementation.

Cervical pregnancies account for less than 1% of ectopic pregnancies with an incidence of 1/1000-1/18,000. Factors increasing the risk are dilation and curettage, history of cesarean section, and assisted reproductive technologies. Missed diagnosis may result in complications leading to hysterectomy and death.

Cesarean Scar pregnancies (CSP) are a consequence of previous cesarean delivery and are defined as the implantation of the embryo into the scar tissue formed after previous surgery. The incidence of CSP is estimated to be 32% and 27.5% in the United States and Canada, respectively, although the actual incidence is unknown. An endogenic type of CSP is observed with pregnancy progression towards the uterine cavity, while the exogenic type grows towards the bladder and abdominal cavity. Thus, the first type may result in a viable pregnancy, although with increased risks, the second type has a higher risk of uterine rupture and bleeding in early pregnancy.

Retroperitoneal pregnancies are one of the rare types of ectopic pregnancies and account for less than 1% of all ectopic pregnancies. In these cases, implantation happens along major vessels, increasing mortality risk up to seven times than other ectopic gestations. Due to the distant location from intra-abdominal organs, symptoms might be negligible or nonspecific, making early diagnosis challenging.

Ectopic Pregnancy after Hysterectomy is an easily overlooked type of ectopic gestation leading to delayed diagnosis and management. A review of 57 reported cases shows that fallopian tubes are the most common implantation site, followed by ovaries. According to the report, pregnancy reached a viable gestational age in three cases, and only one resulted in a live birth.

Heterotopic pregnancy is a co-occurrence of ectopic pregnancy with a normal intrauterine pregnancy. The risk of heterotopic pregnancy is 1/4,000 – 1/30,000 in naturally achieved pregnancies, while the implementation of IVF increases this risk up to 1/100. A unique case of heterotopic pregnancy was recently reported from Ethiopia, reporting a 25-year-old woman who delivered live-born twins; a 3300 g healthy baby from intrauterine pregnancy and a 1600 g baby with growth restriction from ectopic (abdominal) pregnancy.