Episode 22 Ectopic Pregnancy

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Hello, my name is Alison Bryant-Smith. I'm a consultant gynaecologist, currently working at the Northern Hospital in Epping, plus privately at Epworth Richmond. I specialize in advanced laparoscopic gynaecology and really love being involved in teaching.

This MOGCAST episode will cover ectopic pregnancy. I hope you'll learn enough background information, plus key take-home messages, to not only ace any relevant exam questions, but, more importantly, to safely manage any such women in future, be it in the general practice or emergency settings.

Ectopic pregnancy is a really important topic for MOGCAST to cover, as it's relatively common and can be fatal. While ectopic pregnancies account for about 2% of all pregnancies, they account for 15% of all maternal deaths. Ectopic pregnancies are the leading cause of pregnancy-related maternal mortality in the first trimester.

Because ectopic pregnancy is so common and can be fatal, there's a golden rule in gynaecology. Every pregnancy is an ectopic pregnancy until proven otherwise. This is an excellent guiding principle for every emergency clinician. Any woman who has a positive urinary beta-hCG at triage has an ectopic pregnancy until proven otherwise on ultrasound.

An ectopic pregnancy is when an embryo develops at a site other than the uterine cavity. Over 95% of ectopic pregnancies develop in the fallopian tube. From a medical student's perspective, that's really the main type of ectopic pregnancy you need to be aware of, if not the only.

The other 5% consists of pregnancies that implant in other weird and wacky locations, such as outside the ovary, inside the cervical canal, an area called the interstitium, where the fallopian tube penetrates through the muscular layer of the uterus or even in the abdominal cavity. In the interests of brevity, I'm only going to discuss tubal ectopic pregnancies today.

The main mechanism that leads to a tubal ectopic is disrupted fallopian tube anatomy and or function. Let's go back to basics, the process of sperm fertilising egg. Sperm enter the vagina, traverse the cervix, enter the uterine cavity and journey up the fallopian tubes. Sperm can survive in the female reproductive tract for up to 5 days.

Meanwhile, an egg is released from an ovary, picked up by the tubal fimbria, the name for the delicate frond-like structures on the lateral ends of both fallopian tubes, and the egg starts its journey down the tube towards the uterine cavity. This journey is facilitated by cilia, microscopic hairs that line the fallopian tube and waft the egg towards the uterine cavity, rather like a conveyor belt. Contractions of the tubal musculature also propel the egg towards the uterine cavity.

While the egg can be fertilised for up to 24 hours after ovulation, transporting the egg from the ovary to the uterine cavity takes about 30 hours. So, logically, fertilisation, sperm uniting with egg, occurs when the egg is still making its way down the fallopian tube. The single-celled zygote divides over the coming 5-6 days to become a blastocyst. Only then does implantation occur.

Hence, slowing down of the tubal conveyor belt can lead to an ectopic pregnancy. Fertilisation may still occur in the tube, but the transport of the blastocyst is so slow that it's still in the tube 5-6 days after fertilisation. It then implants in the fallopian tube, rather than the uterine cavity, and an ectopic pregnancy results. It's helpful to keep this pathophysiology in mind when thinking about the risk factors for ectopic pregnancy.

We've said that ectopic pregnancies account for about 2% of all pregnancies. As for many other conditions, history tends to repeat. If a woman has had an ectopic pregnancy in the past, her relative risk of another is 5-fold, i.e. a 10% risk of recurrence. This is because the underlying pathology that led to the first ectopic and slowed the tubal conveyor belt is still present.

Factors that can impair the function of the tubal conveyor belt include previous STI or pelvic inflammatory disease, which lead to a 6% risk of an ectopic pregnancy, and tubal surgery, such as tubal reanastomosis performed to reverse tubal ligation, which carries a 20% risk. IVF also carries a 20% risk of ectopic pregnancy. In IVF, fertilisation and blastocyst development occur in a petri dish. After 3-5 days, the blastocyst is inserted back through the cervix in the hope that it implants in the uterine cavity. You can envisage how the blastocyst could overshoot the uterine cavity and end up implanting in one or other fallopian tube.

One curious risk factor for ectopic pregnancy is having a progesterone-containing intrauterine device, or Mirena, in situ. Patients using a Mirena are at a very, very low risk, about 0.1% of conceiving any pregnancy, whether intrauterine or ectopic. However, if a pregnancy does occur in the setting of a Mirena, there's a 50% chance that it will be an ectopic. The mechanism here is that progesterone slows down the wafting action of the tubal cilia, thereby slowing down the tubal conveyor belt.

Overall, comparing a patient with or without a Mirena in situ, the patient without the Mirena has a 2% risk of having an ectopic pregnancy. This compares to 50% of 0.1%, i.e. 0.05% risk for the patient with a Mirena.

Another risk factor for ectopic pregnancy is increasing maternal age. As women age, a higher proportion of their pregnancies will be ectopic rather than intrauterine. For example, there's a 2% risk of ectopic at 25 years old, 4% at 35, and 6% at 40. Higher ectopic rates with increasing maternal age most likely reflects the accumulation of other risk factors with time, such as tubal damage from pelvic infection, the need for IVF, previous ectopic pregnancy, etc.

Having said all of that, 50% of patients with an ectopic pregnancy don't have any recognisable risk factor. Hence, another reason for the golden rule, every pregnancy is ectopic until proven otherwise.

So, at this point, I'll summarise what we've covered so far. An ectopic pregnancy is when an embryo develops at a site other than the uterine cavity. Over 95% of ectopics develop in the fallopian tube, and approximately 2% of all pregnancies are ectopic. However, ectopic pregnancies are over-represented in maternal deaths, as they account for 15% of all maternal deaths.

Risk factors for ectopic include previous ectopic pregnancy, tubal damage due to STI, PID, or previous tubal surgery, IVF conception, progesterone-only contraception, and increasing maternal age. Now that we've set the scene, I'm going to move on to clinical presentation and management.

20% of patients with an ectopic pregnancy are hemodynamically unstable at presentation due to a ruptured ectopic pregnancy. This occurs when an ectopic pregnancy grows so large that it ruptures through the surrounding fallopian tube, causing intra-abdominal hemorrhage. Patients in this situation may present with sudden-onset severe and persistent unilateral pelvic pain. Given the intra-abdominal hemorrhage, they may feel faint and look pale and unwell. They may be hypotensive and tachycardic. Abdominal examination may reveal distension, generalised tenderness, and peritonism with guarding and rigidity. Bimanual examination may reveal unilateral adnexal tenderness on the site of the ectopic pregnancy.

Urinary PAHCG will be positive, and a bedside transabdominal ultrasound in ED may show free fluid in the abdomen, i.e. hemoperitoneum. Management of such patients in ED should include two wide-bore IV cannulae and blood tests, such as full blood count, blood group and cross-match to units of blood, and a serum beta-hCG. Keep the patient fasted, provide IV fluid resus, and contact the on-call gynae reg urgently.

The patient may then need urgent laparoscopy to remove all the blood in her tummy, plus a unilateral salpingectomy, excision of the fallopian tube on the affected side, to control the source of the bleeding.

In contrast, approximately 80% of patients who have an ectopic pregnancy are clinically stable when they present. They may have constant and worsening unilateral pelvic pain.

Abdominal examination may reveal unilateral iliac fossa tenderness. Bimanual examination may reveal unilateral adnexal tenderness. Urine beta-hCG will be positive. A transvaginal ultrasound may reveal an empty uterus and or an extra uterine, i.e. tubal, gestational sac.

Initial investigations for hemodynamically stable patients include full blood count, blood group and antibody screen, and a serum beta-hCG. I'm now going to take a bit of a detour to discuss the role of serum beta-hCG in early pregnancy.

Beta-hCG is produced by the placenta during the first trimester. Levels increase up to 10 weeks gestation, then plateau and decline thereafter. There's a huge range of normal beta-hCG for each week of pregnancy.

Hence, having a result of a one-off serum beta-hCG really only tells you whether or not the patient is or has recently been pregnant. You cannot tell her gestation, i.e. number of weeks of pregnancy, from a single one-off beta-hCG result. For example, a serum beta-hCG result of 100,000 may be at 7 weeks gestation when the beta-hCG is trending sharply upwards, 14 weeks gestation when the beta-hCG is coming back down again, or anywhere in between.

In addition, a one-off serum beta-hCG result doesn't give you any information on whether or not the pregnancy is ongoing or miscarrying, nor whether it is intrauterine or ectopic. What's needed here is the so-called serial beta-hCG. Two serum beta-hCG measurements taken approximately 48 hours apart.

In an ongoing intrauterine pregnancy, the patient's serum beta-hCG level should  “double” every 48 hours. I say double while making air-inverted commas because it's not, strictly speaking, doubling. If the second serum beta-hCG result increases by at least 50% on the previous result, we call it doubling.

So if the serum beta-hCG level increases by 50% from one measurement to the next, taken 48 hours later, the pregnancy is likely to be both intrauterine, i.e. not ectopic, and also ongoing, i.e. not miscarrying. If the beta-hCG trend is plateauing or falling, it's likely that the embryo has stopped growing, i.e. the patient is having a miscarriage. If the beta-hCG trend is slowly rising, i.e. less than a 50% increase from one measurement to the next, or just hovering around, neither convincingly rising or falling, it's highly suggestive of an ectopic pregnancy.

Hence, assessing the trend in patient's serial serum beta-hCG results helps you decide whether the pregnancy is likely to be ongoing or miscarrying and intrauterine or ectopic. So after our detour down the beta-hCG path, let's get back on the main road of ectopic pregnancy management.

Let's imagine we have a clinically stable patient in front of us who's had a tubal ectopic pregnancy diagnosed on transvaginal ultrasound. Broadly speaking, management can be broken down into expectant, medical and surgical. There are various factors to consider when weighing up the benefits and drawbacks of each of these approaches. These factors include whether the patient is hemodynamically stable or unstable, the initial serum beta-hCG level and the trend, the patient's past history and future fertility plans, the patient's preference and ultrasound findings such as the size of the gestational sac and whether or not the embryo has a heartbeat.

Various hospitals and esteemed bodies, such as the specialty colleges in Australia, the UK and the US, have differing guidelines. Protocols differ between different hospitals, so please consult with your local guidelines regarding the management of ectopic pregnancy. Occasionally, patients may be counseled towards or may choose one path of management, such as medical.

If that initial management approach fails, they may then need to try a different approach, such as surgical. Expectant management of tubal ectopic pregnancy essentially involves watchful waiting while monitoring the serum beta-hCG level repeatedly. Expected management is appropriate for patients who are clinically stable, have minimal pain, have a low initial serum beta-hCG, such as less than 1500, but again, check your local guidelines, and the beta-hCG should also be falling.

They also need to have a small gestational sac, i.e. less than three centimetres on ultrasound, without any visible heartbeat. Essentially, such patients have had an embryo implant in the fallopian tube, grow a little bit, and then stop growing, hence the falling serum beta-hCG. The gestational sac will either be resorbed in the fallopian tube or will be expelled out the fimbrial end into the peritoneal cavity and slowly resorbed there.

It's vital that patients who choose expected management are compliant with follow-up. Patients who fit these criteria can be managed as outpatients through the hospital's Early Pregnancy Assessment Service, or EPAS. The local protocol may be something along the lines of doing weekly serum beta-hCG and clinical assessment until the beta-hCG falls down to not-pregnant levels.

Medical management of a tubal ectopic pregnancy is appropriate if the patient is hemodynamically stable and has minimal pain, the serum beta-hCG is less than 5,000, for example, and the gestational sac on ultrasound is less than 3.5 centimetres. There should not be a fetal heartbeat, nor a concurrent viable intrauterine pregnancy. This is a rare condition where a woman has both an intrauterine and a tubal ectopic pregnancy developing at the same time, and it's called a heterotopic pregnancy. Essentially, it's like DCDA twins, but one twin is in the uterus and the other one is in the tube. Patients also need to be compliant with follow-up.

Medical management involves a one-off intramuscular injection of low-dose methotrexate, which is a chemotherapy drug. Methotrexate halts the division of rapidly dividing cells, such as embryos. IM methotrexate is administered on day one and a serum beta-hCG taken. Serum beta-hCG is repeated on day four and day seven.

Medical management is considered successful if there's at least a 15% drop between the day four and the day seven beta-hCG levels. The beta-hCG then needs to be repeated weekly until it's fallen to not-pregnant levels. Because methotrexate is a chemotherapy drug and can hang around in the patient's system for a while, the patient shouldn't conceive for three months.

If time is of the essence, so, for example, a 43-year-old woman who doesn't want to wait three months before undertaking another IVF cycle, the patient may prefer to go down the surgical management path instead.

Surgical management of a tubal ectopic pregnancy is appropriate if the patient is hemodynamically unstable, beta-hCG is over 5,000 international units, there's a fetal heartbeat, and/or if there's a contraindication to expectant or medical management. Surgical management involves keyhole surgery, laparoscopy and excision of the affected fallopian tube. Salpinges referring to the fallopian tube and ectomy means cutting out and removing, so a laparoscopic salpingectomy.

Additional management considerations include if the patient is rhesus negative, whether or not anti-D is needed, generally it is. Given the 10% risk of recurrence in future pregnancies, patients should be advised to have an early ultrasound in future to site the embryo and ensure that it's implanted in the uterine cavity rather than elsewhere.

If the patient's been unlucky enough to have had two or more ectopic pregnancies and bilateral salpingectomies, not having any remaining functioning fallopian tubes, she'll clearly need IVF to conceive in future.

So to summarize, some take-home messages about ectopic pregnancy. An ectopic pregnancy is when an embryo develops at a site other than the uterine cavity. The background population risk of an ectopic is approximately 2% and 95% of these implant in one or other fallopian tube. Risk factors for ectopic include previous ectopic, pelvic infection or tubal surgery, IVF and increasing maternal age. Every pregnancy is an ectopic pregnancy until proven otherwise.

A one-off serum beta-hCG only tells you whether or not the patient is or has recently been pregnant. You can't date a pregnancy from a one-off serum beta-hCG. A single result also can't tell you whether the embryo is intrauterine or ectopic, nor whether the pregnancy is ongoing or miscarrying. Two beta-hCG measurements taken 48 hours apart are much more useful.

Management of tubal ectopic pregnancies can be broadly broken down into expectant, medical and surgical.

Check your local hospital protocol regarding eligibility criteria for each management approach.

And once more, for good luck, say it with me, every pregnancy is an ectopic pregnancy until proven otherwise.

If you'd like more detail regarding the diagnosis and management of ectopic pregnancy, I'd recommend seeking out the guideline from the UK's Royal College of Obstetricians and Gynaecologists, or RCOG. Just google RCOG ectopic and this will bring up their excellent green top guideline.

Hopefully you found this podcast informative. All the best with your women's health rotation and stay tuned for more MOGCAST episodes over the coming months.