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Ectopic Pregnancy

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Incidence Rates

Diagnosis

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Diagnosis Of Ectopic Pregnancy

Case: 24 year old G2 P1 with a history of regular menstrual intervals every 28-30 x 3-4 days, a last menstrual period (LMP) starting on February 1, a positive urine pregnancy test on March 4, normally rising serial serum hCG titers (300 IU/L on March 5 and 596 IU/L on March 7), and a transvaginal ultrasound exam on March 15 that could not identify an intrauterine pregnancy (uterus with a normal outer contour and a 10mm endometrial stripe with no identified gestational sac, normal appearing ovaries with an apparent corpus luteum cyst on the left ovary, normal adnexal appearance and no free fluid in the pelvis).

Question: Could a normal intrauterine pregnancy be present? What are the possible diagnoses?

Answer: Establishing the (gestational) age of this pregnancy is very important.

Ovulation usually occurs about 14 days prior to the next menstrual flow since the luteal phase of the menstrual cycle (from ovulation until the onset of menses) is normally 11-14 days in length. Given the history of regular menstrual intervals every 28 days, ovulation probably occurred in this situation around February 14.

The hCG titer is normally about 100 IU/L at the time of a "missed menses" (4 weeks gestational age) and rises by at least 67% (often doubles) every other day in early pregnancy. In this case, the hCG titer was 300 IU/L on March 5 (5 days after the missed menses) which is consistent with a level of 100 IU/L on the day of the missed menses (with a normal rate of rise) and this concentration also increased normally between March 5 and March 7. These results are all consistent with a date of ovulation of February 14.

Therefore, there is strong evidence that the gestational age of this pregnancy is (at least) 4 weeks on March 1, 5 weeks on March 8, and 6 weeks on March 15.

Establishing that this pregnancy is growing normally (given its gestational age) is very important.

Very early evidence suggesting a healthy pregnancy is the history of normally rising hCG titers. If the hCG titers decrease, this is an ominous sign suggesting an unhealthy pregnancy. If the hCG titers plateau at a certain level (during the initial 7-8 weeks of gestation), this suggests either an unhealthy intrauterine pregnancy or an ectopic pregnancy. If the hCG titers are rising normally, this is encouraging but is not able to (does not) define the pregnancy as healthy.

Ultrasonography has revolutionized our ability to evaluate early pregnancy. High resolution transvaginal ultrasound probes can be used to reliably identify an intrauterine gestational (pregnancy) sac just after 5 weeks gestation (3 weeks after ovulation and fertilization of the egg) or when the hCG titer is about 1,500 IU/L. (NOTE: these conditions may be somewhat dependent on the local medical radiologic facilities or type of hCG assay that is used, so the local "discriminatory values" of hCG at which a gestational sac is reliably seen should be determined). Transvaginal ultrasound is usually able to identify the fetal heart tone (heart beat) at about 6 weeks gestation or by the time that the hCG titer is around 20,000 IU/L. Abdominal ultrasound probes have lower resolution for structures within the uterus (since resolution is inversely related to the distance of the viewed object from the probe) yet are still able to reliably identify an intrauterine gestational sac at an hCG titer of about 6,500 IU/L.

If gestational dates are well established, absence of a gestational sac at 6 weeks gestation or absence of a fetal heart beat at 7 weeks gestation is very discouraging in terms of the possibility of a normal intrauterine pregnancy.

Ectopic pregnancies are very difficult to reliably identify on gynecologic examination or ultrasound examination. Occasionally, a fetal heart tone outside the body of the uterus will be identified by ultrasonography and will thereby define the existence of an ectopic pregnancy. More often, ectopic pregnancies are suggested by increasing (or a plateau in) serial hCG titers, absence of a visible intrauterine pregnancy (gestational sac) on ultrasound exam when this structure should be seen (by gestational age or hCG titers), and/or a history of pelvic pain during (usually the first trimester of) pregnancy.

In this (presented) case, there was no evidence suggesting an abnormal pregnancy until the transvaginal ultrasound was performed. At 6 weeks gestation with good dates (a well established time for ovulation), an intrauterine gestational sac should be reliably identified if a normal intrauterine pregnancy is present.

The possible causes for an ultrasound at 6 weeks gestation to reveal an "empty uterus" (the absence of an identifiable intrauterine gestational sac) include a technically difficult ultrasound exam (repeating the exam at a different institution may be suggested), an abnormally growing intrauterine pregnancy (with a collapsed sac), or an ectopic pregnancy.

In the absence of pelvic pain, clinical instability (hemodynamic status should always be assured if there is the consideration of an ectopic pregnancy) or vaginal bleeding, further (timely) evaluation is appropriate. I would suggest repeating a hCG titer (ideally on at least 2 different occasions about 24 hours apart) to determine whether the concentration is continuing to rise or is now falling, repeating the ultrasound examination at a different institution if there is any question about the quality of the initial exam, and discussing the available treatment options for either an abnormal intrauterine pregnancy or an ectopic pregnancy with the couple (so that they are emotionally prepared to deal with this unfortunate situation).

The half life of hCG is about 1-2 days, so that if there is no active hCG production then the serum hCG concentration should decrease to about half (of the current level) every 1-2 days. If the concentration is decreasing at a slower rate, this suggests active hCG production from remaining (growing) pregnancy cells.

If the patient has a hCG titer that is falling at a normal rate (suggesting no active hCG production), is clinically stable and is painfree, then the hCG titers can often be followed until negative (without active management). It is very important to follow the hCG titers all the way to negative since some of the remaining trophoblast (placental) cells may be able to (re)implant and grow, in which case the hCG titers will begin to increase.

If nonactive management is chosen, strict ectopic precautions must be observed (the woman should always be in the immediate presence of an adult who can provide or call for help if needed, have transportation and ready access to a medical center as needed, and know to call for instructions or help if pain or other evidence of problems develop).

The physician should consider active (typically surgical) management for a possible ectopic pregnancy if any of these conditions for expectant management change (while following the serum hCG titers to negative), the woman (or couple) desires a more aggressive or a more definitive approach, or the woman is noncompliant with her medical care. Once active surgical management is elected, a D+C (dilitation and curettage of the uterine cavity) is usually performed initially and if no placental tissue is identified then a laparoscopy (or laparotomy) is immediately performed to assess the possibility of (impending rupture of) an ectopic pregnancy.

Always maintaining a high level of suspicion for an ectopic pregnancy is important.




Case: 24 year old G2 P1 with a history of regular menstrual intervals every 28-30 x 3-4 days, a last menstrual period (LMP) starting on February 1, a positive urine pregnancy test on March 4, normally rising serial serum hCG titers (300 IU/L on March 5 and 596 IU/L on March 7), and a transvaginal ultrasound exam on March 15 that could not identify an intrauterine pregnancy (uterus with a normal outer contour and a 10mm endometrial stripe with no identified gestational sac, normal appearing ovaries with an apparent corpus luteum cyst on the left ovary, normal adnexal appearance and no free fluid in the pelvis).

(Scenario #2) A repeat hCG titer was immediately ordered by the physician, and was found to be 13,000 IU/L on March 15. The patient remains pain free without vaginal bleeding.

Question: What are the possible diagnoses? What treatment plan should be discussed and considered?

Answer: Establishing the (gestational) age of this pregnancy is also very important.

As presented in the initial case discussion of this patient, there is strong evidence that the gestational age of this pregnancy is (at least) 4 weeks on March 1, 5 weeks on March 8, and 6 weeks on March 15.

Establishing that this pregnancy is growing normally (given its gestational age) is very important.

hCG titers generally increase by at least 66% every 2 days in a normal pregnancy (during early pregnancy). The value of 13,000 IU/L at 6 weeks gestation is consistent with a normal intrauterine pregnancy.

Transvaginal ultrasound generally is able to identify an intrauterine gestational sac at 5-6 weeks gestation and/or a hCG concentration of 1,500 to 2,000 IU/L. In this case, the ultrasound exam did not identify a gestational sac when the gestational age was 6 weeks and the hCG titer was 13,000 IU/L.

The possibilities include an abnormal intrauterine pregnancy with a collapsed sac or an ectopic pregnancy. If a miscarriage (spontaneous abortion of an intrauterine pregnancy) was in progress one would generally expect some vaginal bleeding or crampy midline pelvic discomfort.

In this case, there is no evidence of an intrauterine pregnancy, ectopic pregnancies are potentially lethal if they rupture (due to massive intraabdominal bleeding), treatment alternatives are greatest for ectopic pregnancy when the ectopic pregnancy is identified early, and ectopic pregnancies often escape diagnosis with either hCG titers or ultrasonography. Therefore, I would suggest proceeding to active management immediately.

If active management cannot be emotionally or otherwise immediately accepted by the couple, then a second hCG titer on March 16 (the next day) would be obtained. If the hCG titer was not decreasing rapidly (consistent with a half life of 1-2 days) then active management would be very strongly recommended to rule out the possibility of an ectopic pregnancy (especially an ectopic pregnancy that is about to rupture).

Active management options include medical treatment (methotrexate) and surgical treatment (generally D+C followed by laparoscopy -- if no products of conception are identified during evacuation of the uterine cavity).

Methotrexate treatment is slow (takes up to 6 weeks for complete resolution) and this treatment option requires a highly compliant patient who is clinically stable and (generally) healthy. Relative contraindications include identification a fetal heart beat (on ultrasound) outside of the uterus (within an ectopic pregnancy), an hCG titer over 10,000 IU/L, or an ectopic pregnancy known to be over 4cm in diameter. In this situation the hCG titer is over 10,000 IU/L, so this treatment option would be discouraged.

Surgery involves evacuating the uterine cavity with a dilitation and curettage (D+C). If the products of conception are not positively identified, then exploration of the abdomen and pelvis to rule out the impending rupture of an ectopic pregnancy is desirable.




Case: 24 year old G2 P1 with a history of regular menstrual intervals every 28-30 x 3-4 days, a last menstrual period (LMP) starting on February 1, a positive urine pregnancy test on March 4, normally rising serial serum hCG titers (300 IU/L on March 5 and 596 IU/L on March 7), and a transvaginal ultrasound exam on March 15 that could not identify an intrauterine pregnancy (uterus with a normal outer contour and a 10mm endometrial stripe with no identified gestational sac, normal appearing ovaries with an apparent corpus luteum cyst on the left ovary, normal adnexal appearance and no free fluid in the pelvis).

(Scenario #3) A repeat hCG titer was immediately ordered by the physician, and was found to be 13,000 IU/L on March 15.

The patient remained pain free, without vaginal bleeding, and she refused active management until a second hCG titer was obtained. On March 16 the hCG titer was found to be 14,500 IU/L.

Question: What treatment plan should be discussed and considered?

Answer: Establishing the (gestational) age of this pregnancy is very important.

As presented in the initial case discussion of this patient, there is strong evidence that the gestational age of this pregnancy is (at least) 4 weeks on March 1, 5 weeks on March 8, and 6 weeks on March 15.

Establishing that this pregnancy is growing normally (given its gestational age) is very important.

hCG titers generally increase by at least 66% every 2 days in a normal pregnancy (during early pregnancy). In this case, the hCG titer rose from 13,000 IU/L to 14,500 IU/L in one day. This rate of rise is stunted (slow).

The most important variables at this point seem to be an ultrasound, which did not identify an intrauterine gestational sac at 6 weeks gestation (with good dates) or an hCG titer in excess of 2,000 IU/L, no evidence of a spontaneous pregnancy loss, and increasing hCG titers (suggesting the presence of actively growing placental tissue).

I would strongly suggest immediate active management for a possible ectopic pregnancy given that the likelihood of an ectopic pregnancy is high and ectopic pregnancies are very dangerous. Surgical management would be recommended given the hCG values in excess of 10,000 IU/L.

If this couple could not decide on active management given this information, I would suggest a second opinion with another gynecologist or reproductive endocrinologist. Hopefully, hearing a similar recommendation from another source (physician) would allow the couple to choose one of the medically appropriate treatment alternatives.




Case: 24 year old G2 P1 with a history of regular menstrual intervals every 28-30 x 3-4 days, a last menstrual period (LMP) starting on February 1, a positive urine pregnancy test on March 4, normally rising serial serum hCG titers (300 IU/L on March 5 and 596 IU/L on March 7), and a transvaginal ultrasound exam on March 15 that could not identify an intrauterine pregnancy (uterus with a normal outer contour and a 10mm endometrial stripe with no identified gestational sac, normal appearing ovaries with an apparent corpus luteum cyst on the left ovary, normal adnexal appearance and no free fluid in the pelvis).

(Scenario #4) A repeat hCG titer was immediately ordered by the physician, and was found to be 13,000 IU/L on March 15.

The patient began to have intermittent mildly painful midline crampy pains and abundant vaginal bleeding. No "tissue" like material was identified within the blood and blood clots that were passed. A D+C was discussed but it was refused by the couple.

A repeat ultrasound on March 15 following the onset of pain demonstrated an absence of free fluid (possibly blood) within the pelvis. On March 16, the patientís pain and bleeding subsided and the hCG titer was 7,000 IU/L.

Question: What treatment plan should be discussed and considered?

Answer: If there is no active production of hCG, then the half life within the circulation is about 1-2 days. In this case, the hCG concentration decreased significantly from 13,000 IU/L to 7,000 IU/L in one day. This is consistent with a spontaneous abortion.

This patient could reasonably consider conservative management (as long as it is not contraindicated by a change in clinical status) or active management (to bring closure to this unfortunate situation).

If conservative management is desired, the couple should determine the hCG titer every 1-2 days until the rate of decline is well established, and then the hCG titer should be followed until negative. If the patient develops pelvic pain or becomes hemodynamically unstable at any point during the resolution of this pregnancy, then active management should be immediately reconsidered.

Of note, I had a patient in a similar situation that desired conservative management and was followed carefully until her hCG titers were negative. This patient then developed pelvic pain 2-3 days after the hCG titer initially became negative. My ultrasound evaluation at that point (when the hCG titer was actually negative) identified free fluid (possibly blood) in the pelvis. An immediate laparoscopy was performed and this confirmed a ruptured ectopic pregnancy with active bleeding from the fallopian tube. The ectopic pregnancy was large (about 3cm diameter) and was apparently adherent to the fallopian tube (adjacent to or connected to a fairly large blood vessel) even after it stopped producing hCG (after it was no longer alive). This ectopic pregnancy then apparently disconnected from the tube and fell into the lower pelvis (cul de sac behind the uterus) at which time the vessel within the tube began to bleed.

A high suspicion for an ectopic pregnancy is always prudent given its potential for danger




Case: 28 year old G1 P0 with a history of regular menstrual intervals every 30 x 4 days, a last menstrual period (LMP) starting on March 1, a positive urine pregnancy test on April 5, normally rising serial serum hCG titers (280 IU/L on April 5 and 567 IU/L on April 7), and a transvaginal ultrasound exam on April 15 that could not identify an intrauterine pregnancy (uterus with a normal outer contour and a 12 mm endometrial stripe with no identifiable gestational sac, normal appearing ovaries and no free fluid in the pelvis).

A repeat hCG titer on April 15 was 700 IU/L.

Question: What is the meaning of the hCG titer of 700 IU/L on April 15?

Answer: The hCG titers normally increase in early pregnancy by at least 67% (usually double) every other day. Since the hCG concentration was 567 IU/L on April 7, the concentration would be expected to be about 9,000-10,000 IU/L on April 15. An hCG concentration of 700 IU/L is an abnormal rate of rise from the prior values for this patient.

When I get an abnormal or unexpected lab result, I usually repeat it. Therefore, I would order another hCG titer to assure that the value of 700 IU/L is accurate.

If the repeat hCG titer confirms an abnormal rate of increase from the prior values on April 5 and April 7, the patient is clinically stable, and she has no pelvic pain, then I would obtain another hCG titer 1-2 days later to determine whether the levels are hovering around a plateau (eg., 600-800 IU/L) or decreasing.

In the event that the hCG titers are decreasing with a half life of about 1-2 days, I would follow the levels to negative as long as the woman remains clinically stable and pain free.

If the hCG concentrations are maintained at a plateau, this suggests active production by growing pregnancy cells and if persistent then I would suggest active management for a possible ectopic pregnancy.




Case: 27 year old G1 P0 with a history of very irregular menstrual intervals every 24-90 x 3-7 days, a last menstrual period (LMP) starting on February 1, a positive urine pregnancy test on April 15, and a transvaginal ultrasound exam also on April 15 that could not identify an intrauterine pregnancy (uterus with a normal outer contour and a 13 mm endometrial stripe with no identifiable gestational sac, normal appearing ovaries and no free fluid in the pelvis).

Question: Could this woman have a normal intrauterine pregnancy? What are the potential diagnoses?

Answer: Establishing the age of the pregnancy (the gestational age) is critically important in order to interpret this situation. This is because the clinical landmarks for normal development of a pregnancy are predominantly based on the gestational age of the pregnancy.

This woman has a history of highly irregular menstrual intervals roughly every 1-3 months. Therefore, the value of her LMP in terms of predicting when ovulation occurred is reduced. This is because the time that it takes for a woman to make and release a mature egg (ovulate) is (potentially) highly variable while the duration of the luteal phase (from ovulation to the onset of the next menses) is generally fixed at about 2 weeks (even with irregular cycles).

Since we cannot determine the time of ovulation using the LMP, we need to look for additional information in the history. The urine hCG (pregnancy) test was positive on April 15, often turns positive about 3-4 days prior to a missed menses (the urine pregnancy tests currently available in the USA are sensitive to about 20-30 IU/L of hCG, which normally is present during a pregnancy about 10-11 days after ovulation), and confirms that she is at least 3.5 weeks gestation (pregnant) when positive (April 15).

If a woman were 3.5-4 weeks gestation at the time of a transvaginal ultrasound, then one would not expect to identify a gestational sac even in the presence of a normal intrauterine pregnancy.

In the absence of pain or a deterioration of clinical status, I would suggest serial hCG titers (one immediately and another one 2 days later). If these hCG titers are rising appropriately and the patient remains symptom free then I would recheck an ultrasound when the titers are expected to reach about 20,000 IU/L (to identify the presence of a fetal heart beat). A repeat ultrasound would also be suggested earlier than at 20,000 IU/L if and whenever the patient develops worrisome symptoms that might suggest an ectopic pregnancy.

In the absence of pain or a deterioration of clinical status, when the serial hCG titers are rising but at an abnormal rate then I usually will repeat the hCG titers until the clinical situation becomes clearer. Throughout this time period, a high level of suspicion for an ectopic pregnancy is maintained. If (or when) the hCG titers become greater than 1,500 IU/L then a transvaginal ultrasound examination is suggested to reveal the presence of an intrauterine gestational sac (and rule out an ectopic pregnancy- with the understanding that heterotopic pregnancy rates are generally rare).

If the hCG titers are rising or plateauíd at a concentration that is greater than 1,500 IU/L a transvaginal ultrasound examination is suggested. If the ultrasound is unable to identify an intrauterine gestational sac, then I would suggest active management for a possible ectopic pregnancy. An initial D+C (dilatation and curettage) to evacuate the uterine cavity will sometimes identify the products of conception (pregnancy related tissue) and if the products of conception are not identified then an immediate laparoscopy to rule out (and treat) an ectopic pregnancy should be considered.

In the absence of pain or a deterioration of clinical status, when the serial hCG titers are falling at a normal rate of decline then I usually will follow these values until they are negative. If the serial hCG titers are falling slowly (the half life is greater than the normal 1-2 days), actively growing pregnancy cells are most likely present and the woman must be followed closely. Active management for an ectopic pregnancy should be discussed with the couple and strict ectopic pregnancy precautions observed.




Case: 27 year old G1 P0 with a history of regular "monthly" menstrual intervals x 3-5 days, an uncertain last menstrual period (LMP) thought to have started "a month or two" ago, a positive urine pregnancy test on April 15, and a transvaginal ultrasound exam also on April 15 that could not identify an intrauterine pregnancy (uterus with a normal outer contour and a 10mm endometrial stripe with no identified gestational sac, normal appearing ovaries with an apparent corpus luteum cyst on the left ovary, normal adnexal appearance and no free fluid in the pelvis).

Question: Could this woman have a normal intrauterine pregnancy? What are the potential diagnoses?

Answer: Establishing the age of the pregnancy (the gestational age) is critically important. The clinical landmarks for normal development of a pregnancy are (predominantly) based on the gestational age of the pregnancy.

In this case, the date of the LMP is uncertain.

Since we cannot use the LMP to help determine the time of ovulation, we need to consider other information in the patientís history. The urine hCG (pregnancy) test is positive on April 15 to confirm that she is at least 3.5 weeks gestation (pregnant) at that time. Urine pregnancy tests currently available in the USA often turn positive about 3-4 days prior to a missed menses since these urine pregnancy tests are sensitive to about 20-30 IU/L of hCG (which is present during a normal pregnancy about 10-11 days after ovulation).

If the woman is only 3.5-4 weeks gestation at the time of a transvaginal ultrasound, then one would not expect to identify a gestational sac even in the presence of a normal intrauterine pregnancy.

In the absence of pain or a deterioration of clinical status, I would suggest serial hCG titers (one immediately and another one 2 days later). If the initial hCG titer is less than 1500-2000 IU/L (the local discriminatory concentration above which an intrauterine gestational sac should reliably be seen on transvaginal ultrasonography), the serial hCG titers are rising appropriately, and the patient remains symptom free then I would recheck an ultrasound when the titers are expected to reach about 20,000 IU/L (to identify the presence of a fetal heart beat).

Any deviation from the expected clinical course of a normally developing intrauterine pregnancy would trigger a clinical evaluation and possibly active management for a possible ectopic pregnancy.




Case: 28 year old G1 P0 with a history of regular menstrual intervals every 30 x 5-6 days, a LMP of April 1, a positive urine pregnancy test on May 3, calls her physician on May 10 with a 1 day history of vaginal spotting (to light flow). History is significant for surgical removal of a ruptured appendix at 7 years of age.

Question: What clinical evaluation should be done at this time?

Answer: Vaginal bleeding in early pregnancy is not normal (or desirable) but it is relatively common, occurring in about 40% of all (clinically detected) pregnancies. When an otherwise asymptomatic (symptom free) pregnant woman advises me that she is having some vaginal bleeding in the 1st trimester of pregnancy, I recommend an evaluation of the patient.

My initial evaluation includes an assessment of gestational age. This womanís history (LMP of April 1, regular menstrual intervals, positive urine pregnancy test on May 3) suggests that she is at least 5-6 weeks gestation on May 10. At this gestational age, an intrauterine gestational sac can usually be identified (to rule out an ectopic pregnancy) with a transvaginal ultrasound machine if either pelvic pain develops or there is an increased suspicion of an ectopic pregnancy. Also at this gestational age, one would usually find an hCG titer that is greater than 2,500 IU/L.

My initial evaluation also includes a physical examination. A bimanual pelvic exam will be able to determine whether the uterine cervix (mouth of the uterus that projects into the vaginal vault) is dilating (opening at the internal os). The internal os of the cervix should be closed during early pregnancy. If there is uterine (vaginal) bleeding and a closed cervical os then this is called a "threatened abortion" whereas if the (internal) cervical os is open this is called an "inevitable abortion." The physical examination also provides the physician with information about the general clinical appearance of the woman (vital signs, overall comfort level, presence and severity of abdominal pain).

In a clinically stable patient who is pain free and has a closed internal cervical os, I follow serial (usually 2-3) hCG titers to determine whether they are increasing at a normal rate. If the hCG titers are rising normally, I suggest a transvaginal ultrasound examination at 6 weeks gestation or an hCG titer in excess of 20,000 IU/L in order to identify a fetal heart beat. The ability of the pregnancy to develop an active fetal heart is very encouraging.

If a threatened abortion is diagnosed, I suggest decreased activity (or bedrest) and increased fluid intake (hydration) since a threatened abortion can (uncommonly) be due to uterine irritability associated with overactivity or dehydration. Most cases of spontaneous abortion (miscarriage) are due to chromosomal accidents that occurred around the time of fertilization (of the egg) and are not able to be effectively treated in order to prevent the pregnancy loss. Most cases of threatened abortion that will go on to an otherwise normal pregnancy and delivery will do so despite decreased activity or increased hydration. However, a group of women with a threatened abortion may have a (slightly) better chance of developing a normal pregnancy and undergoing delivery at term if they reduce uterine irritability with decreased activity and increased hydration.

In a clinically stable patient with an open internal cervical os, I review the fact that a miscarriage ("spontaneous abortion") is likely. I also review the possibility of an incompetent cervix, which tends to open "painlessly" due to a cervical abnormality (the relative concentration of tougher fibroconnective tissue that composes the cervix is less than normal and this allows the cervix to open without painful uterine contractions). If there are no midline cramps associated with the bleeding and open cervix (and an otherwise normally growing pregnancy), then I suggest a perinatology (high risk pregnancy) consultation to assess the utility of placing a cerclage (suture to close the cervix). If there have been painful contractions and there is a strong desire to carry the pregnancy, then I encourage a conservative approach and suggest decreased activity and increased fluid intake (to decrease uterine irritability).




Case: 33 year old G1 P0 with a history of regular menstrual intervals every 30 x 3-4 days, a LMP of February 1, a positive urine pregnancy test on March 3, calls her physician on March 10 with a 2 day history of persistent left greater than right lower abdominal pain that is moderate in intensity. History is significant for surgical removal of a ruptured appendix at 7 years of age.

Question: What tests are clinically appropriate for this woman?

Answer: The history of regular monthly menstrual flow, a LMP of February 1, and a positive pregnancy test on March 3 strongly suggest that the pregnancy is at least 5-6 weeks gestation on March 10.

The serum hCG titer is usually about 100 IU/L at 4 weeks and it approximately doubles every other day in early pregnancy, such that one would expect a hCG titer of about 2000-3000 IU/L on March 10 (in this situation).

The transvaginal ultrasound can generally detect an intrauterine gestational sac at about 5 weeks gestation or a hCG titer in excess of 1,500 IU/L.

In this situation, I would normally see the woman in my office (as an emergency on the day of the telephone call given the history of pain) to assess her general clinical status (stability) and the amount of pain that she is experiencing. I would obtain a transvaginal ultrasound examination of the pelvis to determine whether an intrauterine gestational sac can be identified and to assess the pelvis for abnormality (such as free fluid in the cul de sac, which may represent blood and a ruptured ectopic pregnancy). I would also obtain a hCG titer to see whether it is within the expected range for a normal pregnancy of this gestational age.

If an intrauterine gestational sac is confirmed on ultrasound examination, then this is very reassuring. The chance of a heterotopic pregnancy (one pregnancy in the uterus and another pregnancy in an ectopic location) is unlikely. In natural cycles (during which no fertility medications were administered), the chance of a heterotopic pregnancy is usually thought to be about 1 in 30,000. This possibility is significantly more likely if FSH containing fertility medications were used during the menstrual cycle in which the pregnancy occurred.

When an intrauterine pregnancy is diagnosed, the cause of the pelvic pain often remains uncertain but (thankfully) generally subsides relatively quickly (within a few days). In situations where the pain subsides and the pregnancy continues to develop normally, the pregnancy is not known to be at increased risk for other problems.

If the woman is not clinically (hemodynamically) stable then she will require aggressive clinical management and possibly surgery (for further assessment) despite the presence of an intrauterine pregnancy.

A spontaneous pregnancy loss (in progress) is a possible cause of pain, and may be suggested if the pain is intermittent, crampy and concurrently associated with vaginal bleeding. If the woman is thought to possibly have a "threatened abortion" then I suggest decreased activity (or bedrest if desired) and increased fluid intake (hydration). This is because overactivity and dehydration can be associated with uterine irritability and by avoiding these conditions one may improve some pregnancy outcomes (will occasionally prevent a miscarriage).

If an intrauterine pregnancy cannot be confirmed, then the womanís clinical status, amount of pain, and hCG titers are generally used to decide on a management plan.

The history of a ruptured appendix does significantly increase this womanís risk for an ectopic pregnancy. As always, maintaining a high level of suspicion for an ectopic pregnancy is very important.




Case: 23 year old G1 P0 with a history of regular menstrual intervals every 29-31 x 5-6 days, a LMP of January 1, a positive urine pregnancy test on February 3, calls her physician on March 10 with a 2 day history of persistent left greater than right lower abdominal pain that is moderate in intensity. History is significant for surgical removal of an ovarian cyst at 19 years of age.

Initial evaluation includes a transvaginal ultrasound examination, a hCG titer, and a physical examination.

Question: Should a serum progesterone concentration be performed during the initial clinical evaluation to help distinguish an ectopic or an abnormal intrauterine pregnancy from a normal intrauterine pregnancy?

Answer: Progesterone is often followed in early pregnancy and may suggest an abnormal pregnancy if the concentration is below a specific level. However, there is a great deal of overlap between the progesterone concentration of a "normal intrauterine pregnancy" and the progesterone concentration of an abnormal pregnancy (an abnormal intrauterine or an ectopic pregnancy). Therefore, progesterone concentrations that are obtained must be interpreted within the total clinical context.

A progesterone concentration of greater than 25 ng/mL has a 95% correlation with a normal intrauterine pregnancy. A progesterone concentration of less than 5 ng/mL has a greater than 98% correlation with an abnormal pregnancy. Most progesterone concentrations are between 10 and 20 ng/mL which have little value in distinguishing a normal from an abnormal pregnancy.

Of note, there are examples of pregnancies with very low progesterone concentrations that have continued on to full term, labor and delivery. Therefore, a very low progesterone concentration should not be used as the sole basis for a change in the clinical management that is recommended.

I do not tend to order progesterone concentrations in pregnancy, but do recognize their potential clinical value. In highly selected situations, I do order the test.




Case: 36 year old G1 P0 with a history of regular menstrual intervals every 30 x 5-6 days, a LMP of September 1, a positive urine pregnancy test on October 5, calls her physician on October 10 with a 2 day history of persistent left greater than right lower abdominal pain that is moderate in intensity. History is significant for surgical removal of a ruptured appendix at 13 years of age.

Initial evaluation includes a transvaginal ultrasound examination, a hCG titer, and a physical examination.

Question: Should a second serum hCG concentration be performed in order to compare it with the initial value that is obtained?

Answer: Most of the urine and serum hCG tests currently available (in the USA) use monoclonal antibodies that recognize unique (antigenic) sites on the hCG molecule, and therefore are highly specific (do not have much cross reactivity to chemically related molecules like TSH, LH or FSH). The urine hCG (pregnancy) tests that are now available (in the USA) are also highly sensitive, and often detect hCG concentrations of 20-30 IU/L (normally found 2-4 days before a missed menses). Therefore, the initial urine hCG (pregnancy) test defines the pregnancy dates to be at least 3.5 weeks gestation on October 5.

If the urine hCG assay was positive on October 5 then on October 10 the serum hCG concentration should be at least 200 IU/L (if the initial hCG on October 5 was only 20 IU/L and there was a normal doubling every other day) and will often be about 2,000 IU/L (if the hCG on the day of missed menses or October 1 was about 100 IU/L and there was a normal doubling every other day).

Since there is a large range of what might be expected "normally" for a single serum hCG titer in this clinical situation, I would obtain serial concentrations (repeat the concentrations) to determine whether there is a normal rate of rise. Occasionally, the clinical situation may not allow time to repeat the hCG concentration, since immediate action may be required.




Case: 28 year old G1 P0 with a history of regular menstrual intervals every 30 x 5-6 days, a LMP of April 1, a positive urine pregnancy test on May 3, calls her physician on May 10 with a 2 day history of persistent left greater than right lower abdominal pain that is moderate in intensity. History is significant for surgical removal of a ruptured appendix at 7 years of age.

Initial evaluation includes a transvaginal ultrasound examination, a hCG titer, and a physical examination.

Question: Should a serum SP1, EPF, or PP5 concentration be performed during the initial clinical evaluation?

Answer: Protein (polypeptide) and steroid hormones that may be correlated with (the health of a) pregnancy are actively being studied to determine whether they have potential clinical merit. At the current time, these concentrations are not of known clinical value in distinguishing a normal pregnancy from an abnormal pregnancy. Therefore, I do not suggest these tests for my patients.




Case: 28 year old G1 P0 with a history of regular menstrual intervals every 30 x 5-6 days, a LMP of April 1, a positive urine pregnancy test on May 3, calls her physician on May 10 with a 2 day history of persistent left greater than right lower abdominal pain that is moderate in intensity. History is significant for surgical removal of a ruptured appendix at 7 years of age.

Question: What risk factors for ectopic pregnancy does this woman have?

Answer: Any intraabdominal process that causes irritation to the delicate reproductive structures within the pelvis can increase a womanís risk for a future ectopic pregnancy.

Recognized risk factors (for ectopic pregnancy) include intraabdominal (especially pelvic) surgery, intraabdominal infections (including appendicitis, pelvic inflammatory disease, peritonitis), chemical or other pelvic irritants (including those produced by endometriosis, foreign bodies, free blood), a prior ectopic pregnancy, a history of IUD use, any destructive process within the uterine cavity, anatomic abnormalities (fibroid uterus, DES exposure in utero, salpingitis isthmica nodosa), and use of ARTs (possibly due to hormonal changes within the uterus and fallopian tubes).

Since many of the conditions that increase a womanís risk for an ectopic pregnancy may have gone unrecognized (undiagnosed) one should always maintain a high level of suspicion.



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