The problematic first-trimester pregnancy

The problematic first-trimester pregnancy

Mark Deutchman

The Problematic First-Trimester Pregnancy The first-trimester obstetric patient who is experiencing pain or bleeding may have a normal intrauterine pregnancy, a threatened miscarriage, an ectopic pregnancy, a blighted ovum or trophoblastic disease. Correlation of clinical findings, quantitative human chorionic gonadotropin levels and diagnostic ultrasound findings can maximize the efficiency of the work-up, provide a definitive prognosis and identify early ectopic pregnancy. Early pregnancy loss is common. Studies of women attempting to conceive have shown that 60 percent initially have positive serum pregnancy tests as measured by the beta subunit of human chorionic gonadotropin (HCG), but the results subsequently revert to negative before the pregnancy becomes clinically recognized.(1) Bleeding during the first half of pregnancy (the definition of threatened abortion) occurs in 25 percent of all diagnosed pregnancies. Half of those with threatened abortion will abort.(1,2)

The presence of pain is known to increase the likelihood of eventual pregnancy loss.(2) The obstetric patient who presents with pain or bleeding in the first trimester is a diagnostic and management challenge because of the wide range of conditions that these symptoms may represent. The causes include normal pregnancy, spontaneous abortion, embryonic death, blighted ovum (anembryonic pregnancy), ectopic pregnancy, trophoblastic disease and nonobstetric conditions such as cervical polyps, ulceration or cancer.

Clinical Evaluation

The history should focus on information about recent health, menstrual history, contraceptive method used, possible date of conception and previous gynecologic and obstetric history. The risk of early pregnancy loss is increased in patients who have a history of first-trimester pregnancy loss, uterine defects and septa, submucous fibroids, lupus anticoagulant, peritonitis and chronic infections such as brucellosis and listeriosis. Cigarette and alcohol use also increase the risk of miscarriage.(2) Controversy still surrounds the relationship between spontaneous abortion and progesterone deficiency or infections with Mycoplasma and Ureaplasma.(1)

The risk of ectopic pregnancy is increased in patients who have had tubal surgery, tubal infections or endometriosis. Patients who become pregnant while taking a progestin-only oral contraceptive or while using an intrauterine contraceptive device are also at increased risk, as are patients who have received large estrogen doses (“morning after” contraception).(3)

The last menstrual period (LMP), although the primary reference point from which to project gestational age, can be associated with up to a two-week discrepancy from the date of actual conception, since ovulation can occur at any time between the eighth and 20th day after the first day of the menstrual period. Uterine size by pelvic examination is reliable only to within two weeks (plus or minus) when the patient is thin and has an anteverted uterus or within four weeks (plus or minus) when the uterus is retroverted (as is the case in 30 percent of women).(4)

DOPPLER EXAMINATION

If the uterus is enlarged clinically and it is possible that at least nine weeks have elapsed since the LMP, Doppler examination may reveal fetal heart tones. If the uterus is retroverted, sensitivity may be increased by gently elevating the uterus during bimanual examination to bring the uterus closer to the abdominal wall and the Doppler transducer. In some patients, however, fetal heart tones may not be heard until 11 or 12 weeks past the LMP.(5)

Although identification of fetal heart tones by Doppler examination substantially reduces the likelihood of ectopic pregnancy, there is always the possibility, although small, of simultaneous intrauterine pregnancy and ectopic pregnancy. A significant pelvic mass, however, will probably be clinically palpable in cases that reach nine or more weeks. Instability of the patient’s vital signs and the presence of signs of generalized peritoneal irritation may shortcut the evaluation, since in such cases culdocentesis may yield nonclotting blood and demonstrate the need for prompt surgical exploration. In as many as 90 percent of patients with ectopic pregnancy, nonclotting blood will be aspirated from the cul-de-sac.(3)

DIAGNOSTIC ULTRASOUND EVALUATION

Diagnostic ultrasound scanning can be the definitive study for identifying an intrauterine pregnancy, determining gestational age and providing short-term prognostic information about whether the pregnancy is likely to continue. It is important, however, to understand the limitations of this technique.(6) If the ultrasound examination is performed by a consultant or in a radiology department, the referring physician must provide appropriate clinical data and must be sure that the person performing the scan is aware of the subtle characteristics of an early first-trimester gestational sac and will take the time and effort needed to obtain good images.(7,8)

The gestational sac can be visualized by about five weeks of gestation by menstrual dates, and at this time, it is about 5 mm in size.(7,9) Cardiac motion can sometimes be seen adjacent to the yolk sac when the mean sac diameter is as small as 8 to 16 mm.(10) The diameter of the gestational sac is a reliable marker of gestational age until about 80 days from the LMP. The sac grows linearly by an average of 1.1 mm per day (range: 1 to 1.5 mm).(11,12) This relationship is expressed by the following formula:(12,13)

Mean sac diameter (mm) + 30 =

Gestational age by LMP (plus or minus 4 days) The mean sac diameter is calculated by averaging the measurements taken in three planes. By the time the mean sac diameter reaches 20 mm, a yolk sac should be visualized, and by the time it reaches 25 mm, an embryo should be seen.(12)

Ultrasound alone can in many cases distinguish a normal gestational sac, before an embryo is visible, from an abnormal sac doomed to miscarriage. The size and appearance of the gestational sac should be evaluated according to major and minor criteria for normalcy. A gestational sac of abnormal size or appearance correlates highly with an abnormal outcome.(14) The two major criteria for a normal-appearing gestational sac are that (1) a sac of 25 mm or more in diameter must reveal an embryo within it and that (2) the sac must be round in shape. Minor criteria for a normal sac include (1) sac location in the fundus of the uterus, (2) the presence of a thick, echogenic decidual ring around the sac and (3) evidence of the double decidual sac sign.(7,15) This sign represents the echo formed from the apposition of the decidua parietalis to the blastocyst.

When a sac with a mean diameter greater than 25 mm lacks an embryo or the sac is grossly distorted, abnormal pregnancy is certain. Using these five criteria, 76 percent of abnormal pregnancies and 93 percent of normal pregnancies will be correctly classified by only one ultrasound scan. Failure to meet any one major criterion or three minor criteria will identify 53 percent of abnormal pregnancies, but will be 100 percent specific in predicting spontaneous abortion. Once embryonic cardiac motion is seen on ultrasound, the risk of spontaneous abortion is only about 3 to 10 percent.(14)

It is sometimes difficult to visualize the uterus of an obese patient or have the patient’s urinary bladder sufficiently full to produce good ultrasound images. These problems are largely alleviated by endosonography, or transvaginal scanning, which is becoming more widely available. This technique does not require a full urinary bladder and utilizes higher frequency transducers, permitting visualization of the gestational sac about one week earlier than by transabdominal scanning.(16,17)

Other advantages of endosonography include the capability of visualizing the yolk sac when the gestational sac is over 8 mm in mean diameter and the embryo when the diameter exceeds 16 mm. Cardiac activity can also be observed earlier in the pregnancy.(18) If the crown-rump length is over 14 mm and no cardiac activity is seen by endosonography, embryonic death is reported to be certain.(19) In addition, endosonography may more readily permit visualization of an extrauterine gestational sac of ectopic pregnancy.(19)

QUANTITATIVE SERUM HCG TESTING

Even with the information provided by ultrasound scanning, the diagnosis of intrauterine pregnancy may still be uncertain, especially if less than six weeks have elapsed since the LMP or the patient is uncertain about menstrual dates and a gestational sac is not visualized. In such cases, quantitative measurement of the beta subunit of maternal serum HCG by radioimmunoassay is extremely helpful, particularly if it is compared with the sonographic findings.

In normal pregnancy, the maternal serum HCG level correlates highly with the gestational sac size. The threshold value above which an intrauterine gestational sac would be expected to be seen on ultrasound examination has been variously reported. In recent studies, this threshold has been about 1,800 mIU per mL (1,800 IU per L) when transabdominal scanning is used.(7,10,20) With transvaginal scanning, the threshold value is 1,000 mIU per mL (1,000 IU per L).(21)

When the HCG is low in relation to the gestational sac size, a 100 percent specificity has been reported in predicting spontaneous abortion or ectopic pregnancy. The sensitivity of noncorrelation is reported to be 68 percent; that is, 32 percent of patients who eventually abort do not have a low HCG level in relation to the gestational sac size.

A high HCG level in relation to the gestational sac size correlates highly with trophoblastic disease.(10) Although the rise in HCG is predictable in normal pregnancies, doubling every two to three days for up to eight weeks, the fall in HCG following spontaneous abortion is variable, depending on how much tissue remains. Table 1 summarizes the correlation of gestational age, sonographic findings and serum HCG levels.

Ectopic Pregnancy

The diagnosis of ectopic pregnancy can be readily made when a living extrauterine embryo is identified on ultrasound examination, but this finding is observed in only 10 percent of cases.(22) A positive pregnancy test in the face of an empty uterus by ultrasound scan signifies an ectopic pregnancy until proved otherwise, except during the three to five weeks following the LMP, when a gestational sac is not visible. The HCG level may also be positive for pregnancy following a recent spontaneous abortion; thus, serial quantitative HCG testing or repeat ultrasound scanning, or both, may be needed to make the diagnosis of spontaneous abortion.

A pelvic mass and free pelvic fluid on ultrasound scanning are helpful ancillary findings. Unfortunately, 20 to 30 percent of patients with ectopic pregnancies do not have abnormal sonographic findings.(22) In addition, pelvic hematomas do not display a consistent appearance on ultrasonography; they may be hyper-, iso- or hypoechoic relative to the uterus, depending on the amount of clotted and unclotted blood.(23,24) For this reason, pelvic hematomas can be confused with uterine or broad ligament fibroids, normal ovaries and functional adnexal cysts.

In patients with a positive pregnancy test but no sonographic evidence of intrauterine pregnancy, the risk of ectopic pregnancy is 20 percent if no pelvic mass or free fluid is seen, 71 percent if fluid is seen, 85 percent if an echogenic mass is seen, 91 percent if a moderate to large amount of fluid is seen and 100 percent if an echogenic mass accompanies a moderate to large amount of fluid or if a living embryo is seen outside of the uterus. In cases of ectopic pregnancy, 70 percent of patients have an empty uterus, 20 percent have increased intrauterine echoes and 10 percent have an intrauterine fluid collection or pseudosac, which usually does not have the normal sonographic characteristics of a gestational sac.

When an abnormal fluid accumulation within the uterus is suggestive of a pseudosac of ectopic pregnancy, the double decidual sac sign in particular should be sought during the ultrasound examination, since its presence helps exclude the possibility of ectopic gestation.(7,8,15) Because this sign can be obliterated by an overdistended urinary bladder, serial scanning after the patient has voided a few ounces of urine at a time may be helpful in demonstrating a normal-appearing sac.(8) Visualization may be improved with transviginal sonography.

If the uterine contents appear convincingly abnormal, dilatation and curettage (D&C) of the uterus can be helpful. If the tissue shows only decidua and no chorionic villi, and the HCG level is still rising or is at a plateau, ectopic pregnancy is the most likely diagnosis.(3,20)

Simultaneous intrauterine pregnancy and ectopic pregnancy is a clinician’s nightmare. A recent review(25) found 600 cases in the literature, yielding a calculated incidence of one case per 7,000 to 8,000 pregnancies. Diagnosis depends on vigilance and is aided by sonographic demonstration of both gestational sacs with cardiac motion within them. Three recently reported cases were all diagnosed after nine weeks of gestation.(25)

Management Approach

In patients with first-trimester pain or bleeding, or in patients who are otherwise at high risk of ectopic pregnancy or spontaneous abortion, ultrasound examination alone may be diagnostic. Ultrasonography in combination with quantitative serum HCG testing can be most helpful when the findings are correlated with the clinical data, such as the date of the LMP. The LMP is the major frame of reference for estimating gestational age, and often is the only information available when the patient is first evaluated. The approach outlined in this article uses the date of the LMP as a starting point from which to determine what tests are most appropriate so that a diagnosis can be made with the least duplication of testing.

Ultrasound is recommended as the first test in patients who present with bleeding or pain and report that five to seven weeks have elapsed since their LMP. A gestational sac should be visible by this time. If the mean gestational sac diameter is less than 20 mm, the double decidual sac sign should be sought.(9,22) If the mean diameter is between 20 mm and 25 mm, a yolk sac should be searched for, since its appearance virtually excludes the possibility of ectopic pregnancy.(26) The presence of a sac with normal characteristics for gestational age by LMP markedly diminishes the likelihood of ectopic pregnancy. In such patients, continued clinical observation is the most appropriate action. A quantitative serum HCG level or a repeat ultrasound scan should be obtained if pain or bleeding persists.

By seven to eight weeks, an embryo should be visualized on ultrasound and the HCG level should be above 20,000 mIU per mL (20,000 IU per L). If an embryo is not seen, the timing of a repeat scan for visualization of the embryo can be calculated by subtracting the mean sac diameter from 25; the remainder represents an estimate of the number of days that must elapse before visualization of the embryo can be expected.(12)

An abnormal-appearing fluid collection within the uterus suggests the presence of a pseudosac of ectopic pregnancy or an anembryonic intrauterine pregnancy (blighted ovum). Depending on physician and patient satisfaction with this differential diagnosis, a D&C can be performed for definitive diagnosis.(3,20) The absence of chorionic villi in the tissue obtained from D&C makes ectopic pregnancy highly likely. If the physician and patient are not comfortable with the sonographic diagnosis, it may be useful to determine the quantitative HCG level. A disproportionately low or high HCG level relative to the sac size correlates with an abnormal pregnancy.

The lack of a gestational sac in a patient who reports that five to seven weeks have elapsed since her LMP raises two questions: Is the menstrual date inaccurate? Is the pregnancy abnormal? In such cases, the quantitative serum HCG level is most helpful. If the HCG is less than 1,800 mIU per mL (1,800 IU per L), the patient’s menstrual date may be incorrect, and she may have a normal intrauterine pregnancy. Other possibilities include spontaneous abortion or molar pregnancy.(20) A repeat ultrasound examination in one to two weeks or a repeat HCG in two or three days, or both, can confirm progression of a normal pregnancy. In this situation, ultrasound offers the advantage of confirming that the pregnancy is intrauterine, but in a patient without pain, it may not be clinically necesary. If the HCG level is between 1,000 and 1,800 mIU per mL (1,000 and 1,800 IU per L), transvaginal scanning may be utilized to visualize a gestational sac that would be too small for detection by transabdominal scanning.(21)

If a gestational sac is not seen and the HCG is greater than 1,800 mIU per mL (1,800 IU per L), the patient either has an ectopic pregnancy or has had a recent spontaneous abortion. Serial HCG testing can help differentiate spontaneous abortion from ectopic pregnancy, since in spontaneous abortion the HCG level will fall, and in ectopic pregnancy it will plateau or rise at a less-than-normal rate.

In patients with inaccurate menstrual dates, it may be useful to reverse the testing sequence and determine the HCG level first. If the HCG is less than 1,800 mIU per mL (1,800 IU per L), ultrasound scanning should be delayed until the expected HCG level is above 1,800 mIU per mL (1,800 IU per L), according to the rule that the HCG doubles every two to three days. Knowing the expected rates of HCG rise and gestational sac growth allows correlation of sonographic and HCG measurements even if they are not determined simultaneously, since available measurements can be extrapolated upward or downward to correlate with one another.

Because quantitative HCG testing is critical in the evaluation of a patient with a problematic first-trimester pregnancy, it is important that the test results be reported by the laboratory as soon as possible. Although the serum slide tests now available are very sensitive (50 mIU per mL [50 IU per L]), they provide only qualitative values. They are too sensitive to be of help in deciding whether or not a gestational sac should be present. (A technique has recently been described for using the serum slide test in a semiquantitative fashion.(27)

Differential Diagnosis

Misdiagnosis of an ectopic pregnancy is always a concern and, in the current medicolegal climate, may be perceived as malpractice.(6) Maintaining a high index of suspicion is the best way to avoid missing the diagnosis. The absence of an intrauterine gestational sac on ultrasound examination in a patient with a positive pregnancy test signifies ectopic pregnancy until proved otherwise. Nonetheless, the quantitative HCG level must be correlated with the sonographic findings.

The clinically stable patient can be managed with watchful follow-up, but the patient must understand that the broad differential diagnosis of pain in the first trimester often requires a series of tests and follow-up examinations to arrive at the correct diagnosis. She must understand that her cooperation is essential. In addition to normal pregnancy and spontaneous abortion, differential diagnoses include pelvic inflammatory disease, ovarian cyst, appendicitis, inflammatory bowel disease, urinary infection, urolithiasis, endometriosis, adnexal torsion and uterine fibroids.

Culdocentesis is a valuable diagnostic aid in the unstable patient and in the patient with sonographic evidence of free pelvic fluid. Sonography may not, however, reveal even significant amounts of free intraperitoneal bleeding if the blood is not liquefied sufficiently to appear as a density different from that of the adjacent pelvic organs. To further complicate diagnosis, 30 percent of patients with a normal intrauterine pregnancy may have free pelvic fluid.(22)

If the uterus does not contain a gestational sac, the HCG level is falling and the patient is stable and not bleeding or cramping excessively, expectant management will suffice in the majority of cases. With this approach, the patient may be spared the expense and trauma of a D&C. This procedure is indicated when the patient is bleeding and cramping heavily or when the clinical examination suggests retained tissue. It is important to have the tissue examined pathologically to rule out hydatidiform mole. Any suggestion of molar degeneration requires extended follow-up with quantitative serum HCG testing to rule out choriocarcinoma. The absence of chorionic villi in the specimen calls for a reappraisal of the case and reconsideration of ectopic pregnancy.

If the uterus contains an empty gestational sac with a mean diameter of 25 mm or more, a blighted ovum is essentially certain. Most of these patients require D&C, although many who have had no bleeding and have planned the pregnancy will want confirmation of the diagnosis by HCG testing or a repeat ultrasound examination before submitting to a D&C.

Illustrative Cases

The following illustrative cases show the importance of correlating clinical data and sonographic findings in patients who present with pain or bleeding during the first trimester of pregnancy.

CASE 1

A 33-year-old woman (gravida 2, para 0) with one previous ectopic pregnancy on the left side reported that 34 days had elapsed since her LMP. Her serum HCG level was 872 mIU per mL (872 IU per L), which was much lower than that which would be expected according to her menstrual date. This finding aroused suspicion of ectopic pregnancy or spontaneous abortion. Alternatively, the discrepancy may have only indicated that the menstrual date was inaccurate.

Since the patient was asymptomatic, she was followed expectantly. Ultrasound examination was performed 18 days later, at 52 days since her LMP. At this time, a 22-mm gestational sac would be expected on the basis of her LMP or a 15-mm sac would be expected on the basis of the previous HCG level. Ultrasound, however, showed an empty uterus with a complex right adnexal mass, including a 2-cm lucent area containing an embryo with cardiac motion. Surgery confirmed a right tubal ectopic pregnancy and tubal reanastomosis was accomplished.

CASE 2

A 22-year-old woman (gravida 5, para 2, abortus 2) presented with pelvic pain. Her LMP was 52 days previously. Ultrasound showed an 8-mm gestational sac and a right adnexal mass. This smaller-than-expected sac could have represented a pseudosac with an accompanying ectopic pregnancy or could have meant that the patient’s intrauterine pregnancy was only 38 days’ gestation and was accompanied by an ovarian cyst. HCG testing the next day revealed a value of 9,600 mIU per mL (9,600 IU per L), and six days later, it was 32,800 mIU per mL (32,800 IU per L).

Repeat ultrasound 14 days after the first study showed a fetus with cardiac motion and a crown-rump length of 1.5 cm, corresponding with a 54-day pregnancy. Her pregnancy was thus intrauterine and two weeks earlier than her LMP suggested.

CASE 3

A 38-year-old woman (gravida 4, para 0) with two previous spontaneous abortions and one ectopic pregnancy was asymptomatic but worried about her pregnancy. Clinical evaluation was difficult because of obesity. At 35 days since her LMP, the HCG level was 1.935 mIU per mL (1.935 IU per L); at 41 days, it had doubled two and one-half times, to 12,060 mIU per mL (12,060 IU per L).

An ultrasound scan at 52 days showed a gestational sac with a mean diameter of 22 mm; an embryo with cardiac activity could not be demonstrated because of the patient’s obesity. A left adnexal mass was also seen. When fetal heart tones were not heard on Doppler examination by 70 days, a repeat ultrasound scan was performed, which showed an intrauterine fetus with a 3-cm crown-rump length and cardiac motion, indicating that the patient’s menstrual date was accurate.

CASE 4

A 32-year-old woman (gravida 3, para 0, abortus 2) was first seen for prenatal care at 12 weeks since her LMP. Fetal heart tones were not audible on Doppler examination. Ultrasound scan showed an irregularly shaped intrauterine sac with no echogenic ring, no embryo and a mean diameter of 44 mm. A blighted ovum was diagnosed; the HCG level was not determined. The patient subsequently underwent D&C.

CASE 5

A 25-year-old woman (gravida 8, para 1, abortus 6) had the onset of mild right-sided pain and spotting at 60 days since her LMP. Her HCG level was 1,058 mIU per mL (1,058 IU per L). Ultrasound examination showed an empty uterus and no adnexal masses. Did she have an ectopic pregnancy, spontaneous abortion or an early intrauterine pregnancy?

Since the patient’s condition was stable, a follow-up examination in five days was scheduled. Two days later, while the patient was out of town, she developed more pain and was evaluated at the local hospital. An ultrasound scan showed a small fluid accumulation in the uterus; the HCG level was not determined. She was told by the physician who examined her that she had an intrauterine pregnancy.

She returned to the office two days later and reported that the pain had increased. A repeat HCG was 1,087 mIU per mL (1,087 IU per L), and an ultrasound scan showed an abnormal-appearing sac in the uterus (pseudosac) and fluid in the cul-de-sac. Culdocentesis yielded nonclotting blood, and surgery revealed a ruptured tubal pregnancy on the right side.

CASE 6

A 26-year-old woman (gravida 2, para 0, abortus 1) presented with spotting ten and one-half weeks since her LMP. Fetal heart tones were not audible on Doppler examination. Ultrasound scan showed complex intrauterine echoes suggestive of hydatidiform mole. The HCG level was over 300,000 mIU per mL (300,000 IU per L). Suction D&C yielded hydatidiform mole. The HCG fell to zero in one month and remained so for an eight-month follow-up period.

CASE 7

A 22-year-old woman (gravida 3, para 0) with two previous unexplained miscarriages was evaluated at 13 weeks since her LMP. Her uterus was smaller than would be expected, and a pelvic mass was thought to be palpable. Ultrasound scan was performed to exclude ectopic pregnancy.

Transverse transabdominal scanning showed an empty intrauterine gestational sac with a mean diameter 1.5 cm and a mass joined to the left side of the uterus. Transverse transviginal scanning helped to delineate the process as a bicornuate uterus. The right horn contained a gestational sac and yolk sac, compatible with a 45-day pregnancy; the left horn showed an endometrial cavity. The patient eventually miscarried.

CASE 8

A 20-year-old woman (gravida 5, para 2, abortus 2) was four months postpartum and had had no menses since her last delivery. She presented with right-sided pain and had a positive pregnancy test. She was taking oral contraceptives. She had a previous leftsided ectopic pregnancy.

A sharply retroverted uterus made transabdominal scanning nondiagnostic. Transverse transvaginal scanning showed an intrauterine gestational sac with a double decidual sac sign and a yolk sac. Embryonic cardiac activity was seen between the yolk sac and uterine wall. The mean sac diameter was 16 mm, compatible with a gestation of 46 days by the menstrual date.

CASE 9

A 28-year-old woman (gravida 3, para 2) had been spotting for one week. She reported that her LMP was nine and one-half weeks previously. A quantitative HCG level one week previously was 18,000 mIU per mL (18,000 IU per L). From these data, a gestational sac of 18 mm would have been expected at the time the HCG level was determined, and after a week, the sac would be expected to have grown to 25 mm, the size at which an embryo should be seen.

Transvaginal scanning in a coronal plane, performed one week after the HCG of 18,000 mIU per dL (18,000 IU per L), showed a gestational sac of only 16 mm, without an echogenic ring and containing only a yolk sac and no embryo. On the basis of these findings, a blighted ovum was suspected. The referring physician wanted additional confirmation, and a repeat quantitative serum HCG was obtained. The level had fallen to 13,000 mIU per mL (13,000 IU per L), confirming the diagnosis of a blighted ovum. A D&C was subsequently performed. REFERENCES (1)Abortion. In: Pritchard JA, MacDonald PC, Gant NF. Williams Obstetrics. 17th ed. Norwalk, Conn.: Appleton-Century-Crofts, 1985:467-72. (2)Scott JR. Spontaneous abortion. In: Danforth DN, Scott JR, eds. Obstetrics and gynecology. 5th ed. Philadelphia: Lippincott, 1986:378-86. (3)Droegemueller WM. Ectopic pregnancy. In: Danforth DN, Scott JR, eds. Obstetrics and gynecology. 5th ed. Philadelphia: Lippincott, 1986:403-18. (4)Sabbagha RE. Ultrasound in obstetrics and gynecology. In: Danforth DN, Scott JR eds. Obstetrics and gynecology. 5th ed. Philadelphia: Lippincott, 1986:259-83. (5)Sacks GA, Fleischer AC. Sonographic evaluation of early pregnancy. Contemp Diagn Radiol 1986;9:1-6. (6)James AE Jr, Fleischer AC, Sacks GA, Greeson T. Ectopic pregnancy: a malpractice paradigm. Radiology 1986;160:411-3. (7)Cadkin AV, McAlpin J. The decidua-chorionic sac: a reliable sonographic indicator of intrauterine pregnancy prior to detection of a fetal pole. J Ultrasound Med 1984;3:539-48. (8)Nelson P, Bowie JD, Rosenberg ER. Early intrauterine pregnancy or decidual cast: an anatomic-sonographic approach. J Ultrasound Med 1983;2:543-7. (9)Shaub MS. Obstetrical ultrasonography. In: Sarti DA, Sample WF, eds. Diagnostic ultrasound, text and cases. Boston: G.K. Hall, 1980:590-608. (10)Cadkin AV, McAlpin J. Detection of fetal cardiac activity between 41 and 43 days of gestation. J Ultrasound Med 1984;3:499-503. (11)Nyberg DA, Filly RA, Filho DL, Laing FC, Mahony BS. Abnormal pregnancy: early diagnosis by US and serum chorionic gonadotropin levels. Radiology 1986;158:393-6. (12)Nyberg DA, Mack LA, Laing FC, Patten RM. Distinguishing normal from abnormal gestational sac growth in early pregnancy. J Ultrasound Med 1987;6:23-7. (13)Lyons EA, Levi CS. Ultrasound in the first trimester of pregnancy. In: Callen PW, ed. Ultrasonography in obstetrics and gynecology. Philadelphia: Saunders, 1983:1-20. (14)Nyberg DA, Laing FC, Filly RA. Threatened abortion: sonographic distinction of normal and abnormal gestation sacs. Radiology 1986;158:397-400. (15)Nyberg DA, Laing FC, Filly RA, Uri-Simmons M, Jeffrey RB Jr. Ultrasonographic differentiation of the gestational sac of early intrauterine pregnancy from the pseudogestational sac of ectopic pregnancy. Radiology 1983;146:755-9. (16)de Crespigny LC, Cooper D, McKenna M. Early detection of intrauterine pregnancy with ultrasound. J Ultrasound Med 1988;7:7-10. (17)Timor-Trisch IE, Rottem S, Thaler I. Review of transvaginal ultrasonography. A description with clinical application. Ultrasound Quarterly 1988;6:1-34. (18)Levi CS, Lyons EA, Lindsay DJ. Early diagnosis of nonviable pregnancy with endovaginal US. Radiology 1988;167:383-5. (19)Pennell RG, Baltarowich OH, Kurtz AB, et al. Complicated first-trimester pregnancies: evaluation with endovaginal US versus transabdominal technique. Radiology 1987;165:79-83. (20)Nyberg DA, Filly RA, Laing FC, Mack LA, Zarutskie PW. Ectopic pregnancy. Diagnosis by sonography correlated with quantitative HCG levels. J Ultrasound Med 1987;6:145-50. (21)Nyberg DA, Mack LA, Laing FC, Jeffrey RB. Early pregnancy complications: endovaginal sonographic findings correlated with human chorionic gonadotropin levels. Radiology 1988;166:619-22. (22)Mahony BS, Filly RA, Nyberg DA, Callen PW. Sonographic evaluation of ectopic pregnancy. J Ultrasound Med 1985;4:221-8. (23)Rochester D, Panella JS, Port RB, Rosenfeld M, Rawal U. Ectopic pregnancy: surgical-pathologic correlation with US. Radiology 1987;165:843-6. (24)Breckenridge JW, Lapayowker MS. Ultrasound in the diagnosis of ectopic pregnancy. Contemp Diagn Radiol 1985;8:1-6. (25)Yaghoobian J, Pinck RL, Ramanathan K, Ibarra J. Sonographic demonstration of simultaneous intrauterine and extrauterine gestation. J Ultrasound Med 1986;5:309-12. (26)Nyberg DA, Mack LA, Harvey D, Wang K. Value of the yolk sac in evaluating early pregnancies. J Ultrasound Med 1988;7:129-35. (27)Gochis P, Hasenyager C, Aiman J. A semi-quantitative human chorionic gonadotropin assay for the detection of ectopic pregnancy. Obstet Gynecol 1988;71:652-6.

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