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HowtoTreat PULL-OUT SECTION www.australiandoctor.com.au inside COMPLETE HOW TO TREAT QUIZZES ONLINE (www.australiandoctor.com.au/cpd) to earn CPD or PDP points. Causes Clinical assessment Investigation Managing miscarriage and ectopic pregnancy Recurrent miscarriage The author DR KRISTY MILWARD, sessional obstetric and gynaecological sonologist, ultrasound department, King Edward Memorial Hospital, Subiaco, WA. Early pregnancy BLEEDING Background EARLY pregnancy bleeding is common, affecting up to 40% of pregnant women. As such it is an extremely common reason for presentation to general practice and emergency services. However, in many cases it does not represent a true medical emergency (albeit an emotional one) and, with a logical approach to assessment, the pregnant woman can often be reassured and the correct diagnosis obtained with a minimum of reviews. It has been shown that early pregnancy assessment units offer a clinical and economic advantage in the care of women with suspected early pregnancy loss. Such dedicated units are www.australiandoctor.com.au gradually becoming more available to receive referrals from GPs. However, many women still have limited access to dedicated services and, with understanding of the issues at hand, the GP is still in an excellent position to provide the necessary basic care. cont’d next page 16 October 2009 | Australian Doctor | 21 HOW TO TREAT Early pregnancy bleeding Causes of early pregnancy bleeding BLEEDING may represent a range of conditions of early pregnancy (table 1). The term threatened miscarriage refers to bleeding that occurs in a pregnancy that is otherwise progressing normally by clinical assessment and investigation. After fetal cardiac motion has become detectable on ultrasound, more than 90% of threatened miscarriages will continue with normal gestation. The cause of the bleeding usually relates to disruption of maternal vessels in the decidua. Miscarriage is the loss of a pregnancy under 20 weeks of gestation. Most occur in the first trimester and a variety of terms is used to describe different clinical presentations (table 2). However, the underlying process and end result for the patient are the same. Molar pregnancy (hydatidiform mole) affects only an estimated one in 1000 pregnancies. It includes partial and complete mole. Table 1: Causes of bleeding in early pregnancy Threatened miscarriage Figure 1: Ultrasound of complete molar pregnancy. The uterus is filled with cystic placental villi, with no associated fetus. Miscarriage (including incomplete/retained products of conception) Molar pregnancy Ectopic pregnancy Extrauterine sources — cervical bleeding (ectropion, polyps, atypia) Table 2: Clinical presentations of miscarriage Complete miscarriage — spontaneous expulsion of products of conception, with resolution of symptoms Incomplete miscarriage — bleeding and cramping, with products of conception visible in the uterine cavity Missed miscarriage — non-viable, intact gestation sac within the uterus, with delay to onset of symptoms of miscarriage type but derived only from paternal genetic material. It is believed to be caused by fertilisation of an empty ovum by a single sperm, the chromosomes of which are then duplicated. The condition is associated with: • Development of a large hydropic placenta. • High beta human chorionic gonadotrophin (betahCG) levels (and associated symptoms, particularly hyperemesis Blighted ovum/anembryonic pregnancy — generally refers to a missed miscarriage in which embryonic development stopped before the embryonic pole was visible. The gestation sac may continue to grow Partial mole is associated with a triploid karyotype. It is believed to be caused by fertilisation of a normal haploid ovum by two haploid sperm. A fetus develops but early demise is common because of the karyotypic anomaly. The placental changes can be subtle and may be unrecognised unless histopathology of products of conception is obtained after curettage. Complete mole is associated with a diploid karyo- and sometimes hyperthyroidism). • Uterine enlargement greater than expected for gestation. Ultrasound reveals a uterus filled with cystic placental villi, with no associated fetus (figure 1). Because of the risk of persistent gestational trophoblastic disease, referral to a specialist is appropriate for surgical evacuation, histopathology and advice about subsequent follow-up or management. Ectopic pregnancy results when implantation of the conceptus occurs at a site other than the uterine cavity. It affects 1% of pregnancies, and almost all (about 98%) occur within the fallopian tubes. Other potential sites of implantation include the peritoneal cavity, uterine cornu (interstitium), caesarean scar, ovary and cervix. Vaginal bleeding unrelated to the pregnancy must always be considered, to avoid missing uncommon but serious secondary pathology. Clinical assessment History A CLEAR history is vital not only in establishing the likely diagnosis but also in guiding appropriate investigation. The prior obstetric and gynaecological history, contraceptive use, pattern of bleeding and associated symptoms can help differentiate between the possible causes of bleeding. The menstrual cycle, contraceptive use and date of first confirmation of pregnancy can help to estimate the likely gestational age. Accurate estimation of gestational age helps both to guide appropriate investigation and to interpret results. Therefore the history should include, at a minimum, the points listed in table 3. Examination Clinical examination should be directed by the history. Vital signs must be assessed when bleeding is heavy or pain is severe. Abdominal palpation is necessary to assess the location and severity of abdominal pain, including presence of an ‘acute abdomen’. If concern exists about the possibil- Table 3: Questions to ask the woman with early pregnancy bleeding What is her age? Miscarriage risk increases with maternal age What was the first day of last menstrual period (LMP) (with an indication as to the degree of certainty)? Is the cycle regular? Ovulation can be predicted to have occurred 14 days before the first missed cycle What is the cycle length? Standard pregnancy dating wheels assume a 28-day cycle; short cycles have early ovulation before day 14, long cycles have late ovulation beyond day 14 Were any contraceptive hormones in use at the time of conception? Ovulation timing cannot be predicted by LMP if this were the case Is an IUD in situ? Although pregnancy is uncommon, up to 50% may be ectopic What was the first date of confirmation of pregnancy (by urine human chorionic gonadotrophin [UhCG] or other)? This date provides a degree of certainty that the patient was at least four weeks pregnant at that time What outcomes have occurred from previous pregnancies, including mode of delivery? Ectopic pregnancy has a 5-15% recurrence rate; recurrent miscarriage increases the risk of repeat miscarriage Was there any delay to conception? Subfertility is associated with an increased risk of ectopic pregnancy Is there any history of gynaecological disease — endometriosis, pelvic infection (associated with increased risk of ectopic pregnancy)? What is the pattern of bleeding? Light prolonged spotting suggests ectopic pregnancy; fresh, heavy or clots is more suggestive of miscarriage Is there associated pain and, if so, what is the nature — crampy, sharp, central, unilateral? Have any ultrasounds or blood tests already been performed during this pregnancy? What were the results? What was the date and result of the last Pap smear? What is the patient’s blood group? Rhesus D-negative women who are not iso-immunised will require prophylactic Rh (D) immunoglobulin (anti-D) ity of cervical bleeding, a speculum examination should be performed. If a recent Pap smear is normal, it may be reasonable to delay speculum examination until there have been repeated episodes of bleeding. In a woman with heavy vaginal bleeding and associated cramping pain, speculum examination should be performed early, as products of conception may be caught in the cervix and visible at the external os. Removal of such products (with a pair of sponge forceps) will frequently result in rapid abatement of symptoms. Bimanual palpation of the pelvic organs may aid in estimating gestation (from uterine size) or assessing pelvic pain, with the finding of ‘cervical excitation’ suggestive of ectopic pregnancy. Cervical excitation refers to pain felt when the cervix is rocked laterally — classically the pain should occur when the cervix is rocked to the side of the ectopic, thereby pushing the fundus to the contralateral side and stretching the adnexal tissues and fallopian tube. However, it is neither a sensitive nor specific finding. Investigation AS with all areas of clinical examination, investigation should be directed by the history and examination findings. Each test requested should aim to answer a specific clinical question and direct further management accordingly. Quantitative beta-hCG level There are two primary uses for a beta-hCG level. The first is as a single level to 22 | Australian Doctor | 16 October 2009 assist in the interpretation of ultrasound findings. The discriminatory level at which an intrauterine pregnancy should be visible varies slightly between laboratories and mode of ultrasound (transabdominal versus transvaginal). With the current quality of image resolution, a healthy gestation sac is often visible with transvaginal sonography at a beta-hCG level of 1500 IU/L. If a patient with a beta- hCG above the discriminatory level has no intrauterine sac (or retained products of conception) visible, the differential diagnosis then falls to ectopic pregnancy or complete miscarriage. Therefore the initial betahCG level can be used to help determine the information that an ultrasound could provide. The second use of betahCG is in serial testing for assessing pregnancies too www.australiandoctor.com.au early to demonstrate by ultrasonography (or where such facilities are not available). After conception, hCG is detectable in maternal plasma after 7-8 days. Mainly produced in the cells of the trophoblast, levels rise rapidly and, in healthy early pregnancy, double every 48-72 hours. Levels that rise appropriately are strongly suggestive of a normal intrauterine pregnancy. Falling results (assuming gestation less than 10 weeks) indicate a failing pregnancy. Ectopic pregnancies are often associated with levels that rise slowly, plateau or even fluctuate. Maximum beta-hCG levels are obtained at about 10 weeks, after which there is a gradual decline to 20 weeks, at which time they stabilise. Serial testing is therefore of most use cont’d page 24 HOW TO TREAT Early pregnancy bleeding from page 22 between four and six weeks, when ultrasonography is less helpful. After a gestation sac has been identified in the uterus, beta-hCG results can become confusing, as levels can continue to rise in the absence of a live fetus if trophoblastic tissue is healthy. Beyond 10 weeks, serial testing should not be performed, as levels will fall naturally and this may be confused with a failing pregnancy. Because of the extremely wide variation in normal beta-hCG levels for each stage of gestation, this test cannot be reliably used as a guide to gestational age of an undated pregnancy. Instead, if dating is unknown, it should be used to indicate the appropriate timing of ultrasound examination (ie, after levels have risen above the discriminatory level). Table 4: Typical gestation at which key findings can be made by ultrasound Ultrasound finding Gestation for transvaginal scan Gestation for transabdominal scan Intrauterine gestation sac Earliest four weeks and three days (sac size 2mm*) Latest five weeks and two days Latest six weeks Yolk sac visible Five weeks and three days Earliest five weeks and five days Latest seven weeks Embryonic pole Five weeks and six days Earliest six weeks Latest eight weeks Cardiac activity CRL ≥ 5mm Earliest five weeks and six days (CRL= 2mm) Latest six weeks and two days (CRL ≥ 5mm) *Minimum size at which the sac can be detected, but not always distinguishable from a pseudosac at this size CRL = crown–rump length from miscarrying intrauterine pregnancies and it is not possible to define a single level at which viability (or otherwise) can be confirmed. Many authors have used progesterone (and other biochemical markers) in models aimed at predicting the success of conservative management of failing pregnancies. Progesterone Ultrasound Serum progesterone levels are higher in healthy intrauterine pregnancies than in ectopic pregnancies or in pregnancies that ultimately miscarry. In the setting of a pregnancy of unknown location, levels <25nmol/L are unlikely to be associated with a healthy, ongoing pregnancy. However, ectopic pregnancies cannot be differentiated With the continuously improving resolution obtained from modern ultrasound machines (including endo-cavitary probes) ultrasonography is increasingly able to answer the important questions raised when there is bleeding in early pregnancy: • What is the location of the pregnancy? • What is the gestation of the pregnancy? • Is a live embryo or fetus present (and if so, how many)? • Is any placental pathology apparent? Additionally, ultrasound is a highly acceptable investigation to the vast majority of pregnant women. Although invasive, with explanation of the benefits most women will also accept transvaginal sonography, which is generally a painless examination (and often better tolerated than a transabdominal scan with a very full bladder). Table 4 shows the typical gestation at which key findings can be made by ultrasound. When referring any patient for an ultrasound it is impor- tant to keep in mind the expected findings for the known (or suspected) gestation and the questions that ultrasound will be able to answer. Ultrasound has the advantage of providing immediate information, which in many situations (especially when gestation is greater than six weeks) will be conclusive with a single examination. However, ultrasound is more costly than pathology testing (MBS provides $60 for early pregnancy scan and $28 for beta-hCG). Thus to minimise costs to the state and patient budgets and maximise useful information in a timely manner, the clinical history and examination findings should direct the physician to choose the most appropriate initial investigation. At any time that an ultrasound is expected to be conclusive it makes sense that this should be first line, and biochemistry is likely to be superfluous. In the setting of a pregnancy of uncertain location, biochemistry can be added to aid in interpretation of the ultrasound findings. If an intrauterine gestation is seen, but of uncertain viability, repeat ultrasound in 710 days is most likely to be the most effective follow-up. If the history suggests that the gestation is too early to expect that ultrasound will contribute to the assessment, serial beta-hCG should be used until levels are high enough to warrant ultrasound examination (or until there is clinical suspicion of ectopic pregnancy). Pregnancies of unknown location These are defined by a positive beta-hCG test, with no ultrasound evidence of intrauterine or extrauterine pregnancy, and no retained products of conception (RPOC). Serial beta-hCG monitoring is indicated. Ultrasonography should be repeated if the level rises above the discriminatory zone, plateaus at <1500 IU/L or there is onset of new symptoms, suggestive of ectopic pregnancy. If the level is falling, conservative management is reasonable, but continued monitoring is necessary until the beta-hCG test is negative. Low progesterone levels are predictive of pregnancies of unknown location likely to resolve spontaneously. Algorithms have been described to aid in the management of these pregnancies. Histological examination of any tissue passed vaginally is helpful in confirming the diagnosis of miscarriage and excluding an ectopic pregnancy. Management of miscarriage THREE options exist for the management of miscarriage — conservative, medical and surgical. Conservative management Conservative management involves awaiting events with the expectation that miscarriage will occur and be completed without need for medical intervention. The patient should be counselled about expectations. This includes heavy vaginal bleeding (heavier than a typical menstrual bleed) with more cramping discomfort or pain. Blood loss and pain typically reach a peak as the sac is passed — the patient may have passage of clots, or may even note the presence of membranous tissue. After the sac has been passed, symptoms of pain typically ease rapidly and vaginal loss gradually slows. Patients should be advised to represent if bleeding is persisting or there are symptoms of infection (ongoing bleeding, malodorous discharge, lower abdominal pain, fever and other systemic symptoms). They should also be advised to present to emergency care if bleeding is very heavy or pain is unmanageable with local heat packs, simple oral analgesics and NSAIDs. The difficulty with this management option is selecting an appropriate population for whom success is likely. Studies have shown that completion of miscarriage is more likely in women with: • A smaller gestation sac. • Incomplete (as compared with missed) miscarriage. 24 | Australian Doctor | 16 October 2009 • Lower levels of beta-hCG and progesterone. In the setting of a missed miscarriage, onset of bleeding may not be for several weeks and, for practical as well as emotional reasons, this may be unacceptable to many women. When conservative management is selected, regular review is reasonable to ensure the patient is still happy with her choice and to reconsider intervention (medical or surgical) if time is passing without miscarriage occurring. If bleeding occurs and takes a course suggestive of complete miscarriage, it is not necessary to repeat the ultrasound scan as a matter of routine. However, complete miscarriage can be difficult to diagnose clinically and, if there is ongoing bleeding, or symptoms of infection, ultrasound is appropriate to evaluate for possible RPOC or endometritis. Be aware that RPOC can be a difficult diagnosis on ultrasound, and when heterogeneous echoes are present with a total anteroposterior thickness <15mm, histological confirmation of retained products after curettage is less likely. Conservative management is usually appropriate in this setting. Pelvic infection rates appear to be lower in the setting of expectant management, and prophylactic antibiotics are not indicated. Medical management Medical management involves use of medication to induce uterine contractions and evacuate the uterine contents. Misoprostol is a commonly used agent in this setting. When given as a single vaginal dose of 800μg, 70% of women will progress to complete miscarriage www.australiandoctor.com.au within three days. A repeat dose can be given to women with RPOC, resulting in successful treatment of up to 50% of these women (15% overall failure rate). Some bleeding may persist for as long as three weeks. Medical evacuation is probably best suited to women with early pregnancy demise and a small fetal pole, as more advanced gestations will typically be associated with blood loss or pain levels that are not acceptable to the patient, resulting in their presentation to emergency care during the course of the miscarriage. Patients should be aware of what to expect and when to present for further attention. Surgical management Referral is required for women for whom surgical management is desired. Patient preference (avoiding delay or bleeding associated with other methods) or other factors may determine need for surgical management. Surgical management is required for: • Late miscarriage, with a larger fetal pole. • Heavy bleeding in the setting of spontaneous or medically managed miscarriage. • Suspected secondary infection with sepsis. Evacuation of the uterus by suction D&C is typically performed under general anaesthesia. The cervix is dilated by mechanical means (although medical ripening with vaginal misoprostol, typically at a dose of 400μg, may be performed before surgery) and suction is used to remove products of conception. Metal curette instruments may be used to check the cavity is empty, although this is not essential. Risks of this method include: • Cervical trauma. • Uterine perforation (with the potential further complication of bowel injury). • Retained products. • Infection. • Development of Asherman’s syndrome (which, if severe, may obliterate the cavity, preventing further pregnancy). It has the advantage of providing a reasonably safe method of emptying the uterus quickly, with minimal discomfort for the patient, and lower blood loss. Return to normal physical health is rapid and many women seem to consider this method the least emotionally traumatic, as they do not have to experience the physical aspects of the miscarriage. The appropriate management choice for any one patient will depend on a variety of factors, including the gestational age, ultrasound findings, surgical risk factors and patient’s preference and previous experiences. If uncertain, patients can be referred to early pregnancy assessment units, where they can receive further counselling about their options, and be provided medical treatment or a booking for day surgery admission for curettage if desired. Management of ectopic pregnancy OF all ectopic pregnancies, 98% occur in the fallopian tube, and the following primarily addresses the management of these. Before the common use of ultrasound to permit early diagnosis of ectopic pregnancy, many cases represented surgical emergencies and were treated by salpingectomy. However, with very early diagnosis, the risk of significant maternal haemorrhage is lower, thereby permitting more conservative management. Referral of any patient with a suspected ectopic pregnancy is appropriate, at the earliest possible convenience. Unstable patients should be transferred as an emergency, after institution of basic resuscitative needs (IV line, fluids). The decision about choice of management is made on an individual basis, taking into account the patient’s: • Clinical condition. • Reproductive history. • Desire for future fertility. • Risk factors for surgery and medical management. • Investigation findings. Surgical treatment may be performed via laparotomy or laparoscopy. The two surgical options are salpingec- Before the common use of ultrasound to permit early diagnosis of ectopic pregnancy, many cases represented surgical emergencies and were treated by salpingectomy. tomy, excising the affected fallopian tube with the pregnancy intact, and salpingotomy, incising the tube over the pregnancy and removing trophoblastic tissue with forceps, leaving the tube to heal. The advantages of salpingectomy include lower recurrence rate of subsequent ectopic pregnancies, (with still reasonably high intrauterine pregnancy rates), and no need for postoperative serial beta-hCG monitoring. However, the cost is infertility if the contralateral tube is lost to sub- sequent ectopic pregnancy or is already obstructed by the underlying process, which may have caused the ectopic. Tubal conservation by salpingotomy may not be possible if significant tubal damage is noted at the time of surgery, or if haemostasis cannot be achieved. If conservation is successful, betahCG levels must be monitored until negative, because of the possibility of retained trophoblastic tissue. Future fertility rates with salpingotomy are slightly higher than for salpingectomy (85% versus 80%), but this is at the cost of a significantly higher rate of recurrent ectopic pregnancy (15% versus 5%). Medical management by systemic methotrexate is suitable for patients who meet certain clinical criteria. They must be clinically stable and willing to attend for serial review and quantitative beta-hCG tests. The initial beta-hCG level should be below a threshold level (which may differ between hospital laboratories and protocols). Any adnexal mass visible on ultrasound should be small and without a live embryo. Free fluid should be of small volume or absent. Additionally patients should not have medical conditions that prevent use of methotrexate. Medical management may also be indicated after failed surgical treatment, such as persisting beta-hCG after salpingotomy. Methotrexate is administered intramuscularly at a dose of 1mg/kg (or 50mg/m 2 of body surface area) after baseline haematology and biochemistry. Admission to hospital is typically recommended, in case of tubal rupture as the ectopic tissue initially swells. Recurrent miscarriage — when and how to investigate MISCARRIAGE is a frequent event. Up to 15% of all conceptions are lost before implantation. An estimated 15% of recognised pregnancies are lost in the early stages of pregnancy. As gestation advances, the miscarriage risk declines, with fewer than 5% of live pregnancies over eight weeks’ gestation ending in miscarriage. For most women (>80%) a successful pregnancy will follow a miscarriage, or even two consecutive miscarriages. The most commonly used definition of recurrent miscarriage is three consecutive pregnancy losses (a situation that affects about 1% of women, but by chance alone would be expected to affect 0.34%). After three miscarriages the chance of success in the subsequent pregnancy is still up to 75%. However, an underlying cause may be present in 50% of couples, so investigation is warranted after three consecutive losses. Earlier investigation (after two miscarriages) may be reasonable in the setting of advanced maternal age, relative infertility or if there are points in the medical history that suggest the possibility of an underlying condition. However, if the couple are young and otherwise healthy, investigation is unlikely to be beneficial after just two losses, although empathy and support are vital because of the high level of anxiety found in Table 5: Causes of recurrent miscarriage Maternal age — associated with increased aneuploidy rates Parental genetic factors — balanced translocations, mosaicism Thrombophilic disorders — antiphospholipid antibodies, inherited thrombophilias Endocrine disorders — diabetes mellitus, thyroid autoantibodies Uterine anatomical disorders — congenital malformations, cervical incompetence Table 6: Routine investigations for recurrent miscarriage Pelvic ultrasound — 3D gynaecological imaging ± sonohysterography to further evaluate the cavity Antiphospholipid antibody screen (lupus anticoagulant, anticardiolipin antibodies — IgG and IgM, antinuclear factor) Thrombophilia screen (antithrombin III, proteins C and S, activated protein C resistance (APCR) ± factor V Leiden mutation if APCR positive) Thyroid peroxidase antibodies and TSH/free T4 Parental karyotyping Table 7: Other investigations for recurrent miscarriage Glucose tolerance test or glycated haemoglobin (if strong family history or other clinical reason to suspect undiagnosed diabetes) Day 3 FSH (marker of ovarian reserve) Luteinising hormone:FSH ratio, sex-hormone-binding globulin, testosterone and free androgen index in women with long cycles Prolactin levels couples with multiple miscarriages. Numerous factors may be involved in the aetiology of recurrent miscarriage. Causes of recurrent miscarriage are listed in table 5. Depending on the underlying diagnosis (if one is present) treatment may be available, although there is still a relative lack of evidence regarding the most appropriate strategies to manage varying conditions. A thorough history is the starting point in assessing recurrent miscarriages. Details of the miscarriages should be obtained (methods of confirmation of pregnancy, gestation at miscarriage, findings of any investigations performed at the time) as this may point to different possible underlying causes (eg, chromosomal or endocrine in early loss; anatomical in later loss). The menstrual, medical and relevant surgical history should be obtained, as should a family history of recurrent miscarriage or thrombosis. General physical examination may yield findings suggestive of endocrine disease, but most conditions associated with recurrent miscarriage and amenable to treatment are diagnosed with laboratory investigations. A list of investigations for women with recurrent miscarriage is provided in table 6. Other investigations are less likely to be beneficial, but may be warranted in some patients, depending on the clinical history and results of other tests (see table 7). Because of the lack of consensus over investigation and management of recurrent pregnancy loss, referral to a specialist for advice is appropriate after preliminary investigation. www.australiandoctor.com.au Serial beta-hCG testing is performed according to protocols of the institution — typically twice a week initially, until readings fall below a certain level, after which weekly testing is acceptable. Monitoring continues until the beta-hCG test is negative, which may take four weeks or more. Patients must use contraception for three months. The anti-folate action of methotrexate increases the risk of neural tube defects in subsequent pregnancies if sufficient delay does not occur. Therefore high-dose (5mg daily) folate supplementation is necessary when there is unintended early pregnancy. Comparison of medical and surgical management (single IM methotrexate versus salpingotomy) shows similar success rates, future reproductive success and ectopic recurrence rates. Adverse effects are more common with medical treatment, and length of followup more prolonged, although immediate recovery is faster. Overall costs of successful medical treatment are lower and patient satisfaction is reported to be improved. Summary of recommendations Referral of patients to a dedicated early pregnancy assessment unit (if available) is associated with clinical and economic advantages — Level IV evidence. Expectant management of incomplete miscarriage is highly effective — Level Ib evidence. Medical treatment of incomplete and early miscarriage is an alternative to surgical evacuation, with similar efficacy — Level Ib evidence. Vaginal, sublingual and oral dosing of misoprostol have similar efficacy for medical uterine evacuation — Level Ib evidence. Medical treatment of missed miscarriage requires a higher dose (or longer duration of treatment) with misoprostol — Level Ib evidence. Histological examination of tissue passed at spontaneous or medically managed miscarriage is desirable, particularly to confirm the diagnosis of miscarriage and exclude ectopic pregnancy and gestational trophoblastic disease — Level IV evidence. cont’d next page 16 October 2009 | Australian Doctor | 25 HOW TO TREAT Early pregnancy bleeding Author’s case studies Early light spotting with a history of previous miscarriage A 26-YEAR-old woman presents with one day of light spotting in early pregnancy. She has had a previous nine-week miscarriage. Her menstrual cycle is regular, 24 days in length and her last menstrual period began five weeks ago. She had a positive urine hCG one week ago. She has had no pain. Her Pap smears are up to date and the last result was normal. Her blood group is A-negative (antibody screen negative). Her pulse is 80 beats per minute and blood pressure 105/60mmHg. Her abdomen is soft and non-tender. Speculum examination is not performed. At five weeks’ gestation, with positive urine test a week earlier, a transvaginal ultrasound might show a small intrauterine gestation sac (assuming all is well), but no yolk sac or fetal pole. However, pregnancy may be more advanced because of the shorter cycle. If no sac is visible, the differential diagnosis would include early miscarriage, ectopic or normal intrauterine pregnancy with ovulation later than expected (and positive urine at the limits of sensitivity). There is nothing in the history that suggests urgency of investigation, although with the history of miscarriage, the woman is likely to be anxious. An ultrasound performed as the initial investigation may be able to confirm intrauterine gestation or may reveal a small adnexal mass if the location is ectopic. It is likely that a fetal pole will not be seen, which may then prompt a further ultrasound a week later. If biochemistry is chosen as the initial investigation, a single test will need to be followed either by ultrasound (if the result is above the discriminatory level) or further testing in 2-3 days if the result is lower than expected. Either option may be taken. If the patient can be reassured, selecting ultrasound as the initial option, but delaying the examination by a couple of days, may help to improve the chance of a conclusive result. Alternatively, two beta-hCG levels 72 hours apart, with an Take-home messages Figure 2: The tiny fetal pole is immediately adjacent to the yolk sac. Figure 3: M-mode confirms fetal cardiac activity. Figure 4: The endometrium is regular, with no evidence of a gestation sac. Figure 5: Calipers outline the ectopic mass, adjacent to the left ovary. ultrasound scheduled to follow, could be selected. In the given case, the patient was seen in the early pregnancy assessment unit and had both beta-hCG and transvaginal ultrasound performed. The beta-hCG level was 17,500 IU/L, and transvaginal scan showed a single intrauterine pregnancy. The crown–rump length (CRL) was 2mm (figure 2), with car- diac activity demonstrated (figure 3). These findings are average for five weeks and six days’ gestation, and consistent with early ovulation in a short menstrual cycle. Although the patient is Rh negative, current guidelines suggest that there is insufficient evidence to use prophylactic anti-D in the setting of threatened miscarriage with an ongoing pregnancy. Early spotting with groin pain A 30-year-old woman presents with spotting and intermittent left iliac fossa pain in early pregnancy. She is at six weeks and four days’ gestation by certain LMP (with a regular 28day cycle). Blood group is B-positive. Her pulse and blood pressure are normal. The abdomen is soft and non-tender to palpation. Speculum examination reveals a closed cervix, with a small amount of fresh blood at the os. Bimanual palpation is unremarkable. Transvaginal ultrasound as first-line investigation is unable to demonstrate an intrauterine pregnancy. There is no ultrasound evidence of ectopic pregnancy. Beta-hCG performed on the same day (to aid interpretation of the ultrasound) is 960 IU/L. This is below the discriminatory level, so it is not possible to exclude an early intrauterine pregnancy with ovulation later than expected. Ectopic pregnancy and failing intrauterine pregnancy also cannot be ruled out. As the patient is stable, review with repeat betahCG is scheduled for 48 hours later. At the review appointment, the beta-hCG has risen to 1430 IU/L (a rise of <66%). The patient has had an increase in left iliac fossa pain, prompting repeat ultrasound. The uterus is empty (although the hCG is still below the discriminatory zone) (figure 4). However, a left adnexal mass (typical donut-shape) is now visible superior to the left ovary (figure 5). There is no free fluid in the pelvis. The patient was referred to a tertiary centre. Her FBC, EUC and LFTs were normal. After counselling she elected to be treated with IM methotrexate and was admitted for observation. Serial beta-hCG monitoring subsequent to the methotrexate showed a gradually falling level, which became negative after five weeks. Light early bleeding with mild cramping and suprapubic tenderness A 34-year-old woman presents with two days of light vaginal bleeding at seven weeks and four days’ gestation by LMP. She had mild cramping on the first day of bleeding. Her menstrual cycle is regular and 28 days in length. She is G3P2 and the pregnancy is planned. Urine hCG was positive on day 30 of the cycle. Her last Pap smear, taken 14 months ago, was normal. Blood group is O-positive. Her pulse and blood pressure are normal. Her abdomen is soft, with mild suprapubic tenderness. Ultrasound is the appropriate first-line investigation, as a normal intrauterine pregnancy will be clearly visible, with expected CRL of 14mm. If an ectopic is present, it is likely that a mass would be visible at this gestation. It would be reasonable to await ultrasound results before deciding whether beta-hCG testing is necessary. In this case ultrasound reveals an intrauterine gestation sac with a single fetal pole. The CRL is 4mm and no fetal cardiac activity is present. The findings are consistent with a gestation of six weeks and one day. Missed miscarriage cannot be diagnosed on ultrasound findings alone (requiring a CRL of 5mm with no fetal cardiac motion to confirm a non-viable pregnancy). In this situation repeat ultrasound may be recommended in 7-10 days to assess progress. However, using the clinical history to aid interpretation of the ultrasound it is possible to confirm missed miscarriage. The patient gives a reliable history, with home pregnancy testing at the time of the missed period, so dates could not be more than 3-4 days out. Conservative management could be selected, but medical management would also be appropriate. When diagnosing miscarriage and planning medical or surgical intervention, it is vital that the patient accepts there is sufficient evidence that the pregnancy is not ongoing. If there is any doubt, there is no harm in waiting for a repeat scan, assuming the patient is advised of what to do should heavy bleeding commence. Take a detailed history, attempting to date the pregnancy as best able. Utilise past history to ascertain risks of miscarriage or ectopic pregnancy (keeping in mind that many women have no risk factors for either outcome). Select the most appropriate first-line investigation to best answer the clinical question at hand — don’t just order tests as routine. Consider results of investigations in the light of the known clinical history. Aim to minimise follow-up investigations when possible — if ultrasound has shown an early intrauterine sac, wait for repeat ultrasound rather than performing serial betahCG. Transvaginal ultrasound is relatively inexpensive, easy to obtain and acceptable to most women. Don’t forget the blood group and anti-D prophylaxis for Rh (D)negative women with miscarriage or ectopic pregnancy. When to refer Missed or incomplete miscarriage when conservative management is not desired or has failed. Advise such women about the option of medical management. Suspected ectopic pregnancy. Molar pregnancy. Recurrent miscarriage after preliminary investigations. Further reading Available on request from julian.mcallan@ reedbusiness.com.au Online resource UpToDate For Patients provides clear information for patients and comprehensive details for members: www.uptodate.com/patients GP’s contribution Case study DR LINDA MANN Leichhardt, NSW 26 CS, 39, has one live child and has had five ‘miscarriages’. In three of these miscarriages the beta-hCG test became negative before eight weeks’ gestation, with conservative management. Two of her miscarriages were managed surgically. CS has been assessed by a private specialist group and no remediable cause for her recurrent miscarriage pattern has been determined. She has a regular 28-day cycle. She is now pregnant (positive urine | Australian Doctor | 16 October 2009 beta-hCG on day 35 of her cycle), and presents at five weeks’ gestation with faint bleeding, which is a pattern she has had before. She has not had any pain and there is no tenderness on examination. We had discussed early transvaginal ultrasound at six weeks when her last miscarriage occurred. Questions for the author How do I manage this very anxious woman? This situation obviously requires a www.australiandoctor.com.au great deal of compassion and understanding for her inevitable anxiety. With her given presentation, the question is going to be whether or not the pregnancy is progressing as expected. There is no significant reason to suspect ectopic pregnancy at present. Ultrasound at this time could only be expected to demonstrate the location of the pregnancy (assuming normal progress). No fetal pole will be visible and therefore no reassurance can be given regarding viability. The options are to wait for an ultrasound at or beyond six weeks or to arrange serial biochemistry. The decision will depend on CS’s preferences. Two beta-hCG levels 48 hours apart will provide the fastest information and, if the rise is reassuring, CS may be more comfortable with waiting a few more days to have an ultrasound without further beta-hCG monitoring. If results are not as reassuring or symptoms are continuing, ongoing betacont’d page 28 HOW TO TREAT Early pregnancy bleeding from page 26 hCG levels can be performed until a diagnosis is made or ultrasound is indicated. If she has an ongoing pregnancy, what discussion should we have about the risks of prenatal diagnosis? At 39 her background risk of having a fetus affected by trisomy 21 is about one in 70. If she is concerned about this risk and desires more information, my advice would be to recommend first trimester screening (FTS) rather than a diagnostic procedure. FTS will provide her with a pregnancy-specific risk assessment with no risk to the pregnancy from screening. Patients of this age can still achieve a low-risk result from screening (best result is 20-fold reduction in risk, to one in 1400). Even if she receives a high-risk result (greater than one in 300) knowing the pregnancy-specific risk may help her decide whether or not to accept the risk of miscarriage from a diagnostic procedure such as amniocentesis. A result of one in 250, for example, while still ‘high risk’ may be quite acceptable to her given her background risk and previous losses. FTS detects up to 93% of fetuses affected by trisomy 21 in women of CS’s age. General questions for the author Can bleeding in early pregnancy be related to a bleeding diathesis? Should I test for this in women who have bleeding with no apparent uterine cause? While a bleeding diathesis may exist in women with pregnancy bleeding, testing for this when no other cause is apparent is not generally required. Bleeding at the placental-decidual interface is frequently not visible on ultrasound. In addition to this, women with underlying medical conditions will often already have been diagnosed because of other bleeding issues, including menorrhagia. However, if a patient with persisting unexplained bleeding also has a prior history of abnormal bleeding unrelated to pregnancy, further testing may be warranted. For women who have conservative therapy of miscarriage, how long until normal cycles usually resume? When do they need to resume contraception if that is their choice? Ovulation and return of menstrual cycles should not occur until the miscarriage has occurred and beta-hCG levels are negative. As the How to Treat Quiz timing of actual miscarriage (spontaneous expulsion of pregnancy tissue) is extremely variable with conservative management, so will be the time to next ovulation. It may be difficult to predict ovulation timing, and if contraception is desired, I would advise that caution is best from the beginning, and recommend use of barrier contraception (to avoid confusion as to the cause of any irregular bleeding) until the miscarriage is complete and hormonal methods can be started, if preferred. Ovulation and conception in the first month after a miscarriage is not uncommon. Can GPs supervise medical management of miscarriage? There is no particular reason why a GP overseeing care of women having conservative management of miscarriage might not also offer medical management. In both situations arrangements need to be in place for review of progress (either in person or by telephone contact). A plan also needs to be made for where the patient should seek assistance in the event of very heavy vaginal bleeding or unmanageable cramping pain. If this is not the managing GP, it would be reasonable to provide the patient with documentation regarding ultrasound and biochemistry results, as well as confirmation of date and dose of misoprostol used. Thus, if an emergency arises out of hours the patient can self-refer to the local hospital or other service and provide all the necessary details to the new managing medical officer. Misoprostol is not approved for use in management of miscarriage, thus requiring private prescription (or supply directly from the GP). Apart from ectopic pregnancy, when do we need to monitor post-event betahCG? In addition to ectopic pregnancy follow-up (medical or tube-conserving surgery) beta-hCG monitoring is required for pregnancies of unknown location, due to the possibility of an ectopic location. Molar pregnancies (both partial and complete mole) also require serial monitoring after surgical intervention. Weekly levels should be performed until three consecutive negative levels are obtained. In women at high risk of recurrent disease (based on presence of a number of specific features) extended monitoring for up to six months is appropriate. Correction How to Treat Depression in Adolescents (25 September 2009) should have stated that 60% of youth with major depressive disorder (rather than youth in general) report suicidal ideation and 30% will actually make an attempt. Australian Doctor apologises for the error. INSTRUCTIONS Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. Early pregnancy bleeding — 16 October 2009 1. Which TWO statements are correct? a) Miscarriage is the loss of a pregnancy up to 24 weeks’ gestation b) After fetal cardiac motion has become detectable on ultrasound, up to 65% of threatened miscarriages will continue with normal gestation c) ‘Missed miscarriage’ refers to a non-viable, intact gestational sac within the uterus, with delay to onset of symptoms of miscarriage d) ‘Blighted ovum’ generally refers to a missed miscarriage in which embryonic development stopped before the embryonic pole was visible 2. Which TWO statements are correct? a) About 1% of pregnancies are ectopic b) About 65% of ectopic pregnancies occur in the fallopian tube c) Partial hydatidiform mole is associated with a diploid karyotype d) Ultrasound in complete hydatidiform mole reveals a uterus filled with cystic placental villi, with no associated fetus 3. Which TWO statements are correct? a) A beta-hCG level is a reliable guide to gestational age of an undated pregnancy b) In healthy early pregnancy, beta-hCG levels double every 48-72 hours c) After a gestation sac has been identified in the uterus, beta-hCG levels can continue to rise in the absence of a live fetus d) Falling beta-hCG levels after 10 weeks’ gestation are indicative of a failing pregnancy ONLINE ONLY www.australiandoctor.com.au/cpd/ for immediate feedback 4. Which THREE statements are correct? a) While the discriminatory level at which an intrauterine pregnancy should be visible varies, a healthy gestation sac is often visible with transvaginal sonography at a beta-hCG level of 1000 IU/L b) If the beta-hCG is above the discriminatory level but no intrauterine sac (or retained products of conception) is visible, the differential diagnosis is ectopic pregnancy or complete miscarriage c) In pregnancies of unknown location, ultrasonography should be repeated if the beta-hCG level plateaus at <1500 IU/L or there is onset of new symptoms suggestive of ectopic pregnancy d) If an intrauterine gestation is seen on ultrasound but is of uncertain viability, repeat ultrasound in 7-10 days is most likely to be the most effective follow-up 5. Which TWO statements are correct? a) The earliest gestation at which an intrauterine gestation sac could be expected to be seen on transvaginal ultrasound would be four weeks and three days b) The earliest gestation at which fetal cardiac activity could be expected to be seen on transvaginal ultrasound is five weeks and six days c) A single serum progesterone level of <25nmol/L is confirmation that the pregnancy is not viable d) Serum progesterone levels can differentiate ectopic pregnancies from miscarrying intrauterine pregnancies 6. Which TWO statements about management of miscarriage are correct? a) All patients who have conservative management of miscarriage must have a follow-up ultrasound to ensure complete evacuation of the uterus b) Prophylactic antibiotics should be routinely prescribed for conservative management of miscarriage c) Indications for surgical management include late miscarriages and heavy bleeding d) Many women consider surgery the least emotionally traumatic method of managing miscarriage 7. Which THREE statements about the medical management of miscarriage using misoprostol are correct? a) Medical evacuation is probably best suited to women with early miscarriage and a small fetal pole b) About two-thirds of women treated with a single dose of misoprostol will progress to complete miscarriage within three days c) The overall failure rate of management of miscarriage with misoprostol is about 30% d) Bleeding may persist for up to three weeks after management with misoprostol 8. Which THREE statements about the management of ectopic pregnancy are correct? a) Referral of any patient with a suspected ectopic pregnancy is appropriate, at the earliest possible convenience b) Comparison of medical and surgical management for ectopic pregnancy shows similar success rates, future reproductive success and ectopic recurrence rates c) Adverse effects are more common with surgical treatment compared with medical treatment of ectopic pregnancy d) Medical management of ectopic pregnancy with methotrexate may be indicated after failed surgical treatment 9. Which TWO statements about management of ectopic pregnancy are correct? a) Rates of recurrent ectopic pregnancy after salpingotomy are very similar to those after salpingectomy b) Future fertility rates with salpingotomy are slightly higher than for salpingectomy c) It may take four weeks or more for beta-hCG levels to become negative after management of ectopic pregnancy with methotrexate d) Patients who have been treated with methotrexate for ectopic pregnancy can try for another pregnancy the following month 10. Which TWO statements about recurrent miscarriage are correct? a) Even after two consecutive miscarriages, most women will be able to achieve a successful pregnancy b) About 1% of women suffer recurrent miscarriage (three consecutive pregnancy losses) c) After three miscarriages the chance of success in the subsequent pregnancy is about 30% d) An underlying cause may be found in up to 20% of couples after three consecutive pregnancy losses CPD QUIZ UPDATE The RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. HOW TO TREAT Editor: Dr Wendy Morgan Co-ordinator: Julian McAllan Quiz: Dr Wendy Morgan NEXT WEEK The incidence of several important STIs is steadily increasing in Australia, amid an ongoing chlamydia epidemic. The next How to Treat comprises the first part of a two-part series on STIs. Part 1 focuses on screening, while in the following week part 2 looks at investigation and management. The author is Dr Catriona Ooi, director, sexual health, Hunter New England Area Health Service, NSW. 28 | Australian Doctor | 16 October 2009 www.australiandoctor.com.au