Abstract
Early pregnancy problems are common and cause significant physical and psychological morbidity and mortality. Miscarriage is thought to affect one in five pregnancies and ectopic pregnancy to occur in 1 in 100 gestations though these rates are higher in pregnancies resulting from assisted reproductive techniques (ART) than in spontaneous pregnancies. According to the third annual report of the Confidential Enquiry into Maternal Deaths by MBRRACE-UK, in 2009–2014, 12 women died from early pregnancy-associated causes [1]. Nine of these women died as a direct result of an ectopic pregnancy and three women died following termination or attempted termination of pregnancy. In the triennium 2012–2014, the maternal mortality rate due to early pregnancy problems was 0.29 per 100,000 maternities.
1 Introduction
Early pregnancy problems are common and cause significant physical and psychological morbidity and mortality. Miscarriage is thought to affect one in five pregnancies and ectopic pregnancy to occur in 1 in 100 gestations though these rates are higher in pregnancies resulting from assisted reproductive techniques (ART) than in spontaneous pregnancies. According to the third annual report of the Confidential Enquiry into Maternal Deaths by MBRRACE-UK, in 2009–2014, 12 women died from early pregnancy-associated causes [1]. Nine of these women died as a direct result of an ectopic pregnancy and three women died following termination or attempted termination of pregnancy. In the triennium 2012–2014, the maternal mortality rate due to early pregnancy problems was 0.29 per 100,000 maternities.
2 Terminology
It is important that the terminology used in early pregnancy problems does not distress women further. For this reason the term ‘abortion’ should be avoided, and the term ‘miscarriage’ used instead to describe a non-viable intrauterine pregnancy. It is also important that terminology is used consistently to allow comparison of research data. The European Society of Human Reproduction and Embryology (ESHRE) early pregnancy special interest group published a consensus statement in 2015 advocating the use of terminology as in Table 24.1 [2].
Table 24.1 Terminology for classifying pregnancy failure prior to viability for research purposes [2]
3 Diagnosis of Ectopic Pregnancy and Miscarriage
Ultrasound in the early stages of pregnancy (up to 10 weeks of gestation) is important and necessary for many clinical reasons. A recent RCOG Scientific Impact Paper [3] reassures that ultrasound for clinical reasons is safe during the early stages of pregnancy and the benefits outweigh any potential risks. During the first 10 weeks of pregnancy the fetus is most vulnerable because it is extremely small, the cells are dividing quickly and the placenta is not attached so there is limited blood flow. Certain types of ultrasound (colour and pulse waved Doppler) use a higher power output and should not be recommended at all during the early stages of pregnancy. Ultrasound for non-medical reasons is not recommended. It is important that healthcare professionals have a good knowledge of the safety principles of ultrasound.
Transvaginal ultrasound is more effective than transabdominal ultrasound for visualising the structures of the pelvis and should be the preferred approach for the assessment of an early pregnancy [4]. A transabdominal ultrasound scan should be considered for women with an enlarged uterus or other pelvic pathology, such as fibroids or a large ovarian cyst.
3.1 Pregnancy of Unknown Location
If a woman has a positive pregnancy test and no intrauterine or extrauterine pregnancy is visible on transvaginal ultrasound scan, this is termed a pregnancy of unknown location (PUL). PULs include complete miscarriages that have not been seen previously on ultrasound scan, viable intrauterine pregnancies that are too small to visualise and some ectopic pregnancies. Two measurements of human chorionic gonadotrophin (hCG) taken 48 hours apart can be used to determine subsequent management. A single progesterone measurement may also help to identify PULs that are likely to resolve spontaneously. It is important to remember that neither hCG nor progesterone concentrations can be used to identify the location of a pregnancy and that no method is validated in ART. When the serum hCG increases by more than 63% in 48 hours a transvaginal ultrasound should be performed 7–14 days later to determine the location of the pregnancy. An earlier repeat scan should be considered when the initial hCG is 1500 IU/litre or more. When there is a decrease in serum hCG of more than 50% after 48 hours, a continuing pregnancy is unlikely and a urine pregnancy test should be done in 14 days. When the change in serum hCG concentration is between a 50% decline and 63% rise, the woman should be referred to the early pregnancy service within 24 hours [4].
3.2 Miscarriage
If on transvaginal ultrasound an intrauterine pregnancy is seen and the crown–rump length is less than 7 mm and there is no visible heartbeat, a second scan should be performed a minimum of 7 days after the first before making a diagnosis. Further scans may be needed before a diagnosis can be made. If on transvaginal ultrasound scan an intrauterine gestation sac is seen with a mean gestation sac diameter >/= 25 mm (with no obvious fetal pole) or a fetal pole with crown rump length >/=7 mm (the latter without evidence of fetal heart activity), a second opinion and/or second scan a minimum of 7 days later should be performed. If there is no growth, this is suggestive of a diagnosis of miscarriage [4].
The presence of transvaginal bleeding or lower abdominal pain and ultrasound images showing heterogenous irregular echoes in the midline of the uterine cavity [5] suggest the diagnosis of an incomplete miscarriage. Retained products are usually seen as a well-defined area of hyperechoic tissue within the uterine cavity as opposed to blood clots, which are poorly outlined. Blood clots will be also seen sliding within the uterine cavity when pressure is applied on the uterus by a transvaginal probe [6]. If a measurable focus of hyperechoic tissue is seen, in 85% chorionic villi are identified on evacuation of retained products of conception (ERPC) [7].
3.2.1 Complete Miscarriage
The diagnosis of a complete miscarriage can only be made by ultrasound if an intrauterine pregnancy has been seen previously. If this is the case and on a transvaginal ultrasound scan the ET < 15 mm and there is no evidence of retained products of conception (RPOC) there is unlikely to be a significant amount of RPOC and so this can be labelled a complete miscarriage. It should be remembered, however. that even with a 2 mm ET, 57% may still have chorionic villi present. The cessation of pain and bleeding is also suggestive of a complete miscarriage.
3.2.2 Threatened Miscarriage
Women with vaginal bleeding and a confirmed viable intrauterine pregnancy should be reassessed if the bleeding becomes heavier or persists for more than 14 days. Whether or not the use of progesterone treatment for women who bleed in early pregnancy reduces the risk of miscarriage will hopefully be answered by the ongoing randomised controlled trial PRISM. In ART, luteal support with progesterone is conventionally continued until between 8 and 12 weeks gestation. There is, however, increasing evidence that early cessation of progesterone support does not increase miscarriage rates even in presence of bleeding [8].
3.2.3 Management of Miscarriage
Until recently the mainstay of treatment for the management of miscarriage has been surgical management, or the evacuation of RPOC, under general anaesthetic. Over the past decade, however, the focus has shifted from urgent surgical management to more individualised treatment and patient choice between expectant, medical and semi-elective surgical management.
It is currently recommended that expectant management should be used as first-line management in women with a confirmed diagnosis of miscarriage for the first 7–14 days. In situations where expectant management is not suitable, such as when there is an increased risk of haemorrhage or there is evidence of infection, or if expectant management is not acceptable to the woman, other management options should be explored [4]. Sufficient information and appropriate support should be provided regardless of the treatment method.
The success rate of expectant management varies widely. The type of miscarriage is significant with higher success rates seen in incomplete miscarriages (80–94%) and lower success rates in early embryonic demise (28–76%) [9]. The chance of successful resolution also increases with the length of the follow-up. Women should be counselled to allow 2 weeks for expectant management and around 50% will resolve in this time. If there is no evidence of infection, women can continue with expectant management after this if they wish, and should be reviewed again at a minimum of 14 days. The infection rate with expectant management is 2% at 14 days and 3% at 8 weeks, and this is not significantly different from surgical management [10].
Medical management offers women the option of active treatment of miscarriage without the need for surgery and can be offered in the outpatient setting. The most commonly used drug is misoprostol, a prostaglandin analogue. This is licensed for oral use only but can be administered vaginally, sublingually or rectally. The antiprogesterone drug mifepristone should not be used to treat missed or incomplete miscarriage as it has not been shown to increase success rates compared to misoprostol alone. Current guidelines suggest a single vaginal dose of 800 micrograms of misoprostol for women with a missed miscarriage and 600 micrograms (or 800) for women with an incomplete miscarriage. Pain relief and antiemetics should also be offered. Women should be advised to seek help if bleeding has not started 24 hours after treatment and if the urine pregnancy test at 3 weeks after medical management is positive [4].
The success rate of medical management depends on the type of miscarriage, the drug regimen and the time allowed for products to be passed. Studies show success rates ranging from 70–96% for incomplete miscarriages and 52–92% for embryonic demise. For women diagnosed with incomplete miscarriages, medical management does not increase the rate of success over expectant management alone. Complications of medical management include the diarrhoea and vomiting associated with prostaglandin use and heavy bleeding requiring emergency evacuation in around 5% of cases [11].
Surgical management of miscarriage is the most successful option for the management of miscarriage, with a complete evacuation rate of 97% [12]. It is the most appropriate treatment for women who present with excessive bleeding, are haemodynamically unstable, have signs of infected RPOC or where there is a provisional diagnosis of gestational trophoblastic disease. Other women may prefer surgical intervention because it is quick and this may help with the grieving process. Suction curettage under general anaesthesia or manual vacuum aspiration under local anaesthetic in an outpatient setting can be used to remove RPOC. Cervical priming with misoprostol can be used to reduce the risk of uterine perforation. All at-risk women should be screened for Chlamydia trachomatis.
The MIST trial [10] looked at the incidence of infection in women managed surgically, medically and expectantly and no difference in the rate of infections was seen. Excessive bleeding is less likely to occur with surgical management than with expectant or medical management. Cervical damage and uterine perforation are uncommon complications of surgical management, with rates of 0.3% and 1.9% respectively. Intrauterine adhesions can form as a result of the trauma to the endometrium during surgical curettage in up to 8% of women. These can be a cause of subfertility and recurrent miscarriage. Fetomaternal haemorrhage can occur in surgical procedures and it is therefore recommended that non-sensitised RhD negative women who undergo evacuation should be given anti-D.
3.3 Ectopic Pregnancies
Any pregnancy implanted outside the uterine cavity is termed an ectopic pregnancy. More than 10,000 ectopic pregnancies are diagnosed annually in the United Kingdom with an incidence of around 11 per 1,000 pregnancies [1]. Ectopic pregnancy continues to be a cause of maternal death although the case fatality rate has fallen over recent years, most likely due to earlier diagnosis and treatment. Risk factors include tubal damage following surgery or infection, smoking and IVF, although the majority of women with an ectopic pregnancy do not have an identifiable risk factor. Ectopic pregnancies can be divided into those that are extrauterine (tubal, ovarian and abdominal) and those that are uterine (interstitial, cervical, caesarean scar and cornual). Around 95% of ectopic pregnancies occur within the fallopian tube, with the ampullary region of the tube being the most common site.
3.3.1 Tubal
Tubal ectopic pregnancies should be positively identified using transvaginal ultrasound. An inhomogenous or noncystic mass that moves separate to the ovary is most commonly seen, though an empty extrauterine gestational sac or an extrauterine gestational sac containing a yolk sac and/or embryonic pole may be present [14]. Free fluid is also often seen on ultrasound and is not diagnostic of ectopic pregnancy though it can be the result of a tubal rupture or of blood leaking from the fimbrial end of a tube [15].
Tubal ectopic pregnancies can be treated surgically, medically or expectantly. The serum hCG level is not useful for making a diagnosis of ectopic pregnancy but is useful for determining the success of conservative management options. The National Institute for Health and Care Excellence (NICE) recommends that medical management with systemic methotrexate should be the first-line management for women who are able to return for follow-up and who meet the following criteria:
no significant pain
an unruptured ectopic pregnancy with a mass smaller than 35 mm with no visible heartbeat
a serum hCG between 1500 and 5000 IU/litre
no intrauterine pregnancy (as confirmed on ultrasound scan) [4].
Methotrexate should not be given at the first visit because of the chance that there is a viable intrauterine pregnancy.
For women who have minimal pain, have low (less than 1500 IU/litre) and declining hCG levels, and are willing and able to attend for follow-up, expectant management is a reasonable option. Success rates vary from 57 to 100% and depend upon case selection [16].
Women who have a tubal ectopic pregnancy and significant pain, an adnexal mass of 35 mm or larger, a visible fetal heartbeat on ultrasound scan, a serum hCG level of 5000 IU/litre or more or where treatment with methotrexate is not an acceptable option, should be offered surgery as first-line treatment. A laparoscopic approach is generally preferred to an open approach and in the presence of a healthy contralateral tube, salpingectomy should be performed rather than salpingotomy as there is a lower rate of persistent trophoblast. However, salpingotomy should be considered in women with a history of fertility-reducing factors (previous ectopic pregnancy, contralateral tubal damage, previous abdominal surgery or previous pelvic inflammatory disease) [13].
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