Miscarriage and ectopic pregnancy

Question 1

What is NICE guideline for first line management of first trimester miscarriage?

Answer 1

Use expectant management for 7 to 14 days as the first-line management strategy for women with a confirmed diagnosis of miscarriage.

Explore management options other than expectant management if:
• the woman is at increased risk of haemorrhage (for example, she is in the late first trimester) or
• she has previous adverse and/or traumatic experience associated with pregnancy (for example, stillbirth, miscarriage or antepartum haemorrhage) or
• she is at increased risk from the effects of haemorrhage (for example, if she has coagulopathies or is unable to have a blood transfusion) or
• there is evidence of infection.

Question 2

USS criteria to diagnose miscarriage

Answer 2

TV scan, two opinions and:

• CRL>7mm with no FH
• MSD >25 with no fetal pole

Or

• 2x USS 7-14 days apart with CRL <7mm with no FH /MSD <25mm with no fetal pole

If a TA scan, then needs to be 14 days apart

Empty uterus- consider possibility of PUL and follow up until HCG negative

Question 3

Expectant management of miscarriage

Answer 3

• Can be used for first 7-14 days
• If symptoms suggestive of miscarriage during this time which then resolve, recommend a urine pregnancy test in 3 weeks
• If not - then refer for consideration of medical/surgical management

Question 4

Medical management

Answer 4

Do not offer mifepristone as a treatment for missed or incomplete miscarriage. (despite latest evidence of benefit…)

• Offer vaginal misoprostol. Oral administration is an acceptable alternative if this is the woman’s preference.
• For women with a missed miscarriage, use a single dose of 800 micrograms of misoprostol, 600mcg for incomplete (or can align protocol and use 800mcg for both)
• Advise the woman that if bleeding has not started 24 hours after treatment, she should contact her healthcare professional to determine ongoing individualised care
• Inform women undergoing medical management of miscarriage about what to expect throughout the process, including the length and extent of bleeding and the potential side effects of treatment including pain, diarrhoea and vomiting.
• Advise women to take a urine pregnancy test 3 weeks after medical management of miscarriage unless they experience worsening symptoms, in
  which case advise them to return to the healthcare professional responsible for providing their medical management.

Question 5

Medical management for ectopic should be first line management for women with:

Answer 5

• no significant pain
• an unruptured ectopic pregnancy with an adnexal mass smaller than 35 mm with no visible heartbeat
• • a serum hCG level less than 1500 IU/litre
• no intrauterine pregnancy (as confirmed on an ultrasound scan).

Methotrexate should only be offered on a first visit when there is a definitive diagnosis
of an ectopic pregnancy, and a viable intrauterine pregnancy has been excluded. Offer
surgery where treatment with methotrexate is not acceptable to the woman.

Question 6

Surgical management for ectopic should be first line management for women with:

Answer 6

an ectopic pregnancy and significant pain
an ectopic pregnancy with an adnexal mass of 35 mm or larger
an ectopic pregnancy with a fetal heartbeat visible on an ultrasound scan
an ectopic pregnancy and a serum hCG level of 5000 IU/litre or more.

Question 7

Offer the choice of either methotrexate or surgical management to women with an ectopic pregnancy who have:

Answer 7

• a serum hCG level of at least 1500 IU/litre and less than 5000 IU/litre,
• who are able to return for follow-up
• no significant pain
• an unruptured ectopic pregnancy with an adnexal mass smaller than 35 mm with no visible heartbeat
• no intrauterine pregnancy (as confirmed on an ultrasound scan).

Advise women who choose methotrexate that their chance of needing further
intervention is increased and they may need to be urgently admitted if their condition
deteriorates. [

Question 8

HCG monitoring after methotrexate for PUL/ectopic

Answer 8

Take 2 serum hCG measurements in the first week (days 4 and 7) after treatment and then
1 serum hCG measurement per week until a negative result is obtained. If hCG levels plateau or rise, reassess the woman’s condition for further treatment.

Question 9

Salpingectomy vs salpingotomy

Answer 9

• Only consider salpingotomy for women who may have contralateral tube damage to preserve fertility
• Women will require measurement of HCG weekly until negative after salpingotomy

Inform women having a salpingotomy that 5-11% have residual gestational tissue and require further
treatment. This treatment may include methotrexate and/or a salpingectomy.

HOWEVER women with abnormal contralateral tube have been demonstrated to have higher spontaneous pregnancy rates if salpingotomy performed.

Question 10

USS features of ectopic pregnancy:

1. Features indicating there is an ectopic
2. Features highly suggestive of ectopic

Answer 10

1. an adnexal mass, moving separate to the ovary, comprising a gestational sac or containing a yolk sac or
   • an adnexal mass, moving separately to the ovary, comprising a gestational sac and fetal pole (with or without fetal heartbeat).
2. an adnexal mass, moving separately to the ovary, with an empty gestational sac (sometimes described as a ‘tubal ring’ or ‘bagel sign’) or
   • a complex, inhomogeneous adnexal mass, moving separate to the ovary

Question 11

Offer expectant management for ectopic pregnancy for women who are:

Answer 11

are clinically stable and pain free and
• have a tubal ectopic pregnancy measuring less than 35 mm with no visible heartbeat
on transvaginal ultrasound scan and
• have serum hCG levels of 1,000 IU/L or less and
• are able to return for follow-up.

Question 12

Monitoring of women with expectant management of ectopic:

Answer 12

For women with a tubal ectopic pregnancy being managed expectantly, repeat hCG levels on days 2, 4 and 7 after the original test and:
• if hCG levels drop by 15% or more from the previous value on days 2, 4 and 7, then
repeat weekly until a negative result (less than 20 IU/L) is obtained or
• if hCG levels do not fall by 15%, stay the same or rise from the previous value, review the woman’s clinical condition and seek senior advice to help decide further
management.

Question 13

Definition of ectopic pregnancy

Answer 13

Occurs when developing blastocyst becomes implanted at site other than the endometrium of the uterine cavity
Most common extra-uterine location is the fallopian tube, which accounts for 98% of all ectopic gestations
Ampullary 	70%
Isthmic 		12%
Fimbrial 		11.1%
Ovarian 		3.2%
Interstitial 	2.4%
Abdominal 	1.3%

Question 14

Risk factors for ectopic pregnancy

Answer 14

High:

• Previous ectopic
• Previous tubal surgery or ligation
• Tubal pathology
• In utero DES exposure
• Current IUD use

Medium:

• Infertility
• Previous cervicitis/PID/multiple sexual partners
• Smoking

Low:

• Early age of intercourse
• Previous pelvic surgery

Question 15

History and examination findings in women with an ectopic pregnancy?

Answer 15

Clinical history:
Classic symptoms can occur in both ruptured and unruptured cases;
Abdominal pain
Amenorrhoea
Vaginal bleeding
In addition, normal pregnancy discomforts (breast tenderness, frequent urination, nausea) often present
Also, intra-abdominal bleeding may irritate the diaphragm and cause shoulder pain
Blood pooling in the cul-de-sac may cause an urge to defecate
Lightheadedness or shock suggests tubal rupture → resulting in severe intra-abdominal haemorrhage

Clinical examination:
Vital signs may reveal orthostatic changes and, occasionally, low grade fever
Adnexal, cervical motion, and/or abdominal tenderness
Adnexal mass, and mild uterine enlargement
Physical examination is often unremarkable in a woman with a small, unruptured ectopic pregnancy

Question 16

What is an interstitial ectopic?

Answer 16

Uncommon, comprising about 2% of all ectopic pregnancies
Interstitial portion of fallopian tube is the proximal segment embodied within the muscular wall of the uterus
Can grow larger than those within fallopian tube because surrounding myometrium more expandable than tube
May be misdiagnosed as intrauterine because of advance gestational age and partial endometrial implantation
Clue to correct diagnosis is its eccentric location and thin (less than 5 mm) myometrial mantle
USS shows gestational sac or hyperechoic mass in cornua (sens 80%, spec 99%), with myometrial thinning
Unique anatomical location often leads to delay in diagnosis, thus rupture of uterus is a common presentation
Maternal mortality rate remains at 2 to 2.5% because of misdiagnosis of intrauterine pregnancy

Question 17

USS features of cervical ectopic

Answer 17

empty uterus,
barrel-shaped cervix,
gestational sac present below the level of the internal cervical os,
the absence of the ‘sliding sign’
blood flow around the gestational sac using colour Doppler

Question 18

USS features of interstitial ectopic

Answer 18

empty uterine cavity,
products of conception/gestational sac located laterally in the interstitial(intramural) part of the tube
surrounded by less than 5 mm of myometrium in all imaging planes
presence of the ‘interstitial line sign’

Question 19

What are the surgical, pharmacological or conservative treatment options for cervical pregnancy?

Answer 19

Medical management with methotrexate can be considered for cervical pregnancy.

Surgical methods of management are associated with a high failure rate and should be reserved for those women suffering life-threatening bleeding.

A serum b-hCG level greater than 10 000 iu/l is associated with a decreased chance of successful methotrexate treatment

Question 20

What are the surgical, pharmacological or conservative treatment options for caesarean scar pregnancy?

Answer 20

Women diagnosed with caesarean section scar pregnancies should be counselled that such pregnancies are associated with severe maternal morbidity and mortality.

Medical and surgical interventions with or without additional haemostatic measures should be considered in women with first trimester caesarean scar pregnancy.

There is insufficient evidence to recommend any one specific intervention over another for caesarean scar pregnancy, but the current literature supports a surgical rather than medical approach as the most effective.

Question 21

What are the long-term fertility prospects following an ectopic pregnancy?

Answer 21

In the absence of a history of subfertility or tubal pathology, women should be advised that there is no difference in the rate of fertility, the risk of future tubal ectopic pregnancy or tubalpatency rates between the different management methods.

Women with a previous history of subfertility should be advised that treatment of their tubal ectopic pregnancy with expectant or medical management is associated with improved reproductive outcomes compared with radical surgery.

Women receiving methotrexate for the management of tubal ectopic pregnancy can be advised that there is no effect on ovarian reserve.

Question 22

USS features that may distinguish between an early IUP and a pseudosac

Answer 22

IUP:
- intradecidual and double decidual signs

intradecidual sign: a fluid collection with an echogenic rim located ‘within a markedly thickened decidua on one side of the uterine cavity’.

Double decidual sign: an intrauterine fluid collection surrounded by ‘two concentric echogenic rings’.

Question 23

Adverse effects of methotrexate

Answer 23

Success rate 65-95% depending on factors such as HCG level and rise, size of ectopic etc.

Side effects: marrow suppression, pulmonary fibrosis, nonspecific pneumonitis, liver cirrhosis, renal failure and gastric ulceration.

The most common adverse effects are excessive flatulence and bloating due to intestinal gas formation, a transient mild elevation in liver enzymes and stomatitis.

Question 24

Risk factors for recurrent miscarriage

Answer 24

Epidemiological risk factors:

• Age of woman (particularly if >35, up to 50% if >40), also higher if paternal age >40
• Smoking
• Alcohol use
• Caffeine
• Obesity

Medical conditions:

• Anti-phospholipid syndrome (present in 15% of women with recurrent miscarriage, only 2% in general population) - can be treated with heparin to reduce risk
• Inherited thrombophilias

Genetic abnormalities:

• Chromosomal abnormalities- 2-5% of couples may have balanced reciprocal or robertsonian translocation
• Embryonic chromosomal abnormalities

Anatomical/structural pathology

• Uterine abnormalities
• Cervical weakness (more for 2nd trimester loss)

Endocrine disorders:

• Diabetes and thyroid disease if not well controlled
• PCOS

Infections:
- Severe infection can cause miscarriage. Association between BV and 2nd trimester loss but no evidence for 1st trimester

Question 25

How does antiphospholipid syndrome cause adverse pregnancy outcomes?

Answer 25

3 antibodies: – lupus anticoagulant,
anticardiolipin antibodies and anti-B2 glycoprotein-I antibodies

Pathogenesis:
inhibition of trophoblastic function and differentiation,
activation of complement pathways at the maternal–fetal interface resulting in a local inflammatory response
in later pregnancy, thrombosis of the uteroplacental vasculature.

In vitro studies have shown that the effect of antiphospholipid antibodies on trophoblast function and complement activation is reversed by heparin

Question 26

Investigations for recurrent miscarriage and second trimester loss

Answer 26

• Antiphospholipid screen
• Karyotyping of POC
• Pelvic USS to assess pelvic anatomy
• Women with second-trimester miscarriage should be screened for inherited thrombophilias including factor V Leiden, factor II (prothrombin) gene mutation and
  protein S

Question 27

Treatment for recurrent miscarriage

Answer 27

Pregnant women with antiphospholipid syndrome should be considered for
treatment with low-dose aspirin plus heparin to prevent further miscarriage

The finding of an abnormal parental karyotype should prompt referral to a clinical
geneticist

There is insufficient evidence to assess the effect of uterine septum resection in
women with recurrent miscarriage and uterine septum to prevent further miscarriage.

PRISM and PROMISE trials found small benefit in giving progesterone to women with PV bleeding and hx of recurrent miscarriage

Question 28

How do mifepristone and misoprostol work?

Answer 28

Mifepristone is a progesterone receptor (and glucocorticoid) antagonist. As progesterone supports uterine quiescence and vascularity of the decidua, blocking it causes shedding of the decidua and sensitises the myometrium to the effects of misoprostol.

Misoprostol is a PGE1 analogue, and binds prostaglandin receptors in the myometrium to cause uterine contractions.

Question 29

What is the evidence for mifepristone prior to misoprostol in the management of first trimester miscarriage?

Answer 29

Large multi centre RCT in Netherlands 2021
- Mifepristone vs placebo followed by course of misoprostol

Findings:

• Increased successful complete miscarriage at follow-up USS at 6 weeks - NNT 4.9
• Reduced risk of requiring secondary surgery

Cochrane 2011

• Combined regimens are more effective than single agents.
• The dose of mifepristone can be lowered to 200 mg without significantly decreasing the method effectiveness.
• Vaginal misoprostol is more effective than oral administration
• sublingual or buccal misoprostol is equally as effective as vaginal, but has more significant side effects

Question 30

Risk of ectopic after previous ectopic pregnancy.

Answer 30

18.5% after one ectopic pregnancy.

Current evidence suggests no statistically significant difference in the rate of ectopic pregnancy between different treatment options, including: salpingectomy, salpingostomy, methotrexate and conservative management.

Question 31

What is effect of different treatment options for ectopic pregnancy on future fertility?

Answer 31

There is no statistically significant difference in future pregnancy rates between the different treatment options, as long as the contralateral tube is structurally normal and the patient does not have issues with subfertility.

In patients with subfertility or known deformity of the contralateral fallopian tube, tube-preserving surgery, methotrexate or conservative measures have been demonstrated to result in higher pregnancy and live birth rates. (De Bennetot et al. 2012)