Recurrent Pregnancy Loss

Question 1

What is the definition of recurrent pregnancy loss (RPL)?

Answer 1

> /=2 consecutive losses

Question 2

What is the definition of, and how common is early 1st trimester PL?

Answer 2

Early 1st trimester PL = btw conception and 9 6/7 wks, occurs in up to 20% of pregnancies

Question 3

What percentage of clinically identified pregnancies end with early PL? Of all conceptions?

Answer 3

At least 15-20% of clinically identified pregnancies end w/ early PL.
Only 50-60% of all conceptions advance to 20 weeks.

Question 4

What is the chance of a viable next pregnancy after one uncomplicated early PL in a healthy, young woman?

Answer 4

75%

Question 5

What workup or therapy is indicated after one PL?

Answer 5

None.

Question 6

Which women should be offered work-up for RPL?

Answer 6

Women with >/= 2 primary RPLs

Women with >/= 3 secondary RPLs

Question 7

What history should be obtained in the work-up for RPL?

Answer 7

Smoking, alcohol, caffeine use
Illicit drug use
Environmental exposures
Working conditions
Medical/obstetric/family hx

Question 8

What is the differential diagnosis of RPL?

Answer 8

Uterine anomalies
Antiphospholipid antibody syndrome
Parental chromosome abnl
Diabetes
Thyroid disease

Question 9

Should women with RPL be tested for diabetes or thyroid disease?

Answer 9

Only if suggested by history and/or physical examination.

Question 10

What percentage of women with RPL have uterine anomalies?

Answer 10

10-15%

Question 11

What is the most common uterine anomaly associated with RPL? Next most common?

Answer 11

Septate uterus, followed by didelphys and bicornuate.
Uterine synechiae and DES are also assoc with RPL.
Arcuate uterus and uterine leimyoma have not been consistently associated with RPL.

Question 12

What studies are recommended to evaluate for uterine anomalies in RPL?

Answer 12

3D sonohysterography (day 8-10 of follicular phase)
HSG
Hysteroscopy
2D sonohysterography
MRI

Question 13

Is there evidence to support hysteroscopic correction of uterine anomalies as therapy for RPL?

Answer 13

There are no trials regarding this intervention.

There is a high likelihood of successful pregnancy in women with unrepaired septa.

Repair of bicornuate or unicornuate uteri is usually not suggested, as outcomes are usually good without repair, and surgical repair is usally assoc with higher risk of complications.

Question 14

How frequently do couples with recurrent miscarriage have translocation as a cause?

Answer 14

A balanced reciprocal translocation or robertsonian translocation in one partner occurs in 2-4% of couples with recurrent miscarriage.

Question 15

How frequently do embryos of couples with balanced reciprocal or Robertsonian translocations have unbalanced translocations?

Answer 15

50-70% of the time

Question 16

What therapy is available for RPL in couples with an abnormal karyotype?

Answer 16

Genetic counseling
Prenatal diagnosis
Gamete donation
Preimplantation genetic screening with IVF is not supported by RCTs and should therefore not be recommended (Branch NEJM 2010)

Question 17

What is the live birth rate for a couple with a structural chromosomal abnl - spontaneous conception vs IVF with PCD?

Answer 17

EB OB - Ironically, couples with a structural chromosomal abnormality who conceive spontaneously have a higher rate of live births (50% to 65%) than those conceiving after in vitro fertilization with preimplantation genetic screening, which is associated with a 29% live birth rate per oocyte retrieval and 38% per embryo transfer.

Question 18

What is the most common cause of embryonic loss before 10w gestation?

Answer 18

Aneuploidy

Question 19

What percentage of early PL are caused by cytogenetic abnormalities?

Answer 19

At least 50%

Question 20

Collectively, what is the most common aneuploidy found in early PL?

Answer 20

Trisomy, followed by polyploidy and monosomy X

Question 21

What is the most common single aneuploidy found in early PL?

Answer 21

45,X

Question 22

What are the clinical criteria for the diagnosis of antiphospholipid syndrome (APS)?

Answer 22

APS diagnosis requires the presence of at least one clinical and one laboratory criteria.

Clinical criteria:

1. One or more episodes of arterial, venous, or small vessel thrombosis, confirmed by objective criteria (imaging or pathology), and/or
2. Pregnancy morbidity
   a. One or more unexplained deaths of a morphologically normal (by US or path) fetus >/= 10w gestation, and/or
   b. One or more premature births of a morphologically normal neonate befoe 34w due to eclampsia, preeclampsia, or placental insufficiency, and/or
   c. Three or more unexplained consecutive SABs before 10w, with anatomic/hormonal/chromosomal causes excluded.

Question 23

What are the laboratory criteria for the diagnosis of APS?

Answer 23

APS diagnosis requires the presence of at least one clinical and one laboratory criteria.

1. Lupus anticoagulant present in plasma, on 2 or more occasions, at least 12w apart (tests = LA, DRVVT, or aPTT)
2. Anticardiolipin antibody of IgG or IgM isotype in serum or plasma, >40 GPL or MPL, or >99th percentile, on 2 or more occasions, at least 12w apart
3. Anti-B2 glycoprotein 1 of IgG or IgM isotype in serum or plasma, >40 GPL or MPL, or >99th percentile, on 2 or more occasions, at least 12w apart

Question 24

Does ACOG recommend screening women with a history of preterm severe preeclampsia or IUGR for APS?

Answer 24

No. “Although preterm severe preeclampsia and early onset placental insufficiency are indicated as clinical criteria for the diagnosis of APS by expert consensus, insufficient evidence currently exists to support that screening and treatment of women with these conditions improves subsequent pregnancy outcomes.”

Question 25

What are the maternal complications of APS?

Answer 25

Venous & arterial thromboembolism (5-12%, 60% venous)
Preeclampsia (18-48%)
Autoimmune thrombocytopenia (40-50%)

Question 26

What are the fetal complications of APS?

Answer 26

Pregnancy loss, fetal death
Fetal growth restriction
Preterm birth (due to FGR or preeclampsia)
Placental abruption

Question 27

How should APS, with a previous thrombotic event, be managed during pregnancy and the postpartum period?

Answer 27

ACOG - Prophylactic heparin throughout pregnancy and 6w postpartum. Patients in most series also received low-dose aspirin, but the benefit of adding aspirin is unknown.

The data are insufficient to support or refute a specific practice, but many experts recommend serial US assessment and antepartum testing in the third trimester.

Question 28

How should APS, without a previous thrombotic event, be managed during pregnancy and postpartum?

Answer 28

ACOG - The optimal treatment of women with APS w/o a preceding thrombotic event has not been well studied. However, expert consensus suggests that clinical surveillance or prophylactic heparin use antepartum in addition to 6 weeks of postpartum anticoagulation may be warranted. A meta-analysis suggested that, for women with recurrent pregnancy loss and APS, prophylactic use of heparin and low-dose aspirin may reduce pregnancy loss by 50%.

The data are insufficient to support or refute a specific practice, but many experts recommend serial US assessment and antepartum testing in the third trimester.

Question 29

At what dose and when should low dose aspirin be started for APS?

Answer 29

Therapy is usually begun once fetal viability is established, but there is insufficient evidence regarding best time of initiation of therapy. Low-dose aspirin dose is usually about 75 to 100 mg daily, and some experts recommend starting it even preconception in severe cases.

Question 30

Dosing of prophylactic heparin

Answer 30

1st trimester - 5000 to 7500 U SC q 12 hrs
2nd trimester - 7500 to 10000 U SC q 12 hrs
3rd trimester - 10,000 U SQ q 12 hrs

Question 31

Dosing of prophylactic LMWH

Answer 31

Enoxaparin (Lovenox) 30 to 40 mg SQ q 12 hrs, or
Dalteparin (Fragmin) 5000 U SQ q 12 hrs

May adjust prophylaxis in high-risk cases to a heparin (anti-Xa) level range of 0.2 to 0.4. Anti-Xa level is usually drawn four hours after injection. Anti-Xa levels have not been adequately evaluated prospectively to show a reduction in the incidence of complications.

Question 32

Dosing of therapeutic heparin

Answer 32

Usually enoxaparin 1 mg/kg q12h SQ, or dalteparin 200 U/kg q12h SQ.

Therapeutic intravenous UFH doses need to be adjusted to keep activated partial thromboplastin time (aPTT) two to three times normal.

Therapeutic LMWH must be adjusted to heparin (anti-Xa) level 0.5 to 1.2. After initial therapy, subcutaneous therapeutic LMWH or UFH should be continued for a minimum total duration of six months.

Question 33

How common is heparin-induced thrombocytopenia, and when does it usually occur?

Answer 33

HIT occurs in <5% of women on heparin therapy, is usually mild, and starts usually 3 to 15 days after initiation of therapy. Check platelet counts initially and then weekly in the first three weeks of therapy.

Question 34

How should anticoagulation and anesthesia be managed near-term and at delivery?

Answer 34

If on UFH, regional anesthesia can be administered usually six to eight hours after the dose, or at least when the aPTT is within normal limits.

If on LMWH, regional anesthesia should be delayed until >24 hours after the last dose, since there is a risk of spinal hematoma if regional anesthesia is performed within 24 hours. That is why a woman on LMWH might be switched off LMWH on to UFH weeks before any chance of labor or delivery (usually around 36 weeks if no other risk of preterm birth).

Question 35

How effective is prednisone for the treatment of APS?

Answer 35

ACOG - The efficacy of prednisone in pregnancies complicated by APS remains uncertain and, because of the risks associated with the prophylactic use of prednisone for this indication, its use is discouraged solely for the treatment of APS.

Question 36

How effective is IVIG for the treatment of APS?

Answer 36

ACOG - A small RCT demonstrated no greater benefit from IVIG (plus heparin and aspirin) than from heparin and aspirin alone. Because the efficacy of IVIG has not been proved in appropriately designed studies and the drug is extremely expensive, its use is not recommended.

Question 37

What is appropriate long-term postpartum management of APS?

Answer 37

In studies of women w/ APS, including studies of women without prior thrombosis, one half developed thromboses during 3-10 years of follow-up and 10% developed systemic lupus erythematosus.

No method currently predicts which patients with antiphospholipid syndrome using anticoagulants will develop recurrent thrombosis once treatment is discontinued. In addition, no evidence exists to support long-term treatment when thrombotic events occur in the presence of other risk factors. Therefore, for long-term management postpartum, patients with antiphospholipid syndrome should be referred to a physician with expertise in treatment of the syndrome, such as an internist, hematologist, or rheumatologist.

Question 38

Does the use of estrogen-containing oral contraceptives increase the risk of thrombosis in women with APS?

Answer 38

Yes. Experts concur that women with APS should not use estrogen-containing contraceptives, but that progesterone-only forms of contraception are appropriate.

Question 39

When should a karyotype of products of conception be obtained?

Answer 39

In women with >/= 2 RPLs.

Question 40

Which infectious agents have been proven to cause RPL?

Answer 40

None. Chlamydia, mycoplasma/ureoplasma, and BV are associated with sporadic PL, not RPL.

Question 41

When are EMB or progesterone levels recommended in the work-up of RPL?

Answer 41

Never. Hypothesis: Corpus luteum doesn’t make enough P to sustain early decidua for placentation. EMB has a 2 day discrepancy with endometrial cycle in 50% of normal cycles, and there is high interobserver variation in EMB interpretation. There is insufficient evidence that progesterone supplementation improves outcomes in RPL.

Question 42

What percent of couples with unexplained RPL have successful next pregnancies?

Answer 42

60-70%, decreases to 40% in women over 40.

Question 43

Is there evidence for progesterone therapy in unexplained RPL?

Answer 43

Yes. Evidenced Based Obstetrics - in women w/ >/= 3 consecutive SABs, progesterone is associated with a statistically significant 61% decreased in miscarriage rate, compared with placebo or no treatment, in 3 small trials. No differences found regarding route (PO, IM or PV) or dose. Also no difference in adverse outcomes.

Question 44

Is there evidence that supports a policy of bed rest to prevent PL on women with confirmed fetal viability and vaginal bleeding in the 1st half of the pregnancy?

Answer 44

No. Cochrane review - RR 1.54, 95% CI 0.92-2.58.