الفهرس 
(1) IntroductionOnly 14 pages are availabe for public view
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Abstract
Concerns have been raised by a lot of researchers about psychological impact on all women who experienced early pregnancy loss.so, different causes and different methods for management of early pregnancy loss were put in consideration.
This research (systematic review) helps to analyze results obtained from previous studies through certain search strategy aiming at answering questions about different causes of early pregnancy loss, relation of toxoplasmosis to early pregnancy loss and recent trends in management of early pregnancy loss.
In order to answer these questions navigation through the internet and visiting websites was done using keywords searching for studies published during the last 10 years concerned with recent trends in management of early pregnancy loss.
This was followed by identification of large number of studies which were considered potentially relevant from which those fulfilling the inclusion criteria were considered eligible. Data were extracted from these studies, summarized, tabulated clearly and analyzed to help answering the suggested questions.
As regards the prevalence of early pregnancy loss:
1- Spontaneous abortion is between 15% and 20% of all clinical pregnancies.
2- 25% of miscarriages occur by 12 weeks gestation.
3- The risk of early miscarriage may increase with increasing age of the male partner.
4- In assisted reproduction (IVF or ICSI), 22% of the achieved pregnancies were lost before the onset of menses.
As regards the risk factors and different causes of early pregnancy loss:
● Genetic causes and early pregnancy loss:
1- Increase risk for fetal aneuploidy is associated with increase risk of early miscarriage.
2- Routine karyotype analysis after 1 miscarriage is not cost-effective or prognostic. However, after 2 SABS, analysis of abortuses is useful.
● Auto-immune diseases and early pregnancy loss:
1- There is a strong relationship between early pregnancy loss and anti-phospholipid syndrome and heritable thrombophilias.
2- Subcutaneous heparin 5000 IU given twice a day with low dose aspirin 81 mg/d increases fetal survival rates from 50% to 80% among women who have had at least 2 losses and who have un equivocally positive results for APLA.
● Uterine anomalies and early pregnancy loss:
1- Anatomic uterine defects may be associated with early pregnancy loss due to impaired vascularization and fetal growth restriction.
2- Surgical correction of uterine anomalies improves pregnancy outcomes.
● Maternal infections and early pregnancy loss:
1- There is some sort of relation between genital infection (chronic cervicitis and bacterial vaginosis) and early pregnancy loss.
2- (3-4%) of CMV positive infections are associated with early pregnancy loss.
3- There is a weak relation between HIV infections, Rubella virus infections, Herpes Simplex infections and early pregnancy loss.
● Medical diseases of the mother and early pregnancy loss:
1- Persistent high blood pressure may be associated with death of the embryo in the 1st trimester.
2- Uncontrolled diabetes mellitus is associated with increase risk of early pregnancy loss.
3- There is a weak relation between thyroid disorders and early pregnancy loss.
● Pregnancies with PCOs and early pregnancy loss:
1- 25% of pregnancies with PCOs end with miscarriage in the first trimester.
2-Treating with the drug metformin significantly lower the rate of miscarriage in women with PCOs.
● Maternal habits and environment in relation to early pregnancy loss:
1- Excessive smoking in the 1st trimester of pregnancy is associated with increase risk of early pregnancy loss.
2- Women who reported consuming 200 mg or more of caffeine per day experienced a 25% miscarriage rate, compared to 13% among women who reported no caffeine consumption. Thus, excessive caffeine consumption by the pregnant woman is a risk factor for early pregnancy loss.
3- There is some sort of relationship between morbid obesity and early pregnancy loss.
4- Most strenuous types of exercise correlated with higher risk of miscarriage prior to 12 weeks gestation.
5- There is a relationship between Environmental toxins( such as heavy metals, organic solvents and ionizing radiation) and early pregnancy loss.
As regards blighted ovum and its management:
1- Blighted ovum accounts for 10 to 15% of all miscarriages and may recur by about 3%.
2- All cases of blighted ovum may be caused by chromosomal abnormality possibly related to Trisomies 16 and 22.
3- Routine karyotyping for parents is not necessary except after two abortions.
4- Methotrexate followed by misoprostol is more effective than using misoprostol alone in management of blighted ovum.
As regards to relation of toxoplasmosis to early pregnancy loss:
1- Congenital toxoplasmosis results from a primary (and often asymptomatic) acute infection acquired by the mother during pregnancy and this results in 1st trimester abortion.
2- Women infected before conception ordinarily do not transmit toxoplasmosis to the fetus unless the infection is reactivated during pregnancy by immunosuppression, so, screening for all cases is not necessary.
3- It is rare for toxoplasmosis to cause multiple abortions.
4- The percentage of surviving fetuses born with toxoplasmosis increases from 15% to 30% to 60% for maternal infections acquired in the 1st, 2nd, or 3rd trimesters of pregnancy, respectively.
5- Detection of specific IgM antibody in the newborns suggests congenital infection (Maternal IgG crosses the placenta but IgM does not).
6- Detection of toxoplasma-specific IgA antibodies is more sensitive than IgM in congenitally infected infants.
7- Immunodiagnosis of toxoplasmosis in a pregnant woman:
● Test serum for presence of toxoplasma-specific IgG antibodies.
a- IgG negative: Not infected, Retest after 3 weeks to rule out seroconversion.
b- IgG positive: Infected.
● In infected patients (positive IgG), to determine approximate time of infection, test serum for presence of Toxoplasma-specific IgM antibodies.
a- IgG positive, IgM negative: Infected for more than one year
b- IgG positive, IgM positive: Infection within one year or false-positive IgM result.
● In this group of patients, IgG avidity status is to be done:
a- IgG avidity high: Infected at least 16 weeks to one year previously.
b- IgG avidity low: Recent infection of less than 16 weeks duration possible.
8- Treatment of acutely infected pregnant women can decrease the incidence of fetal infection.
9- Pyrimethamine should not be used until after the 1st trimester of pregnancy. Spiramycin 1 g po tid has been used safely to reduce the risk of transmission in pregnant women during the 1st trimester but is less active than pyrimethamine -sulfonamide combinations and does not cross the placenta.
As regards Protocols for management of missed abortion and blighted ovum:
1- Conservative or Expectant management for spontaneous abortion:
If you choose the conservative line, when do you expect the pregnancy to be expelled?
● Conservative management means no specific intervention; but waiting for spontaneous passage of fetal tissue that usually occurs within three to four weeks.
What is the chance of complete abortion, retained parts, severe hemorrhage and infection?
● There are some theoretical risks of expectant management including intra-uterine infection (9%), maternal coagulopathy (5%) and inevitable abortion with severe bleeding (15%) may occur. These risks have prompted some authors to advise termination within 2 weeks of the demise and to institute surveillance for infection and coagulopathy. Examples of such surveillance include weekly visits for counseling and support. And examination for evidence of infection, cervical dilatation or bleeding. Determination of weekly complete blood count (CBC), platelet count, and fibrinogen level after 3 weeks of expectant therapy has also been advised. This latter recommendation is based on a reported 25% chance of consumptive coagulopathy if a dead fetus remains in utero for longer than 4 weeks.
● The chance of complete abortion after conservative management is 37%.
● Expectant management is an effective and acceptable method to offer women who miscarry. Patient counseling is particular important for those women with an intact sac who wish to take an expectant approach. They should be aware that complete expulsion may take several weeks and that overall efficacy rates are lower. They may wish to consider a medical approach or to commence expectant management with the option of surgical evacuation at a later date, if required.
2- Misoprostol alone for management of missed abortion and blighted ovum:
● Misoprostol can be used as a single dose 800µg vaginally with 90% success rate comparing to using a single dose 400µg vaginally with 32% success rate.
● Misoprostol can be used as repeated doses 400µg vaginally every 12 hours or 200µg every 6 hours with 92% success rate.
● Vaginal administration of misoprostol has been shown to be more effective in comparison with the oral route in the context of medical management of miscarriage.
● Many studies show no difference between sublingual or vaginal misoprostol.
3- Methotrexate followed by misoprostol in management of missed abortion and blighted ovum:
● Medical termination of pregnancy using a combination of methotrexate and misoprostol is more successful in the first trimester than using misoprostol alone especially in management of blighted ovum.
● Combined regimens ( Misoprostol with Methotrexate) are more effective than single agents.
4- Mifepristone followed by misoprostol in management of missed abortion:
● It has been shown that for termination of early pregnancy a single dose of 200 mg mifepristone is as effective as 600 mg, when used in combination with a prostaglandin analogue. However, a higher dose of mifepristone may be required for medical treatment of miscarriage.
● Combined regimens ( Misoprostol with Mifepristone) are more effective than single agents.
● In the combined regimen, the dose of mifepristone can be lowered to 200mg without significantly decreasing the method effectiveness.
A suggested protocol for management of a case of early pregnancy loss:
1- Diagnosis of early pregnancy loss:
Criteria for diagnosis of missed abortion:
● Failure to identify fetal cardiac pulsation when an embryo is 5mm length.
● Failure to identify fetal cardiac pulsation when the gestational sac is 19mm length.
● The previous landmarks can be used along with serial HCG to determine if a pregnancy is non-viable.
Criteria for diagnosis of blighted ovum:
● Failure to identify an embryo in a gestational sac measuring at least 20 mm via transabdominal ultrasound.
●Failure to identify an embryo in a gestational sac measuring approximately 18mm or more via transvaginal ultrasound.
● Failure to identify a yolk sac in a gestational sac measuring 25mm or more.
Criteria for diagnosis of pregnancy of uncertain viability:
● Intrauterine sac (< 20mm mean diameter) with no obvious yolk sac or fetus.
● Fetal echo < 6mm crown-rump length with no obvious fetal heart activity.
● In order to confirm or refute viability, a repeat scan at minimal interval of one week is necessary.
2- Investigations:
● Investigations for genetic causes:
Fetal karyotype:
● Although cost may be an issue, fetal karyotype should be considered and this may be of greater emotional value in patients with recurrent early pregnancy loss.
Paternal karyotype:
● The incidence of structural chromosomal abnormalities, usually a balanced translocation is increased in couples with recurrent miscarriage. All the four factors, namely low maternal age at second miscarriage, a history of three or more miscarriages, a history of two or more miscarriages in a brother or sister and a history of two or more miscarriages in the parents of either partner increases the probability of carrier status. After on miscarriage, it is generally accepted to refrain from karyotyping. The incidence of carrier status after one miscarriage is 2.2%. It is thus advised to refer for parental karyotype only when the probability of carrier status is ≥ 2.2%.
● Investigations for immunological causes:
a- Consider testing for antiphospholipid syndrome with lupus anticoagulants screen, and testing for anticardiolipin antibodies if the patient has recurrent early pregnancy loss before 10 weeks or, 1 or more unexplained deaths at ≥ 10 weeks of a morphologically normal fetus.
b- Routine screening is not currently advised for isolated cases of fetal demise due to heritable thrombophilias (including factor V Leiden deficiency, activated protein C resistance, protein G20210A and protein S deficiency) except in cases of recurrent early fetal demise.
● Investigations for hormonal (LPD) causes:
Determination of mid-luteal progesterone before pregnancy in patients with previous recurrent early miscarriage is essential for diagnosis of luteal phase defect (LPD) (If the level is < 10mg per ml).
● Investigations for infectious causes:
a- Evaluation for infection in early pregnancy loss should be limited to women with chronic cervicitis or recurrent bacterial vaginosis( A high swab from upper vagina and cervix, stained with gram negative stain, can determine the causative organism).
b- Infections with bacteria, viruses or parasites can all interfere with early pregnancy development, but none seems to be a significant cause of recurrent miscarriage.
c- Toxoplasmosis, Rubella, Cytomegalovirus, Herpes ( TORCH) screen is therefore of limited value in the investigation of recurrent miscarriage.
● Investigations for endocrinological causes:
Clinically overt diabetes and thyroid disease are associated with fetal loss. However, the utility of screening for asymptomatic disease with glycosylated hemoglobin and ̷ or thyroid-stimulating hormone (TSH) is not routinely advised.
● Investigations for anatomical causes:
a- Consideration should be given to assessment of the uterine cavity (through laparoscopy, HSG, and or hysteroscopy) after the patient recovers (3 months postabortive) to exclude any uterine abnormality.
b- Using 3D ultrasound, it has been reported that women with a subseptate uterus have a higher incidence of first trimester loss. But, women with an arcuate uterus have a greater proportion of second trimester loss and preterm delivery.
3- Treatment of a case of early pregnancy loss:
a- Expectant or conservative management:
● Expectant management is an effective and acceptable method to offer women who miscarry.
● This is the most suitable for women who are psychic and irritable about the complications of medical and surgical termination of early miscarriage.
● And should be advised to be aware that complete evacuation may take up to 4 weeks and the overall efficacy rates are lower than medical and surgical termination of early miscarriage.
b- Medical termination:
● Medical evacuation is an alternative technique that complements, but does not replace surgical evacuation. Its availability has led to an improvement in choice for women who miscarry.
● The main reasons given for the choice of women who expressed a strong preference for medical management were ‘avoidance of general anesthesia’ and the feeling of being ‘more in control.’
● Various medical methods have been described using prostaglandin analogues (misoprostol) with or without antiprogesterone priming (mifepristone) or methotrexate.
Medical termination of missed abortion and blighted ovum:
● Misoprostol can be used as a single dose 800µg (4 tablets) vaginally which can be repeated after 24 hours for management of missed abortion (4-8 weeks gestation) or blighted ovum.
Or
● Misoprostol can be used as repeated doses 400µg vaginally every 12 hours or 200µg every 6 hours which can be repeated after 24 hours for management of missed abortion (8-12 week gestation).
N.B.:
The choice depends on the gestational age.
● Medical termination of pregnancy using a combination of a single dose of methotrexate (50 mg i.m.) plus calcium lucoverin(5mg i.m.) followed by 400µg misoprostol vaginally 5 days later should be considered with blighted ovum or cases failed to misoprostol alone.
● It has been shown that for termination of early pregnancy loss using a single dose of 200 mg mifepristone orally is as effective as 600 mg, when used in combination with a prostaglandin analogue ( 400µg misoprostol vaginally) 2 days later which can be used up to 9 weeks gestation and should be considered in cases failed to misoprostol alone.
● Combined regimen (Methotrexate or Mifepristone followed by Misoprostol) is more effective than using misopristol alone for management of early pregnancy loss in patients with cardiac problems and diabetes mellitus.
● Misoprostol up to 4 tablets (800µg) every 12 hours which can be repeated after 24 hours can be used safely up to 12 weeks gestation for management of early pregnancy loss in patients with history of one cesarean section or one hysterotomy without risk of rupture uterus.
● Misoprostol up to 2 tablets( 400µg) every 12 hours which can be repeated after 24 hours can be used safely up to 12 weeks gestation for management of early pregnancy loss in patients with history of repeated cesarean sections (up to 5 sections) without risk of rupture uterus.
c- Surgical uterine evacuation:
● This was based on an assumption that retained tissue increases the risks of infection and hemorrhage and would not be passed spontaneously. It remains the treatment of choice if there is excessive and persistent bleeding, if vital signs are unstable or in the presence of retained infected tissue.
● Reported serious complications of surgery include perforation, cervical tears, intraabdominal trauma, intrauterine adhesions and hemorrhage.
● The advantages of prostaglandin administration prior to surgical evacuation of cases of missed abortion or blighted ovum are well established, with significant reductions in dilatation force, hemorrhage and uterine/cervical trauma.
4- Hospital admission:
● Expectant management may be followed by minimal bleeding as any retained tissue will usually undergo resorption. Occasionally, the passage of tissue may be associated with heavy bleeding, so, it is important that all women undergoing medical or conservative management have direct telephone access to staff for advice and support. Hospital beds must be available as admission may be required (evidence level ІV).
● Medical management may be undertaken successfully on an outpatient basis especially in very early pregnancy loss (6-8 weeks gestation) or blighted ovum or incomplete abortion. But, it is preferable to admit the patient with early pregnancy loss (more than 8 weeks gestation) to avoid risk of severe bleeding and possibility of shock before arrival to hospital (evidence level ІV)..
● Hospital admission should be considered in cases of early pregnancy loss with rheumatic heart disease, prosthetic valves, heart failure or uncontrolled diabetes mellitus (evidence level ІV)..
Recommendations:
The following recommendations are based primarily on good and consistent scientific evidence (level A):
1- Medical abortion should be considered a medically acceptable alternative to surgical abortion in carefully counseled and informed women.
2- The U.S. Food and Drug Administration (FDA) – approved protocol of 600mg of mifepristone (ant progesterone priming) orally followed approximately 48hours later by 400µg of misoprostol orally as a safe and effective for medical abortion before 12weeks gestation.
3- Compared with the FDA- approved regimen, mifepristone-misoprostol regimen using 200mg of mifepristone orally and 800µg of misoprostol vaginally are associated with a decreased rate of continuing pregnancy, decreased time to expulsion, fewer side effects and lower cost for women with pregnancies up to 12 weeks gestation based on last menstrual period.
4- A methotrexate-misoprostol regimen is appropriate for medical abortion in pregnancies up 12 weeks gestation, especially in cases with blighted ovum.
5- Mifepristone-misoprostol regimen using 200mg of mifepristone orally and 800µg of misoprostol vaginally are generally preferred to regimen using methotrexate and misoprostol or misoprostol only for medical abortion.
6- A patient can administer misoprostol safely and effectively, orally or vaginally, in her home as part of a medical abortion regimen.
The following recommendations are based primarily on limited scientific evidence (level B):
1- The patient must be informed of the need for a surgical abortion in the event of failed medical abortion.
2- Gestational age should be confirmed by clinical evaluation or ultrasonography.
The following recommendations are based primarily on consensus and expert opinion (level C):
1- No need for anti-D immune globulin for cases of spontaneous early abortion (without surgical intervention).
2- No data exist to support the universal use of prophylactic antibiotic for medical abortion.
N.B.:
After pregnancy termination, cases of recurrent early pregnancy losses need to be offered the following investigations:
● Recommended investigations:
1- Parental karyotype (after two miscarriages).
2- Antiphospholipid antibodies (LAC and aCL).
3- Pelvic ultrasound (SIS), hysterosalpingogram and hysteroscopy and laparoscopy in cases of inconclusive findings.
4- Full blood count (Blood sugar level and thyroid function tests).
● Non-recommended investigations:
1- Feto-placental karyotypes.
2- Testing of uterine or peripheral blood NK cell.
3- Luteal phase endometrial biopsy.
4- Homocysteine or folic acid level.
5- Thrombophillia screening.