Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase III Study Analyzing the Effectiveness of Dalteparin Therapy as Intervention in Recurrent Pregnancy Loss
Brief Summary: With this clinical trial the investigators will analyze whether the rate of pregnancy losses before the 24th week of gestation can be reduced by dalteparin treatment in habitual aborters.


Options:
A: Inclusion Criteria:

* Single pregnancy, 5th to 8th week of gestation
* Documented foetal heart activity in US
* History of recurrent pregnancy loss, defined as:

  * 2 or more early (\< 12 weeks of gestation) pregnancy losses or
  * 1 or more late (\> 12 weeks of gestation) pregnancy loss
* at least 18 years of age
* Written informed consent of the patient

Exclusion Criteria:

* Previous pregnancy losses caused by foetal structural or chromosomal anomalies
* Uterine anomalies
* Maternal infection which caused previous pregnancy loss
* Risk group II or III according to ETHIG I risk stratification (clinical need for heparin prophylaxis)
* Acute thromboembolic event (need of heparin therapy)
* Known hypersensitivity to any of the trial drugs or its ingredients (i.e. thrombocytopenia type II caused by allergic reaction to heparin)
* Antiphospholipid antibody syndrome
* Diabetes mellitus
* Ongoing nicotine or drug or alcohol abuse
* Known HIV infection
* Expected low compliance (e.g. by travel distance to trial site)
* Current or recent (within 30 days prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial
B: Inclusion Criteria:

Women must be at high risk for thromboembolism for one of the following reasons:

1. Known low risk thrombophilia (Known = diagnosed prior to enrollment and low risk thrombophilia includes heterozygous factor V Leiden or prothrombin gene variant or protein C deficiency or protein S deficiency. If not previously tested then assumed not to have thrombophilia).
2. Immobilization (defined as \>90% of waking hours in bed, of a week or more at any point in the antepartum period).

OR any two of the following reasons:

1. Postpartum infection (fever (temperature\>38.5oC) and clinical signs/symptoms of infection and elevated neutrophil count (higher than local lab normal))
2. Postpartum hemorrhage (Estimated blood loss \>1000 ml during delivery and postpartum)
3. Pre-pregnancy BMI \>25 kg/m2
4. Emergency cesarean birth (emergency = not planned prior to onset of labour)
5. Smoking \>5 cigarettes per day prior to pregnancy
6. Preeclampsia (blood pressure ≥ 140mmHG systolic and/or ≥90 mmHg diastolic on at least one occasion and proteinuria (1+ on urine dipstick or 300mg/dl or total excretion of 300mg/24 hours) or typical end-organ dysfunction.
7. Infant birth weight (adjusted for sex and gestational age) \<3rd percentile (i.e., small for gestational age).

Exclusion Criteria:

1. Less than 6 hours or more than 36 hours since delivery at the time of randomization
2. Need for anticoagulation as judged by the local investigator, may include but not limited to:

   1. Personal history of previous provoked or unprovoked VTE (DVT or PE)
   2. Continuation of LMWH that was started in the antenatal period for VTE prophylaxis
   3. Mechanical heart valve
   4. Known high-risk thrombophilia (Known = diagnosed prior to enrolment and high-risk thrombophilia includes deficiency of antithrombin (at least 1 abnormal lab result), persistently positive anticardiolipin antibodies (\> 30U/ml on two measurements a minimum of six weeks apart), persistently positive Anti B2 glycoprotein antibodies (\> 20U/ml on two measurements a minimum of six weeks apart), persistently positive lupus anticoagulant (positive on two measurements a minimum of six weeks apart), homozygous factor V Leiden (FVL), homozygous prothrombin gene mutation (PGM), compound heterozygosity factor V Leiden (FVL) and prothrombin gene mutations (PGM), more than 1 thrombophilia (any combination of 2 or more: FVL, PGM, protein C deficiency, protein S deficiency). If not previously tested then assumed not to have thrombophilia).
3. Contraindication to heparin therapy, including:

   1. History of heparin induced thrombocytopenia (HIT)
   2. Platelet count of less than 80,000 x 106/L on postpartum Complete Blood Count(CBC)
   3. Hemoglobin ≤ 75 g/L on postpartum CBC
   4. Active bleeding at any site (not resolved prior to randomization)
   5. Excessive postpartum vaginal bleeding (\>1 pad per hour prior to randomization).
   6. Documented gastrointestinal ulcer within 6 weeks prior to randomization
   7. History of heparin or LMWH allergy
   8. Severe postpartum hypertension (systolic blood pressure (SBP) \> 200mm/hg and/or diastolic blood pressure (DBP) \> 120mm/hg)
   9. Severe hepatic failure (INR \>1.8 if liver disease suspected)
4. Have received more than one dose of heparin or LMWH since delivery
5. \< age of legal majority in local jurisdiction (age \<18 in Canada)
6. Prior participation in PROSPER
7. Unable or refused to consent
C: Inclusion Criteria:

One or more of the following:

* Previous preeclampsia
* Previous unexplained intra-uterine growth restriction
* Previous recurrent miscarriage:

  * three(3) or more unexplained miscarriage at less than 10 weeks gestation;
  * two (2) or more unexplained fetal loss between 10 and 16 weeks gestation;
  * one (1) or more unexplained fetal loss at or greater than 16 weeks gestation
* Previous abruptio placenta
* Previous personal history of VTE:

  * Previous documented secondary proximal VTE,
  * Previous documented calf-vein thrombosis (idiopathic or secondary),
  * Previous superficial phlebitis
* First degree relative with symptomatic thrombophilia
* Pregnancy - \> 4weeks gestation and \< 20 weeks gestation
* Thrombophilia:
* Two abnormal tests, and no normal tests

  * 3.1 Protein S
  * 3.2 Protein C
  * 3.3 Antithrombin
* Two positive tests

  * 3.4 Anticardiolipin immunoglobulin M (IgM) (\>30 U/ml)
  * 3.5 Anticardiolipin immunoglobulin G (IgG) (\>30 U/ml)
  * 3.6 Anti-b2 glycoprotein IgG (\>20 U/ml)
  * 3.7 Anti-b2 glycoprotein IgM (\>20 U/ml)
  * 3.8 Lupus anticoagulant
* One positive test

  * 3.9 Factor V Leiden (heterozygous or homozygous)
  * 3.10Prothrombin gene defect (heterozygous or homozygous)

Exclusion Criteria:

* Less than 4 weeks gestation or greater than 20 weeks gestation
* No confirmed thrombophilia
* Contraindication to heparin therapy

  * History of heparin induced thrombocytopenia
  * Platelet count less than 100,000 109/L
  * History of osteoporosis or steroid use
  * Actively bleeding
  * Documented peptic ulcer within 6 weeks
  * Heparin, bisulfite or fish allergy
  * Severe hypertension (Systolic Blood Pressure \>200mmhg and/or Diastolic Blood Pressure \>120mmHg)
  * Serum creatinine greater than 80 umol/L (1.3mg/dl) and an abnormal 24 hour urine creatine clearance (\<30ml/min)
  * Severe hepatic failure (INR \>1.8)
* Geographic inaccessibility
* Need for anticoagulants, discretion of the investigator such as but not limited to:

  * Recurrent fetal loss and phospholipid antibody syndrome
  * Prior idiopathic proximal VTE:
  * History of idiopathic deep venous thrombosis (DVT) or pulmonary embolism (PE) treated with anticoagulants (\> 1 month of heparin or warfarin) or inferior vena cava (IVC) interruption;
  * Idiopathic is a VTE occurring outside all of the following periods: antepartum, postpartum, oral contraceptive use, surgery, immobilization, cast, and malignancy
  * Mechanical heart valve
* Legal lower age limitations (country specific)
* Prior participation in TIPPS
* Unable/unwilling to provide informed consent
D: Inclusion Criteria:

* Women experiencing one or two pregnancy losses at any point in gestation in the past that were not elective termination(s). At least one of these losses must be well documented by one of the following:

  * Sonogram demonstrating anembryonic loss, embryonic loss or fetal death.
  * Histologic confirmation of products of conception that were spontaneously passed per vagina or surgically obtained.
  * Hospital records of fetus delivery.
  * Late menses and positive serum hCG or positive urine hCG documented by hospital or clinic records followed by either a negative hospital/clinic pregnancy test or a decline in urinary hCG level over 3 days.
  * Home pregnancy tests without hCG confirmation from a healthcare provider (either serum or urine) will not be accepted.
* No more than 5 pregnancies in total including the pregnancy loss(es).\*
* Up to two prior pregnancies that did not end in a loss.\*

  \*Women may have up to two pregnancies beyond 20 weeks that were not losses, two spontaneous pregnancy losses at any time in the past, and up to one therapeutic or elective termination (two therapeutic or elective terminations if no other pregnancies). Ectopic and molar pregnancies would, for the purpose of enrollment, be considered in the same category as therapeutic termination pregnancies. Women with more than two live births or those with more than two losses, regardless of the week of gestation of the loss, are excluded.
* Presence of intact tubes (both), ovaries (both), and uterus.
* Between 18 and 40 years of age at time of baseline visit.
* Regular menstrual periods between 21 - 42 days in length (within the last 12 months). Regular menstrual periods are defined as no more than an 8-day difference between the woman's shortest and longest cycle.
* No more than one missed menses in the past 12 months (other than those missed due to pregnancy or breastfeeding).
* Actively trying to conceive with a male partner and not using contraception by the baseline visit.
* Not currently pregnant at the baseline or randomization visits.
* Ability and willingness to give informed consent.
* Willingness to be randomized and to take daily study pills for 6 months to a possible 15 months

Exclusions Criteria:

* Known allergies to aspirin or non-steroidal anti-inflammatory agents.
* Clinical indication for anticoagulant therapy. These include prior or current thrombosis, antiphospholipid syndrome (APS) or known major thrombophilia.
* Clinical indication for chronic use of NSAIDs such as rheumatoid arthritis.
* Indication for additional folic acid supplementation, such as prior infant with neural tube defect (NTD), seizure disorder.
* Medical contraindication to aspirin therapy. These include uncontrolled asthma, nasal polyps, bleeding disorders, or history of gastrointestinal ulcer.
* Presence of major medical disorders (regardless of severity). These include diabetes, hypertension, systemic lupus erythematosus (SLE), untreated or active cancer (any cancer in remission or non-melanoma skin cancer is not included in the exclusion criteria), liver disease, renal disease, rheumatoid arthritis, cardiac disease, pulmonary disease other than mild asthma, neurologic disease requiring medical treatment, uncontrolled hypothyroidism, uncontrolled seizure disorder. Untreated vitamin B12 deficiency, severe anemia (Hct \< 30%), hemophilia, gout, nasal polyps, among others.
* Currently undergoing/planned use of assisted reproductive techniques during trial (IVF; IUI; Clomid).
* History of infertility or sub-fertility. This includes any of the following:

  * No conception after ≥ 1 year of unprotected intercourse and actively trying to conceive.
  * Any prior medical treatment for infertility.
  * Prior treatment for known pelvic inflammatory disease.
  * Known male infertility or sperm abnormality (current partner).
  * Known tubal occlusion, anovulation, uterine abnormality, or endometriosis stage III or IV.
  * History of polycystic ovarian syndrome.
* Presence of unstable mental disorder. These include bipolar illness, schizophrenia, uncontrolled depression, uncontrolled anxiety disorder.
* Known current or recent alcohol abuse or illicit drug use.
* Current diagnosis of sexually transmitted infection (STI) (temporary exclusion)

Answer: A