Walking and Dietary Modification for Recurrent Early Miscarriages
Condition: Recurrent Miscarriage
MeSH terms: Abortion, Spontaneous; Abortion, Habitual
Study type: Interventional

Summary: 
      This study is part of a big one aiming to evaluate how lifestyle interventions during
      pregnancy affect obstetric results, neonatal metabolism and the intelligence of the offspring
      (study not yet completed). Data regarding obstetric and neonatal results were entered in
      NCT01409382, but we decided to split results in two for the sake of clarity.

      A cohort of women with early pregnancy losses without antiphospholipid antibodies was
      selected for two reasons. One is that these women follow strictly the recommendadtions. The
      second is that no medication has been shown to increase the rate of take-home babies in women
      with early miscarriages who test negative for antiphospholipid antibodies. We decided to
      focus on the fibrinolytic system because trophoblast migration and placental vasculogenesis
      and angiogenesis depend on plasmin-dependent extracellular matrix remodeling. Plasminogen
      activator inhibitor (PAI)-1 inhibits the generation of plasmin. Since both glucose and
      insulin increase PAI-1 synthesis, hyperglycemia itself, or by stimulating insulin production,
      reduces plasmin generation, which may impair placentation.

      Abnormalities in glucose metabolism may be also deleterious to embryos by causing epigenetic
      changes. Chromosomal abnormalities are considered an important cause of early pregnancy
      losses.

      Several lines of evidence lend support to the hypothesis that carbohydrate metabolism
      abnormalities contribute to the pathogenesis of recurrent early pregnancy losses. One is that
      of the pregnancies of the women with polycystic ovary syndrome, around 30 and 50% end with
      first-trimester miscarriages. Hyperinsulinemia is a prevalent feature of the syndrome, and
      interventions proven effective in reducing insulin levels, such as metformin, have been shown
      to reduce the rate of early miscarriages. The other is that patients with body mass index of
      ≥25 kg/m2 have significantly higher odds of early miscarriage, regardless of the method of
      conception.

      The investigator's hypothesis was that a balanced diet combined to regular exercise, by
      improving glucose homeostasis, would increase the take-home baby rate in women with
      consecutive early miscarriages. Moderate exercises are usually well tolerated not only by the
      mother, but also by the fetus, as indicated by tests of fetal well-being, including umbilical
      artery systolic to diastolic ratio.
    

Detailed description: 
      Women aged 18 to 40 years trying to conceive spontaneously were eligible if they had two or
      more consecutive pregnancy losses in the first trimester, documented by pathology or
      ultrasound-confirmed gestational sac.

      All participants underwent ultrasound examination before inclusion in the study. Exclusion
      criteria were any of the following: anatomic anomalies that may increase the risk of
      pregnancy losses, not amenable to surgical correction during pregnancy, such as uterine
      septum; antiphospholipid antibodies; prior second- or third-trimester losses; current
      multiple gestation; disabilities such as hemiplegia or paraplegia; renal or liver failure;
      conditions requiring a priori anticoagulation.

      Participants were enrolled by staff at the participating center. Randomization to the
      intervention protocol Walking and Diet (W&D) or to a control group was performed before
      pregnancy occurred by a statistician using a computer-generated random-number table. This was
      not a double blind study, but care was taken to ensure that appointments of the patients
      assigned to the intervention protocol did not coincide with those of controls.

      The intervention was standardized by training of research staff. Women assigned to W&D were
      instructed to walk at a moderate pace (4 km/h) for at least 40 minutes, seven days a week.
      Besides, those who remained seated most of the day were advised to walk 25 to 30 minutes
      twice a day, avoiding hence more than 12 hours of physical inactivity. Walking could be
      replaced by stationary bicycle rides or swimming when convenient, which often occurred near
      term and when the mother was obese. Strenuous exercises were discouraged.

      Patients assigned to protocol W&D were also informed of the importance of a balanced diet and
      recommended to avoid high-glycemic index meals (high-carbohydrate, low-fiber). Sucralose
      could be used as a sweetener. As a strategy to promote satiety and reduce carbohydrate
      intake, W&D participants were also advised to eat at least two daily servings of protein-rich
      food. The intervention began when participants wished to conceive, continuing until delivery.
      Careful instructions about walking speed and diet were given to participants assigned to W&D
      at enrolment and at each consultation. During exercise, neither fetal nor maternal cardiac
      rate were assessed.

      Non-adherence to the intervention protocol was suspected when non-obese participants assigned
      to W&D gained > 1 kg in 4 weeks until the 28th week of gestation, > 1.5 kg from the 28th to
      the 32nd week, and > 2 kg in 4 weeks thereafter, in the absence of edema. The threshold was
      lower for obese participants: > 700 g in 4 weeks until the 28th week of gestation, > 1 kg
      from the 28th to the 32nd week, and > 1.5 kg in 4 weeks thereafter21. Excessive weight gain
      aroused the suspicion of protocol violation because high carbohydrate consumption, especially
      when combined with physical inactivity stimulates the pancreas to overproduce insulin, a
      hormone that promotes fat storage. To enhance adherence to the protocol, W&D participants who
      gained excessive weight were recommended to increase the frequency, duration and intensity of
      the physical activity and to increase the protein intake. Participants of the W&D group who
      had a successful pregnancy volunteered to encourage mothers assigned to the intervention
      protocol, especially those who gained excessive weight.

      At enrollment and during first-trimester consultations, W&D participants were explained that
      antiemetics such as ondansetron should be taken before nausea became severe, in order to help
      them tolerate balanced meals.

      No recommendations regarding diet or physical activity were given to controls. Antiemetics
      such as ondansetron were given to controls who complained of hyperemesis.

      All participants were given folic acid tablets 5 mg daily until 14 weeks of gestation, as
      prevention of neural tube defects. In both groups, participants reporting abdominal pain,
      cramps, and vaginal bleeding during the first-trimester were medicated with vaginal
      progesterone. Subcutaneous heparin was given to all participants whose pregnancies were
      complicated with nephrotic range proteinuria or any evidence of placental insufficiency.
      Antihypertensive medications included methyldopa, amlodipine and hydralazine. No patient
      received aspirin or metformin in this study.

      Appointments were scheduled according to the routine. Maternal weight and blood pressure were
      assessed at every appointment and all mothers were screened for gestational diabetes
      according to the American Diabetes Association recommendations.

      Obstetric and neonatal outcomes were obtained from the hospital records. Neonates were
      classified as small, appropriate or large for gestational age according to Olsen et al.
      growth curves.

      Written informed consent was obtained from each participant after a full explanation of the
      study.
    

Intervention name(s): Walking & dietary modification
Intervention type(s): Behavioral
Intervention description(s): Daily walking at a moderate pace (4 km/h) > 40 min, 7/7. Those remaining seated most of the day should walk 25-30 min twice a day, avoiding >12 h of physical inactivity. Walking may be replaced by stationary bicycle rides or swimming when convenient, which often occurred near term and when the mother was obese.
At least two daily servings of protein-rich food (≥ 4 g/kg of meat, poultry, fish or eggs) per day. Avoidance of high-carbohydrate, low-fiber meals, such as snacks, candies, fiber-free juices, coconut water or sugar-sweetened beverages. Sucralose could be used as a sweetener. Participants are recommended to use ondansetron for nausea and vomiting prevention
Other intervention name(s): W&D
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: prevention; carbohydrate; exercise; neonatal hypoglycemia