Hyperinsulinemia, Hypoglycemia, Miscarriages, Pregnancy, Sedentary Lifestyle
Conditions
Keywords
neonatal hypoglycemia, pregnancy, physical activity, sedentary lifestyle, high-glycemic index diet, take-home baby, recurrent miscarriages, preterm delivery
Brief summary
tPA has a pivotal role in placentation, mediationg activation of growth factors, such as vascular endothelial growth factor and brain-derived neurotrophic factor, degradation of extracellular matrix and basement membrane (directly or through activation of matrix metalloproteinases) and formation of hemidesmosomes. A high-carbohydrate intake combined with lack of physical activity provides a strong stimulus for maternal insulin production. In this scenario, either β-cells are dysfunctional and diabetes supervenes, or excessive amounts of insulin are produced, providing pathological stimulation of PAI-1 synthesis. Given that PAI-1 is a major tPA inhibitor, PAI-1 excess may affect placentation, increasing the risk of first trimester losses, preterm deliveries and intrauterine growth restriction. Our hypothesis was that prematurity was not the cause of neonatal hypoglycemia, but a parallel occurrence of a strong stimulus for maternal, fetal and neonatal production of insulin.
Detailed description
In an observational study, we sought to determine whether markers of hyperinsulinemia or situations that increase maternal insulin requirements would increase the risk of neonatal hypoglycemia. Mothers were selected if they had grade III obesity, acanthosis nigricans (surrogates of chronic maternal hyperinsulinemia), any invasive bacterial infection or if they had used corticosteroid within seven days before delivery (surrogates of subacute insulin resistance), if they reported to have consumed a high-glycemic index diet within 24 hours before delivery or if they were physically inactive within 24 hours before delivery (conditions that could increase maternal insulin requirements close to delivery). Based on the finding that that the risk of neonatal hypoglycemia increased fivefold with inactivity (95% CI: 2-11, P \<0.001), 11-fold with high-carbohydrate intake (95% CI: 4-24, P \<0.001) and 329-fold with both risk factors (95% CI: 32-3362, P \<0.001), next we have evaluated how a protocol combining exercises and a balanced diet throughout pregnancy influences maternal and neonatal outcomes. One of the outcomes analyzed was neonatal hypoglycemia.
Interventions
BEHAVIORALDaily brisk walking plus a carbohydrate-restricted diet
Daily brisk walking at moderate speed (4 km/h) for at least 40 minutes per day, 7 days a week. Patients will be recommended to avoid high-glycemic index meals (such as snacks, candies, fiber-free juices and sugar-sweetened beverages), and to eat at least two daily servings of meat, poultry, fish (e.g. 2 g/kg) or other protein-rich food, starting when they decided to get pregnant and continuing until delivery. Recommendations will be emphasised at every appointment. Antidepressants will not be discontinued in both groups, but patients on paroxetine and sertraline, will be switched to fluoxetine.
Sponsors
Rio de Janeiro State Research Supporting Foundation (FAPERJ)
Hospital dos Servidores do Estado do Rio de Janeiro
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
No minimum to 40 Years
Healthy volunteers
No
Inclusion criteria
recurrent early unexplained miscarriages
Exclusion criteria
(i) antiphospholipid antibodies, (ii) second- or third-trimester losses, (iii) multiple pregnancy, (iv) anatomical abnormalities that could increase the risk of early miscarriages, (iv) any condition requiring a priori anticoagulation, (v) protocol violation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neonatal Hypoglycemia | 1, 2 and 4 h after birth. | Any glucose level equal or below 40mg/dL at 1, 2 or 4 h after birth, obtained by heelstick. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Refractory Hypoglycemia | One hour after feeding or after intravenous dextrose | Any glucose level ≤ 40/dL at 1, 2 or 4 h: 1. Neonates with hypoglycemia (glucose level equal or below 40 mg/dL at 1, 2 or 4 h) will be offered milk. Neonates unable to suckle, will be treated with intravenous dextrose for one hour. 2. A new heel stick blood sample will be drawn to assess glucose levels. 3. Neonates with persistent hypoglycemia will be considered as refractory hypoglycemia. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pregnancy and Neonatal Outcomes | Three years | Early miscarriages, 2nd and 3rd trimester losses, preterm deliveries, take-home babies, neonatal hypoglycemia: number of babies |
Countries
Brazil
Participant flow
Recruitment details
Recruitment has started in March 2011 at a High-Risk Maternal and Fetal Unit of a tertiary hospital. Enrollment started in May 2011.
Participants by arm
| Arm | Count |
|---|---|
| Lifestyle Counseling Daily brisk walking plus a carbohydrate-restricted diet | 240 |
| Standard Follow-up Prenatal care will proceed according to the routine | 240 |
| Total | 480 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not manage to get pregnant | 64 | 70 |
| Overall Study | Had a 2nd trimester loss after accident | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Multiple pregnancy | 2 | 4 |
| Overall Study | Protocol Violation | 0 | 3 |
| Overall Study | Still pregnant when study ended | 13 | 2 |
Baseline characteristics
| Characteristic | Standard Follow-up | Lifestyle Counseling | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 240 Participants | 240 Participants | 480 Participants |
| Age, Continuous | 33 years STANDARD_DEVIATION 8 | 34 years STANDARD_DEVIATION 6 | 33 years STANDARD_DEVIATION 7 |
| Region of Enrollment Brazil | 240 participants | 240 participants | 480 participants |
| Sex: Female, Male Female | 240 Participants | 240 Participants | 480 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 160 | 0 / 159 | 0 / 160 | 0 / 159 |
| serious Total, serious adverse events | 36 / 160 | 10 / 159 | 84 / 160 | 22 / 159 |
Outcome results
Primary
Neonatal Hypoglycemia
Any glucose level equal or below 40mg/dL at 1, 2 or 4 h after birth, obtained by heelstick.
Time frame: 1, 2 and 4 h after birth.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lifestyle Counseling | Neonatal Hypoglycemia | 3 neonates |
| Standard Follow-up | Neonatal Hypoglycemia | 15 neonates |
Secondary
Refractory Hypoglycemia
Any glucose level ≤ 40/dL at 1, 2 or 4 h: 1. Neonates with hypoglycemia (glucose level equal or below 40 mg/dL at 1, 2 or 4 h) will be offered milk. Neonates unable to suckle, will be treated with intravenous dextrose for one hour. 2. A new heel stick blood sample will be drawn to assess glucose levels. 3. Neonates with persistent hypoglycemia will be considered as refractory hypoglycemia.
Time frame: One hour after feeding or after intravenous dextrose
Population: All hypoglycemic neonates were screened for refractory hypoglycemia. Only neonates born to mothers who were physically inactive and reported excessive carbohydrate consumption displayed refractory hypoglycemia.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lifestyle Counseling | Refractory Hypoglycemia | 0 neonates with refractory hypoglycemia |
| Standard Follow-up | Refractory Hypoglycemia | 3 neonates with refractory hypoglycemia |
Other Pre-specified
Pregnancy and Neonatal Outcomes
Early miscarriages, 2nd and 3rd trimester losses, preterm deliveries, take-home babies, neonatal hypoglycemia: number of babies
Time frame: Three years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lifestyle Counseling | Pregnancy and Neonatal Outcomes | Early Miscarriages | 19 participants (babies) |
| Lifestyle Counseling | Pregnancy and Neonatal Outcomes | Second and Third Trimester Losses | 0 participants (babies) |
| Lifestyle Counseling | Pregnancy and Neonatal Outcomes | Live Born | 140 participants (babies) |
| Lifestyle Counseling | Pregnancy and Neonatal Outcomes | Term | 126 participants (babies) |
| Lifestyle Counseling | Pregnancy and Neonatal Outcomes | Take-home babies | 140 participants (babies) |
| Lifestyle Counseling | Pregnancy and Neonatal Outcomes | Neonatal hypoglycemia | 3 participants (babies) |
| Standard Follow-up | Pregnancy and Neonatal Outcomes | Take-home babies | 83 participants (babies) |
| Standard Follow-up | Pregnancy and Neonatal Outcomes | Early Miscarriages | 62 participants (babies) |
| Standard Follow-up | Pregnancy and Neonatal Outcomes | Term | 57 participants (babies) |
| Standard Follow-up | Pregnancy and Neonatal Outcomes | Second and Third Trimester Losses | 7 participants (babies) |
| Standard Follow-up | Pregnancy and Neonatal Outcomes | Neonatal hypoglycemia | 15 participants (babies) |
| Standard Follow-up | Pregnancy and Neonatal Outcomes | Live Born | 91 participants (babies) |
Comparison: Take home babiesp-value: <0.0595% CI: [1.5, 7.6]Chi-squared