Premature labor - Treatment

In our country, threatened premature birth is recognized as an indication for hospitalization.

If pregnancy can be prolonged, treatment should be aimed, on the one hand, at suppressing the contractile activity of the uterus, and on the other hand, at inducing the maturation of the fetal lung tissue (at 28–34 weeks of pregnancy). In addition, it is necessary to correct the pathological process that caused the premature birth.

To stop tonic and regular contractions of the uterus, complex treatment and individual selection of therapy are used, taking into account the obstetric situation.

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Non-drug treatment of preterm labor

The preferred position is on the left side, which helps restore blood flow, reduce contractile activity of the uterus and normalize uterine tone in 50% of pregnant women with threatened premature birth. According to other studies, prolonged bed rest, used as the only treatment method, does not produce positive results.

There is no convincing evidence of the benefits of hydration (increased fluid intake, infusion therapy) used to normalize fetoplacental blood flow to prevent premature birth.

Drug treatment of premature birth

If conditions are present, preference is given to tocolytic therapy. The drugs of choice at present are β-adrenergic agonists, the drug of second choice is magnesium sulfate, which allows for a rapid and effective reduction in the contractile activity of the myometrium.

Beta-adrenergic agonists can be used to delay delivery when preventing respiratory distress syndrome with glucocorticoids or when it is necessary to transfer the mother to a perinatal center where there is the possibility of providing highly qualified care to premature infants.

Of the β-adrenergic agonists, hexoprenaline, salbutamol, and fenoterol are used.

Mechanism of action: stimulation of β2-adrenoreceptors of uterine smooth muscle fibers, which causes an increase in the content of cyclic adenosine monophosphate and, as a consequence, a decrease in the concentration of calcium ions in the cytoplasm of myometrial cells. Contractility of the smooth muscle of the uterus decreases.

Indications and necessary conditions for the appointment of β-adrenergic agonists

• Therapy for threatened and incipient premature labor.
• An intact amniotic sac (an exception is the situation with leakage of amniotic fluid in the absence of chorioamnionitis, when it is necessary to delay labor for 48 hours to prevent fetal respiratory distress syndrome by using glucocorticoids).
• The opening of the cervical os is no more than 4 cm (otherwise the therapy is ineffective).
• A living fetus without developmental abnormalities.
• No contraindications for the use of β-adrenergic agonists.

Contraindications

Extragenital pathology of the mother:

• cardiovascular diseases (aortic stenosis, myocarditis, tachyarrhythmia, congenital and acquired heart defects, heart rhythm disturbances);
• hyperthyroidism;
• angle-closure glaucoma;
• insulin-dependent diabetes mellitus.

Obstetric contraindications:

• chorioamnionitis (risk of generalization of infection);
• detachment of a normally or low-lying placenta (risk of developing a Couvelaire uterus);
• suspicion of uterine scar failure (risk of painless uterine rupture along the scar);
• conditions when prolongation of pregnancy is not advisable (eclampsia, preeclampsia).

Contraindications from the fetus:

• developmental defects incompatible with life;
• antenatal death;
• distress not associated with uterine hypertonicity;
• pronounced fetal tachycardia associated with the characteristics of the cardiac conduction system.

Side effects

• From the mother's body: hypotension, palpitations, sweating, tremor, anxiety, dizziness, headache, nausea, vomiting, hyperglycemia, arrhythmia, myocardial ischemia, pulmonary edema.
• From the fetus/newborn: hyperglycemia, hyperinsulinemia after birth due to ineffective tocolysis and, as a consequence, hypoglycemia; hypokalemia, hypocalcemia, intestinal atony, acidosis. When using tablet preparations in average doses, side effects are not expressed. The drugs used.
• Hexoprenaline. In case of threatened or beginning premature labor, it is advisable to start with intravenous drip administration of the drug at a rate of 0.3 mcg per minute, i.e. 1 ampoule (5 ml) is dissolved in 400 ml of 0.9% sodium chloride solution and administered intravenously by drip, starting with 8 drops per minute and gradually increasing the dose until the contractile activity of the uterus decreases. The average rate of administration is 15-20 drops per minute, the duration of administration is 6-12 hours. 15-20 minutes before the end of intravenous administration, oral administration of the drug is started at a dose of 0.5 mg (1 tablet) 4-6 times a day for 14 days.
• Salbutamol. Intravenous tocolysis: the rate of intravenous administration of the drug is 10 mcg/min, then gradually increased under the control of tolerability at 10-minute intervals. The maximum permissible rate is 45 mcg/min. The drug is taken orally at 2-4 mg 4-6 times a day for 14 days.
• Fenoterol. For intravenous tocolysis, 2 ampoules of 0.5 mg fenoterol are diluted in 400 ml of 0.9% sodium chloride solution (1 ml - 2.5 mcg fenoterol), which is administered intravenously at a rate of 0.5 mcg / min. Every 10-15 minutes, the administered dose is increased until the effect is achieved. The average rate of administration is 16-20 drops per minute, the duration of administration is 6-8 hours. 20-30 minutes before the end of intravenous administration, the drug is taken orally at a dose of 5 mg (1 tablet) 4-6 times a day for 14 days.

There is evidence that long-term oral use of beta-adrenergic agonists is inappropriate due to receptor desensitization. Some foreign authors recommend using tocolytics for 2–3 days, i.e. during the period when fetal distress syndrome prevention is performed.

Intravenous tocolysis is performed with the woman lying on her left side under cardiac monitoring.

During the infusion of any beta-adrenergic agonists, it is necessary to monitor:

• mother's heart rate every 15 minutes;
• maternal blood pressure every 15 minutes;
• blood glucose level every 4 hours;
• volume of administered fluid and diuresis;
• amount of blood electrolytes once a day;
• RR and lung condition every 4 hours;
• the condition of the fetus and contractile activity of the uterus.

The frequency of side effects as a manifestation of the selectivity of action on receptors depends on the dose of beta-adrenomimetics. If tachycardia and hypotension occur, the rate of administration of the drug should be reduced; if chest pain occurs, the administration of the drug should be stopped.

The use of calcium antagonists (verapamil) to prevent the side effects of beta-adrenergic agonists at a daily dose of 160–240 mg in 4–6 doses 20–30 minutes before taking a beta-adrenergic agonist tablet is justified.

Tocolytic therapy with magnesium sulfate is used in the presence of contraindications to the use of beta-adrenergic agonists or in case of their intolerance. Magnesium sulfate is an antagonist of calcium ions, which participate in the contraction of smooth muscle fibers of the uterus.

Contraindications:

• intracardiac conduction disorder;
• myasthenia;
• severe heart failure;
• chronic renal failure. Intravenous tocolysis with magnesium preparations.

When premature labor begins, intravenous tocolysis with magnesium sulfate is performed according to the following scheme: 4–6 g of magnesium sulfate is dissolved in 100 ml of a 5% glucose solution and administered intravenously 20–30 minutes before. Then switch to a maintenance dose of 2 g/h, increasing it by 1 g every hour if necessary to a maximum dose of 4–5 g/h. The effectiveness of tocolysis is 70–90%.

In case of threatened premature birth, a solution of magnesium sulfate is administered intravenously by drip at a rate of 20 ml of a 25% solution per 200 ml of a 0.9% sodium chloride solution or 5% glucose solution at a rate of 20 drops per minute or intramuscularly a 25% solution 2 times a day, 10 ml each.

The tocolytic concentration of the drug in serum is 5.5–7.5 mg% (4–8 mEq/L). In most cases, this is achieved at an infusion rate of 3–4 g/h.

When performing tocolysis with magnesium sulfate, it is necessary to monitor:

• blood pressure;
• amount of urine (not less than 30 ml/h);
• knee jerk;
• respiratory rate (at least 12–14 per minute);
• the condition of the fetus and contractile activity of the uterus.

If signs of overdose occur (depression of reflexes, decreased respiratory rate), it is necessary to:

• stop intravenous administration of magnesium sulfate;
• Administer 10 ml of 10% calcium gluconate solution intravenously over 5 minutes.

Nonsteroidal anti-inflammatory drugs have antiprostaglandin properties. They are preferred in cases where it is necessary to provide a rapid effect for transporting the patient to the perinatal center.

Indomethacin is used as rectal suppositories of 100 mg, and then 50 mg every 8 hours for 48 hours. The drug is used orally (25 mg every 4-6 hours) with caution due to the ulcerogenic effect on the mucous membrane of the gastrointestinal tract. The drug has a cumulative effect. If necessary, you can resume taking the drug after a 5-day break.

To reduce the risk of stenosis of the arterial duct in the fetus and the development of oligohydramnios, it is necessary to determine the volume of amniotic fluid before the start of treatment and then 48-72 hours after therapy. If oligohydramnios is detected, the use of indomethacin should be discontinued. The use is limited to a gestational age of less than 32 weeks in pregnant women with threatened or incipient premature labor with a normal volume of amniotic fluid.

Contraindications from the fetus include delayed fetal growth, renal abnormalities, oligohydramnios, heart defects involving the pulmonary trunk, and twin transfusion syndrome.

In our country, a scheme for using indomethacin orally or rectally has been developed and is being used. In this case, the course dose should not exceed 1000 mg. To relieve tonic contractions of the uterus, indomethacin is used according to the scheme: 1st day - 200 mg (50 mg 4 times in tablets or 1 suppository 2 times a day), 2nd and 3rd days 50 mg 3 times a day, 4-6th days 50 mg 2 times a day, 7th and 8th days 50 mg at night. If repeated use is necessary, the interval between administration of the drug should be at least 14 days.

Calcium channel blockers - nifedipine - are used to stop labor. Side effects are comparable to those of magnesium sulfate and are less pronounced than those of beta-adrenergic agonists.

Dosage regimen.

• Scheme 1. 10 mg every 20 minutes 4 times, then 20 mg every 4–8 hours for 24 hours.
• Scheme 2. Initial dose 30 mg, then maintenance dose 20 mg for 90 minutes, then if there is an effect, 20 mg every 4–8 hours for 24 hours.
• Maintenance dose 10 mg every 8 hours (can be used long-term up to 35 weeks of gestation).

Possible complications: hypotension (nausea, headache, sweating, feeling of heat), decreased uteroplacental and fetal blood flow. Contraindicated in combination with magnesium preparations due to the synergistic effect on the suppression of muscle contractions, in particular on the respiratory muscles (respiratory paralysis is possible).

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Antibacterial therapy

The effectiveness of antibacterial therapy for stopping threatened preterm labor in the absence of amniotic fluid leakage and signs of infection has not been proven.

Antibacterial therapy has been shown to be effective in preventing preterm birth when Neisseria gonorrhoeae, Chlamydia trachomatis, group B streptococcus, and asymptomatic bacteriuria (especially group B streptococcus) are detected in all women, regardless of history.

It is justified to conduct antibacterial therapy when bacterial vaginosis and trichomonas vulvovaginitis are detected in patients with risk factors for premature birth.

For gonococcal infection, cefixime is used in a single dose of 400 mg or ceftriaxone intramuscularly in a dose of 125 mg. For allergic reactions to the above drugs, an alternative treatment is used with spectinomycin in a single dose of 2 g intramuscularly.

For chlamydial infection, drugs from the macrolide group are used. Josamycin is prescribed at 500 mg 3 times a day for 7 days. Another treatment option is erythromycin at 500 mg 4 times a day for 7 days, spiramycin at 3 million IU 3 times a day, the course is 7 days.

Bacterial vaginosis is considered a risk factor for premature birth. Treatment of bacterial vaginosis in pregnant women should be carried out in the second and third trimesters with a high risk of premature birth (history of late termination of pregnancy and premature birth, signs of threatened premature birth).

Bacterial vaginosis should be treated in patients with factors predisposing to preterm birth, as it increases the risk of premature rupture of membranes, preterm labor, postoperative and postpartum infectious complications.

Effective oral regimens are accepted abroad: metronidazole 500 mg 2 times a day for 7 days, clindamycin 300 mg 2 times a day for 7 days.

In patients diagnosed with bacterial vaginosis without signs of threatened premature labor, local treatment is carried out in the form of vaginal suppositories with metronidazole (500 mg) for 6 days, vaginal forms of clindamycin (cream, balls) for 7 days. In women with threatened premature labor or who are at risk for developing premature labor in bacterial vaginosis, drugs are prescribed orally.

Detection of asymptomatic bacteriuria should be a mandatory examination method and if it is detected (more than 10 ⁵ CFU/ml), treatment is carried out on all patients.

If bacteriuria is detected, treatment begins with a 3-day course of antibacterial therapy, followed by monthly urine culture to monitor for possible recurrence of the disease.

Treatment of patients with identified group B streptococcus, as well as asymptomatic bacteriuria of streptococcal etiology, is carried out taking into account the sensitivity of the isolated microflora, but protected penicillins are recognized as the drugs of choice:

• amoxicillin + clavulanic acid 625 mg 2 times a day or 375 mg 3 times a day for 3 days;
• cefuroxime 250–500 mg 2–3 times a day for 3 days or ceftibuten 400 mg 1 time per day for 3 days;
• fosfomycin + trometamol 3 g once.

If 2 consecutive courses of etiotropic antibacterial treatment are ineffective, suppressive therapy is indicated until delivery and for 2 weeks after delivery. In this case, it is necessary to exclude complicated forms of urinary tract infections, primarily obstructive uropathies.

Suppressive therapy:

• fosfomycin + trometamol 3 g every 10 days, or
• nitrofurantoin 50-100 mg once a day.

Women with trichomonas infection are treated with metronidazole in a single dose of 2 g orally in the second and third trimesters of pregnancy. A single dose of 2 g of metronidazole has been proven to be effective in eliminating trichomonas.

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Use of antibiotics for premature rupture of membranes

Premature rupture of membranes occurs in 30–40% of all cases of premature birth.

When the fetal membranes rupture, infection of the uterine cavity inevitably occurs, but the risk of infectious complications in the newborn is higher than in the mother.

The probability of labor developing after the amniotic fluid has ruptured is directly dependent on the gestational age: the shorter the gestational age, the longer the period before regular labor develops (latent period). Within the first day after premature rupture of membranes, spontaneous labor begins: in 26% of cases with a fetal weight of 500–1000 g, in 51% of cases with a fetal weight of 1000–2500 g, in 81% of cases with a fetal weight of over 2500 g.

Prolongation of the anhydrous period in the absence of clinical manifestations of infection promotes maturation of the fetal lungs. However, prolongation of pregnancy is possible only in the absence of clinical signs of chorioamnionitis, in connection with which it is necessary to conduct a thorough examination of the pregnant woman, which includes:

• 3-hour thermometry;
• heart rate counting;
• monitoring of clinical blood tests - leukocytosis, band-nuclear shift;
• Cervical canal culture for group B streptococci, gonococci and chlamydia.

In addition, the condition of the fetus is monitored - determination of the gestational age of the fetus, assessment of fetometric parameters, detection of intrauterine growth retardation of the fetus, CTG.

Evaluation of the contractile activity of the uterus and the condition of its cervix is very important for determining further tactics for managing the patient.

In the absence of signs of infection and labor, prolongation of pregnancy is possible, since active management tactics (labor induction) worsen perinatal outcomes.

Delivery is indicated when:

• fetal developmental anomalies incompatible with life;
• pregnancy period more than 34 weeks;
• violation of the condition of the fetus;
• chorioamnionitis, when further prolongation of pregnancy is dangerous to the health of the mother.

Antibacterial therapy is indicated in cases of premature rupture of membranes and signs of infection (fever, leukocytosis, band shift in the leukocyte formula). In this situation, broad-spectrum antibiotic therapy is used in combination with drugs with antianaerobic activity (metronidazole). Antibacterial therapy helps reduce the incidence of chorioamnionitis and postpartum endometritis in mothers, and in children - the incidence of pneumonia, sepsis, intraventricular hemorrhage, bronchopulmonary dysplasia.

When group B streptococcus is cultured, it is recommended to administer an antibiotic during labor as a preventative measure for neonatal sepsis: ampicillin 1–2 g intravenously with a repeat administration of 1 g after 4–6 hours.

According to I. Grableet al. (1996), in case of premature rupture of membranes, such treatment allows delaying the development of labor in order to prevent fetal distress syndrome.

Neonatal mortality from sepsis is 5 times higher with postnatal treatment compared with intrapartum treatment of the mother.

Antibacterial therapy regimens for premature rupture of membranes

Several treatment regimens have been proposed for premature rupture of membranes and incipient chorioamnionitis. Preference is generally given to a combination of penicillin-type drugs (protected penicillins are the drugs of choice) with macrolides (primarily erythromycin). Third-generation cephalosporins are used as an alternative. In bacterial vaginosis and planned cesarean section, treatment should be supplemented with drugs with antianaerobic activity (metronidazole). This therapy is especially justified in gestational periods from 28 to 34 weeks, when prolongation of pregnancy increases the chances of survival of the newborn.

• Ampicillin 2 g intravenously every 6 hours for 48 hours, then amoxicillin orally 250 mg every 8 hours in combination with erythromycin 250 mg every 6 hours intravenously for 48 hours, followed by a transition to oral administration at a daily dose of 1–2 g.
• Ampicillin + sulbactam 3 g every 6 hours intravenously for 48 hours, then amoxicillin + clavulanic acid orally every 8 hours for 5 days, course 7 days.
• Ampicillin 2 g intravenously every 4–6 hours in combination with erythromycin 500 mg 4 times a day (daily dose 2 g).
• Amoxicillin + clavulanic acid 325 mg 4 times a day orally or ticarcillin + clavulanic acid in combination with erythromycin at a daily dose of 2 g.
• Cephalosporins: cefotaxime, cefoxitin, cefoperazone, ceftriaxone intravenously up to 4 g/day.
• In case of abdominal delivery, metronidazole is added to the therapy intravenously by drip at 500 mg (100 ml) 2-3 times a day.

Prevention of fetal respiratory distress syndrome

According to the recommendations of American authors, all pregnant women between the 24th and 34th weeks of gestation with threatened and incipient premature labor should be considered as patients who are indicated for antenatal prophylaxis of fetal respiratory distress syndrome with glucocorticoids, which promotes the maturation of fetal lung surfactant.

In our country, prevention of fetal distress syndrome is carried out in gestational periods of 28–34 weeks.

The effect of antenatal prevention of fetal distress syndrome has been proven, its benefit for the newborn outweighs the potential risk and is expressed in a decrease in perinatal morbidity and mortality, the incidence of respiratory distress syndrome, the incidence of intraventricular and periventricular (near-ventricular) hemorrhages, and the incidence of necrotizing enterocolitis.

If the pregnancy term is more than 34 weeks, prevention of respiratory distress syndrome is not indicated.

In case of premature rupture of membranes before 32 weeks, glucocorticoids are used in the absence of signs of chorioamnionitis.

Signs of chorioamnionitis include a combination of maternal body temperature of 37.8°C or higher with two or more of the following symptoms:

• maternal tachycardia (more than 100 beats per minute);
• fetal tachycardia (more than 160 beats per minute);
• pain in the uterus upon palpation;
• amniotic fluid with an unpleasant (putrid) odor;
• leukocytosis (more than 15.0×10 ⁹ /l) with a shift in the leukocyte formula to the left.

In addition to chorioamnionitis, contraindications to glucocorticoid therapy include gastric ulcer and duodenal ulcer, severe forms of diabetes, nephropathy, active tuberculosis, endocarditis, nephritis, osteoporosis, and stage III circulatory failure.

Dosage regimens: 2 doses of 12 mg betamethasone intramuscularly every 24 hours; 4 doses of 6 mg dexamethasone intramuscularly every 12 hours; as an option - 3 intramuscular injections of dexamethasone per day at 4 mg for 2 days.

The optimal duration of prophylaxis is 48 hours. The prophylactic effect of glucocorticoids is realized 24 hours after the start of therapy and lasts for 7 days.

The benefit of repeated courses of prophylaxis has not been proven.

A single repeated (after 7 days) administration of glucocorticoids is permissible if the pregnancy period is less than 34 weeks and there are no signs of fetal lung maturity.

In our country, oral administration of glucocorticoids is also used - dexamethasone 2 mg (4 tablets) 4 times a day for 2 days.

Prognosis for premature birth

The survival of premature infants is determined by a number of factors:

• gestational age;
• birth weight;
• gender (girls have a greater ability to adapt);
• the nature of the presentation (mortality in breech presentation is 5-7 times higher than in cephalic presentation in the case of delivery through the natural birth canal);
• method of delivery;
• the nature of labor (risk factor - rapid labor);
• presence of premature placental abruption;
• severity of intrauterine infection of the fetus;
• multiple pregnancy.