Preterm labor and birth
Synonyms and keywords: Preterm delivery, Premature labour, Early delivery, Premature birth, Premature labor, Pre term birth

# Overview
Preterm birth is any birth that happens between 20 weeks of gestation and 36 6/7 weeks of gestation. In Europe, it is defined after 22 weeks and before 37 weeks of gestation. The gestation can be dated using first-trimester ultrasound. In the US, approximately 12% of the births are preterm, while in Europe it varies between 5-18%.The diagnosis is made based on clinical criteria which include: cervical dilation of at least 2cm and/or cervical effacement, which happens with regular uterine contractions. It may happen with or without rupture of membrane. Preterm labor and delivery is associated to many risks for the babies such as: respiratory distress syndrome, periventricular leukomalacia, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, late-onset infection, retinopathy of prematurity, cerebral palsy and other adverse neurological outcomes.

# Historical Perspective
- In the 1930s, George Corner was the first to suggest the association between progesterone and the development of preterm labor.
- James Elgin Gill (born on 20 May 1987 in Ottawa, Canada) was the earliest premature baby in the world. He was 128 days premature (21 weeks and 5 days gestation) and weighed 1 lb. 6 oz.  (624 g). He survived and is quite healthy.

# Classification
- Preterm labor may be classified according to the WHO into 3 groups: extremely preterm (<28 weeks), very preterm (28 to 32 weeks), moderate to late preterm (32-37 weeks).

# Pathophysiology
- It is thought that preterm labor is the is mediated by either progesterone, which promotes uterine relaxation to maintain pregnancy and inflammation of the gestational tissues, which acts as a key trigger opposing the effects of progesterone and inducing progesterone withdraw.
- The switch from a quiescent myometrium into an active one is mediated by inflammatory pathways that include IL-8, IL-1, IL-6 and proteins such as oxytocin receptor, connexin 43 and prostaglandin receptor.
- Changes in the extracellular matrix proteins leads to cervical effacement and is the result of an increase in glycosaminoglycans and loss in collagen cross-linking results in a decrease in the tensile strength of the cervix.
- Increase in inflammatory factors such as TNF-alpha and IL-1 lead to the activation of proteases (MMP-8) and dissolution of fibronectin which leads to withdrawal of decidual support for pregnancy. This event causes separation of the chorioamniotic membranes from the decidua and eventually membrane rupture.
- Therefore, the occurrence of preterm labor with intact membranes depends on a balance between pro-labor/pro-inflammatory factors versus pro-pregnancy effects of progesterone.
- Preterm premature rupture of membranes (PPROM) has unknown etiology and may lead to preterm labor.
- Some factors increase the risk of PPROM such as cervical shortening or intra-amniotic infection.

# Causes
- Preterm labor may be caused by infection, uterine ovedistension, decidual senescence, vascular disorders, stress, cervical disease, decline in progesterone action, or breakdown in maternal-fetal tolerance.
- So far, only intra-amniotic infection has been shown to cause preterm delivery. The other factors are being associated based on reports by clinical, epidemiologic, placental pathologic, or experimental studies.
- Intra-amniotic infections can be subclinical. One in four preterm infants are born due to this cause.
The most frequent route is the ascending pathway, but hematogenous dissemination can occur.
Microorganisms are recognized by pattern recognition receptors, such as toll-like receptors (TLRs)
TLRs stimulate the production of chemokines (IL-8, C-C motif ligand 2 (CCL2), etc.), cytokines (IL-1b, TNF-a, etc), prostaglandins and proteases which activate the quiescent myometrium and stimulates parturition.
In 30% of cases of intra-amniotic infection, bacteria can be found in the fetal circulation which causes fetal systemic inflammatory response. These fetuses are at risk for long-term complications, such as cerebral palsy and chronic lung disease, which emphasizes that these complications may not only occur due to immaturity but also inflammatory response.
- The most frequent route is the ascending pathway, but hematogenous dissemination can occur.
- Microorganisms are recognized by pattern recognition receptors, such as toll-like receptors (TLRs)
- TLRs stimulate the production of chemokines (IL-8, C-C motif ligand 2 (CCL2), etc.), cytokines (IL-1b, TNF-a, etc), prostaglandins and proteases which activate the quiescent myometrium and stimulates parturition.
- In 30% of cases of intra-amniotic infection, bacteria can be found in the fetal circulation which causes fetal systemic inflammatory response. These fetuses are at risk for long-term complications, such as cerebral palsy and chronic lung disease, which emphasizes that these complications may not only occur due to immaturity but also inflammatory response.

# Differentiating preterm labor from other Diseases
- Preterm labor diagnosis is not challenging and it must be investigated if it is caused by other diseases that also cause abdominal pain, rupture of membranes and fetal distress.

# Epidemiology and Demographics
- The incidence of preterm labor is approximately 12% of the births in the United States.
- In Europe the incidence varies between 5-18% of the births.
- Approximately 17% of preterm births occur in the Americas (North, Central and South America, and the Caribbean), Europe and Australia.

# Risk Factors
- The most potent risk factor in the development of preterm labor are history of previous preterm birth, smoking, and multiple pregnancy.
- The earlier the preterm birth, the higher the risk of having a new case.
- Other risk factors include: low socio-economic status, ethnicity, smoking, maternal diabetes, short interpregnancy interval. However, when the analysis is performed within women who have had at least three pregnancies (two intervals) and each woman serves as her own control, increased risk is found when the first pregnancy was preterm but not among unselected women. low body mass index, periodontitis, cervical surgery (loop electrosurgical excision procedure/conization), uterus anomaly, pregnancy loss >16 weeks, gestational age, cervical insufficiency, mode of conception (in-vitro fertilization), multiple pregnancy, short cervix (the strongest predictor of premature birth). Finally, use of tobacco and alcohol during pregnancy also increases the chance of preterm delivery. Tobacco is the most commonly abused drug during pregnancy and also contributes significantly to low birth weight delivery. 

# Screening
- There is insufficient evidence to recommend routine screening for preterm labor.

# Natural History, Complications, and Prognosis
- If left untreated, women in preterm labor will progress to delivery. Tocolysis can postpone the delivery in up to 48 hours.
- Common complications of preterm delivery include respiratory distress syndrome, periventricular leukomalacia, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, late-onset infection, retinopathy of prematurity, cerebral palsy and other adverse neurological outcomes.
- Prognosis is generally dependent on gestational age.
Survival rate is about:
40% for newborns at 24 weeks' gestation,
50% for newborns at 25 weeks,
60% for newborns at 26 weeks,
70% for newborns at 27 weeks,
80% newborns born at 28 weeks.
- Survival rate is about:
40% for newborns at 24 weeks' gestation,
50% for newborns at 25 weeks,
60% for newborns at 26 weeks,
70% for newborns at 27 weeks,
80% newborns born at 28 weeks.
- 40% for newborns at 24 weeks' gestation,
- 50% for newborns at 25 weeks,
- 60% for newborns at 26 weeks,
- 70% for newborns at 27 weeks,
- 80% newborns born at 28 weeks.

# Diagnosis

## Diagnostic Study of Choice
- The diagnosis of preterm labor is made when the patient presents with 20-36 6/7 weeks of gestation with uterine contractions occurring at a frequency of four per 20 minutes or eight per 60 minutes and at least 1 of the following 4 diagnostic criteria are met:
Premature rupture of membranes
Cervical dilation greater than 2 cm
Effacement exceeding 50 percent
Change in cervical dilation or effacement detected by serial examinations.
- Premature rupture of membranes
- Cervical dilation greater than 2 cm
- Effacement exceeding 50 percent
- Change in cervical dilation or effacement detected by serial examinations.

## History and Symptoms
- A positive history of regular uterine contractions and loss of amniotic fluid through the vaginal canal before the 36th week of pregnancy is suggestive of preterm labor. The loss of fluid may be absent.
- Patients may also complain of frequent contractions (more than four per hour), cramping, pelvic pressure, excessive vaginal discharge, back ache and low back pain.

## Physical Examination
- Common physical examination findings of preterm labor include regular uterine contractions, cervical dilation of at least 2cm, and it may present with or with our ruptured membranes.
- The assessment of preterm delivery risk based on symptoms and physical examination alone is inaccurate.

## Laboratory Findings
- Altered markers such as: cervical fibronectin, HCG, or phIGFBP-1, presence of fetal fibronectin fFN/PAMG1/IGF-BP 1 in cervical-vaginal secretions
- Serum C-reactive protein, and amniotic fluid interleukins may be useful for predicting spontaneous preterm birth, but its accuracy is questionable.

## Electrocardiogram
- There are no ECG findings associated with preterm labor.

## X-ray
- There are no x-ray findings associated with preterm labor.

## Echocardiography or Ultrasound
- Ultrasound imaging may be helpful in the diagnosis of preterm labor as well as in finding out risk factors for its development.
- Findings on an ultrasound suggestive of a higher risk for preterm labor include short cervical length, especially if smaller than 25 mm.
- It can also be useful on identifying associated conditions with the fetus or placenta, the fetus' position, the volume of amniotic fluid, and estimate the fetus' weight.

## CT scan
- There are no CT scan findings associated with preterm labor.

## MRI
- There are no MRI findings associated with preterm labor.

## Other Imaging Findings
- There are no other imaging findings associated with preterm labor.

## Other Diagnostic Studies
- Uterine monitoring may be helpful in the diagnosis of preterm labor. Findings suggestive of preterm labor include tachysystole (greater than five contractions in 10 minutes).

# Treatment

## Medical Therapy
According to the American College of Obstetricians and Gynecologists guidelines:
- Pharmacologic medical therapy is recommended among patients with preterm labor in which a delay in delivery will be beneficial to the newborn. Such cases include patients presenting a gestational age no higher than 34 weeks.
- The medical therapy of delaying delivery is called tocolysis, and it is effective for up to 48 hours.
- It is generally not indicated if there's no neonatal viability.
- Its use must be used only on women with preterm labor at high risk of spontaneous preterm birth.
- Administering corticosteroids (single course) is recommended for pregnant women between 24 weeks and 34 weeks of gestation who are at risk of delivery within 7 days.
- Antibiotics should not be used to prolong gestation or improve neonatal outcomes if membranes are intact.

## Surgery
- Surgery is ultrasound-indicated. The procedure is called cerclage, made to prevent preterm labor.
- Cerclage is beneficial in women with cervical length <25 mm when placed between 16 and 24 weeks of gestation.

## Primary Prevention
- There are no established measures for the primary prevention of preterm labor.

## Secondary Prevention
- Cerclage is a surgical procedure made in a certain group of patients to avoid the recurrence of preterm labor.
- Administration of progesterone is being investigated for high-risk patients, especially those who had an episode of preterm labor previously.