Preterm birth

In humans preterm birth (partus praetemporaneus or partus praematurus) refers to the birth of a baby of less than 37 weeks gestational age. The cause for preterm birth is in many situations elusive and unknown; many factors appear to be associated with the development of preterm birth, making the reduction of preterm birth a challenging proposition.

Premature birth, commonly used as a synonym for preterm birth, refers to the birth of a baby before the developing organs are mature enough to allow normal postnatal survival. Premature infants are at greater risk for short and long term complications, including disabilities and impediments in growth and mental development. Significant progress has been made in the care of premature infants, but not in reducing the prevalence of preterm birth. Preterm birth is the major cause of neonatal mortality in developed countries.

Classification
In that they continue developing after birth, most animals are not born mature. At birth, a normal human infant is less mature than infants of some other primate species, possibly to allow the disproportionately large head to fit through a pelvis adapted for walking on two legs. Furthermore, since the evolution of conscious thought in humans, there is less selective pressure to have more developed infants at birth because of the increased ability to protect human infants.

In humans whereas the usual definition of preterm birth is birth before 37 weeks gestation, a "premature" infant is one that has not yet reached the level of fetal development that generally allows life outside the womb. In the normal human fetus, several organ systems mature between 34 and 37 weeks, and the fetus reaches adequate maturity by the end of this period. One of the main organs greatly affected by premature birth is the lungs. The lungs are one of the last organs to develop in the womb; because of this, premature babies typically spend the first days/weeks of their life on a ventilator. Therefore, a significant overlap exists between preterm birth and prematurity. Generally, preterm babies are premature and term babies are mature. Prematurity can be reduced to a small extent by using drugs to accelerate maturation of the fetus, and to a greater extent by preventing preterm birth.

Signs and symptoms
Symptoms of imminent spontaneous preterm birth, are signs of premature labor; one sign is four or more uterine contractions in one hour. In contrast to false labor, true labor is accompanied by cervical dilatation and effacement. Also, vaginal bleeding in the third trimester, heavy pressure in the pelvis, or abdominal or back pain could be indicators that a preterm birth is about to occur. A watery discharge from the vagina may indicate premature rupture of the membranes that surround the baby. While the rupture of the membranes may not be followed by labor, usually delivery is indicated as infection (chorioamnionitis) is a serious threat to both fetus and mother. In some cases the cervix dilates prematurely without pain or perceived contractions, so that the mother may not have warning signs until very late in the birthing process.

Mortality and morbidity
The shorter the term of pregnancy, the greater the risks of mortality and morbidity for the baby primarily due to the related prematurity. Preterm-premature babies ("preemies" or "premmies") have an increased risk of death in the first year of life (infant mortality), with most of that occurring in the first month of life (neonatal mortality). Worldwide, prematurity accounts for 10% of neonatal mortality, or around 500,000 deaths per year. In the U.S. where many infections and other causes of neonatal death have been markedly reduced, prematurity is the leading cause of neonatal mortality at 25%. Prematurely born infants are also at greater risk for having subsequent serious chronic health problems as discussed below.

The earliest gestational age at which the infant has at least a 50% chance of survival is referred to as the limit of viability. As NICU care has improved over the last 40 years, viability has reduced to approximately 24 weeks, although rare survivors have been documented as early as 21 weeks. This date is controversial, as gestation in the case reported was measured from the known date of conception (by IVF) rather than, as usual, the date of the mother's last menstrual period, making gestation appear two weeks less than if calculated by the conventional method in this case. As risk of brain damage and developmental delay is significant at that threshold even if the infant survives, there are ethical controversies over the aggressiveness of the care rendered to such infants. The limit of viability has also become a factor in the abortion debate.

Specific risks for the preterm neonate
Preterm infants usually show physical signs of prematurity in reverse proportion to the gestational age. As a result they are at risk for numerous medical problems affecting different organ systems.
 * Neurological problems include apnea of prematurity, hypoxic-ischemic encephalopathy (HIE), retinopathy of prematurity (ROP), developmental disability, cerebral palsy and intraventricular hemorrhage, the latter affecting 25 percent of babies born preterm, usually before 32 weeks of pregnancy. Mild brain bleeds usually leave no or few lasting complications, but severe bleeds often result in brain damage or even death. Neurodevelopmental problems have been linked to lack of maternal thyroid hormones, at a time when their own thyroid is unable to meet postnatal needs.
 * Cardiovascular complications may arise from the failure of the ductus arteriosus to close after birth: patent ductus arteriosus (PDA).
 * Respiratory problems are common, specifically the respiratory distress syndrome (RDS or IRDS) (previously called hyaline membrane disease). Another problem can be chronic lung disease (previously called bronchopulmonary dysplasia or BPD).
 * Gastrointestinal and metabolic issues can arise from hypoglycemia, feeding difficulties, rickets of prematurity, hypocalcemia, inguinal hernia, and necrotizing enterocolitis (NEC).
 * Hematologic complications include anemia of prematurity, thrombocytopenia, and hyperbilirubinemia (jaundice) that can lead to kernicterus.
 * Infection, including sepsis, pneumonia, and urinary tract infection

A large study on children born between 22 and 25 weeks who were currently at school age found that 46 percent had severe or moderate disabilities such as cerebral palsy, vision or hearing loss and learning problems. 34 percent were mildly disabled and 20 percent had no disabilities, while 12 percent had disabling cerebral palsy.



Causes
As the cause of labor still remains elusive, the exact cause of preterm birth is also unsolved. In fact, the cause of 50% of preterm births is never determined. Labor is a complex process involving many factors. Four different pathways have been identified that can result in preterm birth and have considerable evidence: precocious fetal endocrine activation, uterine overdistension, decidual bleeding, and intrauterine inflammation/infection. Activation of one or more of these pathways may happen gradually over weeks, even months. From a practical point a number of factors have been identified that are associated with preterm birth, however, an association does not establish causality.

Maternal background
A number of factors have been identified that are linked to a higher risk of a preterm birth: age at the upper and lower end of the reproductive years, be it more than 35 or less than 18 years of age. Maternal height and weight can also play a role. Further, in the US and the UK, Afro-American and Afro-Caribbean women have preterm birth rates of 15–18%, more than double than that of the white population. This discrepancy is not seen in comparison to Asian or Hispanic immigrants and remains unexplained.

Pregnancy interval makes a difference as women with a 6 months span or less between pregnancies have a two-fold increase in preterm birth. Studies on type of work and physical activity have given conflicting results, but it is opined that stressful conditions, hard labor, and long hours are probably linked to preterm birth. Women who have undergone previous surgically induced abortions have been shown to have a higher risk of preterm birth (less than 37 weeks), as well as extreme preterm birth (less than 28 weeks). The preterm birth link has not been shown in women who terminated their pregnancies medically with pills such as RU-486. Adequate maternal nutrition is important. Women with a low BMI are at increased risk for preterm birth. Further, women with poor nutritional status may also be deficient in vitamins and minerals. Adequate nutrition is critical for fetal development and a diet low in saturated fat and cholesterol may help reduce the risk of a preterm delivery. Obesity does not directly lead to preterm birth; however, it is associated with diabetes and hypertension which are risk factors by themselves. Women with a previous preterm birth are at higher risk for a recurrence at a rate of 15–50% depending on number of previous events and their timing. To some degree those individuals may have underlying conditions (i.e. uterine malformation, hypertension, diabetes) that persist.

Marital status is associated with risk for preterm birth. A study of 25,373 pregnancies in Finland revealed that unmarried mothers had more preterm deliveries than married mothers (P=0.001). Pregnancy outside of marriage was associated overall with a 20% increase in total adverse outcomes, even at a time when Finland provided free maternity care. A study in Quebec of 720,586 births from 1990-97 revealed less risk of preterm birth for infants with legally married mothers, compared with those with common law wed or unwed parents.

Genetic make-up is a factor in the causality of preterm birth. An intra- and transgenerational increase in the risk of preterm delivery has been demonstrated. No single gene has been identified, and it appears with the complexity of the labor initiation, that numerous polymorphic genetic interactions are possible.

Factors during pregnancy
Multiple pregnancies (twins, triplets, etc.) are a significant factor in preterm birth. The March of Dimes Multicenter Prematurity and Prevention Study found that 54% of twins were delivered preterm vs. 9.6% of singleton births. Triplets and more are even more endangered. The use of fertility medication that stimulates the ovary to release multiple eggs and of IVF with embryo transfer of multiple embryos has been implicated as an important factor in preterm birth. Maternal medical conditions increase the risk of preterm birth, and often labor has to be induced for medical reasons; such conditions include high blood pressure, pre-eclampsia, maternal diabetes, asthma, thyroid disease, and heart disease. In a number of women anatomical issues prevent that the baby is carried to term. Some women have a weak or short cervix (the strongest predictor of premature birth)   The cervix may also have been compromised by previous cervical conization or loop excision. In women with uterine malformations the capacity of the uterus to hold the growing pregnancy may be limited and preterm labor ensues. Women with vaginal bleeding during pregnancy are at higher risk for preterm birth. While bleeding in the third trimester may be a sign of placenta previa or placental abruption – conditions that occur frequently preterm – even earlier bleeding that is not caused by these two conditions is linked to a higher preterm birth rate. Women with abnormal amounts of amniotic fluid, too much (polyhydramnios) or too little (oligohydramnios) are also at risk. The mental status of the women is of significance. Anxiety and depression have been linked to preterm birth. Finally, the use of tobacco, cocaine, and excessive 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. Babies with birth defects are at higher risk of being born preterm.

Presence of anti-thyroid antibodies is associated with an increased risk preterm birth with an odds ratio of 1.9 and 95% confidence interval of 1.1–3.5.

A 2004 systematic review of 30 studies on the association between intimate partner violence and birth outcomes concluded that preterm birth and other adverse outcomes, including death, are higher among abused pregnant women than among non-abused women.

The Nigerian cultural method of abdominal massage has been shown to result in 19% preterm birth among women in Nigeria, plus many other adverse outcomes for the mother and baby. This ought not be confused with massage conducted by a fully trained and licensed massage therapist or by significant others trained to provide massage during pregnancy, which has been shown to have numerous positive results during pregnancy, including the reduction of preterm birth, less depression, lower cortisol, and reduced anxiety.

Infection
Infections play a major role in the genesis of preterm birth and may account for 25–40% of events. The frequency of infection in preterm birth is inversely related to the gestational age. Endotoxins released by microorganisms and cytokines stimulate deciduas responses including the release of prostaglandins which may stimulate uterine contractions. Further the decidual response may include release of matrix-degrading enzymes that weaken fetal membranes leading to premature rupture. Intrauterine infection appears to be a chronic process. Typical organisms identified in the uterus before rupture of the membranes are genital Mycoplasma spp and specifically Ureaplasma urealyticum. Micro-organisms may reach the decidua in a number of ways, ascending, hematogeneous, iatrogenic by a procedure, or retrograde through the fallopian tubes. From the deciduas they may reach the space between the amnion and chorion, the amniotic fluid, and finally the fetus. A chorioamnionitis also may lead to sepsis of the mother. Fetal infection not only is linked to preterm birth but to significant long-term handicap including cerebral palsy. It has been reported that asymptomatic colonization of the decidua occurs in up to 70% of women at term using a DNA probe suggesting that the presence of micro-organism alone may be insufficient to initiate the infectious response. Bacterial vaginosis has been linked to preterm birth raising the risk by a factor of 1.5 – 3. As the condition is more prevalent in black women in the US and the UK, it has been suggested to be an explanation for the higher rate of preterm birth in this population. It is opined that bacterial vaginosis before or during pregnancy may affect the decidual inflammatory response that leads to preterm birth. A number of maternal bacterial infections are associated with preterm birth including pyelonephritis, asymptomatic bacteriuria, pneumonia, and appendicitis. Also periodontal disease has been shown repeatedly to be linked to preterm birth. In contrast, viral infections, unless accompanied by a significant febrile response, are considered not to be a major factor in relation to preterm birth.

Diagnosis
Helpful clinical test should predict a high risk for preterm birth during the early and middle part of the third trimester, when their impact is significant. Many women experience false labor (not leading to cervical shortening and effacement) and are falsely labelled to be in preterm labor. The study of preterm birth has been hampered by the difficulty in distinguishing between "true" preterm labor and false labor. These new test are used to identify women at risk for preterm birth.

Fetal fibronectin
Fetal fibronectin has become the most important biomarker—the presence of this glycoprotein in the cervical or vaginal secretions indicates that the border between the chorion and deciduas has been disrupted. A positive test indicates an increased risk of preterm birth, and a negative test has a high predictive value. It has been shown that only 1% of women in questionable cases of preterm labor delivered within the next week when the test was negative.

Ultrasonography of the cervix
Obstetric ultrasound has become useful in the assessment of the cervix in women at risk for premature delivery. A short cervix preterm is undesirable: At 24 weeks gestation a cervix length of less than 25 mm defines a risk group for preterm birth. Further, the shorter the cervix the greater the risk. It also has been helpful to use ultrasonography in women with preterm contractions, as those whose cervix length exceeds 30 mm are unlikely to deliver within the next week.

Prevention
Historically efforts have been primarily aimed to improve survival and health of preterm infants (tertiary intervention). Such efforts, however, have not reduced the incidence of preterm birth. Increasingly primary interventions that are directed at all women, and secondary intervention that reduce existing risks are looked upon as measures that need to be developed and implemented to prevent the health problems of premature infants and children.

Preconceptional
Raising public and professional awareness about the scope of the problem and its significance as the major contributor to infant mortality is a beginning to reduce avoidable risk factor. Among them is the need to reduce repeated uterine instrumentation (i.e. repeated surgical abortions) and to avoid risky choices in infertility treatments. Adoption of specific professional policies can immediately reduce risk of preterm birth as the experience in assisted reproduction has shown when the number of embryos during embryo transfer were limited. Many countries have established specific programs to protect pregnant women from hazardous and night-shift work, and to provide them with time for prenatal visits and paid pregnancy-leave. The EUROPOP study showed that preterm birth is not related to type of employment, but to prolonged work (over 42 hours per week) or prolonged standing (over 6 hours per day). Also, night work has been linked to preterm birth. Health policies that take these findings into account can be expected to reduce the rate of preterm birth. Avoidance of weight extremes and good nutritional support are important. Although a study failed to show that multivitamin preparation taken prior to conception reduces the risk of preterm birth, preconceptional intake of folic acid is recommended to reduce birth defects. There is significant evidence that long term (> one year) use of folic acid supplement preconceptionally may reduce premature birth. Reducing smoking is expected to benefit pregnant women and their offspring.

During pregnancy
Interventions that should have been initiated prior to pregnancy can still be instituted during pregnancy, including nutritional adjustments, use of vitamin supplements, and smoking cessation. Calcium supplementation as well as supplemental intake of C and E vitamins could not be shown to reduce preterm birth rates. Different strategies are used in the administration of prenatal care, and future studies need to determine if the focus should be on screening for high risk women, or widened support for low-risk women, or to what degree these approaches should be merged. While periodontal infection has been linked with preterm birth, randomized trials have not shown that periodontal care during pregnancy reduces preterm birth rates.

Screening of low risk women
Screening for asymptomatic bacteriuria followed by appropriate treatment reduces pyelonephritis and reduces the risk of preterm birth. Extensive studies have been carried out to determine if other forms of screening in low-risk women followed by appropriate intervention are beneficial, including: Screening for and treatment of Ureaplasma urealyticum, group B streptococcus, Trichomonas vaginalis, and bacterial vaginosis did not reduce the rate of preterm birth. Routine ultrasound examination of the length of the cervix identifies patients at risk, but cerclage is not proven useful, and the application of a progesterone is under study. Screening for the presence of fibronectin in vaginal secretions is not recommended at this time in women at low risk.

Self-care
Self-care methods to reduce the risk of preterm birth include proper nutrition, avoiding stress, seeking appropriate medical care, avoiding infections, and the control of preterm birth risk factors (e.g. working long hours while standing on feet, carbon monoxide exposure, domestic abuse, and other factors). Self-monitoring vaginal pH followed by yogurt treatment or clindamycin treatment if the pH was too high all seem to be effective at reducing the risk of preterm birth.

Secondary (reducing existing risks)
Women are identified to be at increased risk for preterm birth on the basis of their past obstetrical history or the presence of known risk factors. Preconception intervention can be helpful in selected patients in a number of ways. Patients with certain uterine anomalies may have a surgical correction (i.e. removal of a uterine septum), and those with certain medical problems can be helped by optimizing medical prior to conception, be it for asthma, diabetes, hypertension and others.

Reducing indicated preterm birth
A number of agents have been studied for secondary prevention of indicated preterm birth. Trials using low-dose aspirin, fish oil, vitamin C and E, and calcium to reduce preeclampsia demonstrated some reduction in preterm birth only when low-aspirin was used. Interestingly, even if agents such as calcium or antioxidants were able to reduce preeclampsia, a resulting decrease in preterm birth was not observed.

Reducing spontaneous preterm birth
Reduction in maternal activity – pelvic rest, limited work, bed rest – is frequently recommended although there is no clear proof of its efficacy. Also, increasing medical care by more frequent visits and more education has not shown a reduction in preterm birth rates. Use of nutritional supplements such as omega-3 polyunsaturated fatty acids is based on the observation that populations who have a high intake of such agents are at low risk for preterm birth, presumably as these agents inhibit production of proinflammatory cytokines. A randomized trial showed a significant decline in preterm birth rates, and further studies are in the making.

Studies examining the use of antibiotics have provided mixed results; a Cochrane review of 15 trials shows no major benefit, in contrast a review by Lamont suggested that treatment of bacterial vaginosis if initiated prior to 20 w gestation is beneficial. It has been suggested that the presence of a chronic chorioamnionitis may not be amenable to antibiotics, thus the difficulty to demonstrate their effectiveness.
 * Antibiotics

Progesterone, often given in the form of 17-hydroxyprogesterone caproate, relaxes the uterine musculature, maintains cervical length, and has anti-inflammatory properties, and thus exerts activities expected to be beneficial in reducing preterm birth. Two meta-analyses demonstrated a deduction in the risk of preterm birth in women with recurrent preterm birth by 40–55%. However, progesterone is not effective in all populations, as a study involving twin gestations failed to see any benefit. In preparation for childbirth, the woman's cervix shortens. Preterm cervical shortening is linked to preterm birth and can be detected by ultrasonography. Cervical cerclage is a surgical intervention that places a suture around the cervix to prevent its shortening and widening. Numerous studies have been performed to assess the value of cervical cerclage and the procedure appears helpful primarily for women with a short cervix and a history of preterm birth. Instead of a prophylactic cerclage, women at risk can be monitored during pregnancy by sonography, and when shortening of the cervix is observed, the cerclage can be performed.
 * Progesterone
 * Cervical cerclage

Management
Tertiary interventions are aimed at women who are about to go into preterm labor, or rupture the membranes or bleed preterm. The use of the fibronectin test and ultrasonography improves the diagnostic accuracy and reduces false-positive diagnosis. While treatments to arrest early labor where there is progressive cervical dilatation and effacement will not be effective to gain sufficient time to allow the fetus to grow and mature further, it may defer delivery sufficiently to allow the mother to be brought to a specialized center that is equipped and staffed to handle preterm deliveries. Centers for the care of women with preterm delivery are usually staffed by maternal-fetal specialists and highly trained staff and linked to neonatal intensive care units (vi). In a hospital setting women are hydrated via intravenous infusion as dehydration can lead to premature uterine contractions.

Glucocorticosteroids
Severely premature infants may have underdeveloped lungs, because they are not yet producing their own surfactant. This can lead directly to respiratory distress syndrome, also called hyaline membrane disease, in the neonate. To try to reduce the risk of this outcome, pregnant mothers with threatened premature delivery prior to 34 weeks are often administered at least one course of glucocorticoids, a steroid that crosses the placental barrier and stimulates the production of surfactant in the lungs of the fetus. Typical glucocorticoids that would be administered in this context are betamethasone or dexamethasone, often when the fetus has reached viability at 23 weeks. In cases where premature birth is imminent, a second "rescue" course of steroids may be administered 12 to 24 hours before the anticipated birth. There is no research consensus on the efficacy and side-effects of a second course of steroids, but the consequences of RDS are so severe that a second course is often viewed as worth the risk. Beside reducing respiratory distress, other neonatal complication are reduced by the use of glucocorticosteroids, namely intraventricular haemorrhage, necrotising enterocolitis, and patent ductus arteriosus.

Despite being used for over 50 years to treat respiratory distress syndrome, glucocorticosteroid therapy is still controversial. Much of this concern is based on when these steroids should be administered (i.e. prenatally or postnatally) or for how long (i.e. acutely or chronically). For instance, clinical research conducted in 2004 has shown that the postnatal administration of dexamethasone can lead to permanent neuromotor and cognitive deficits. This has led to a drastic reduction in the postnatal use of glucocorticosteroids in prematurely born infants. In addition, a recent large scale study has found that a second “rescue” dose of betamethasone prenatally does not improve preterm birth outcomes and leads to decreased weight, length, and head circumference. Other side effects of corticosteroids are diabetes mellitus, osteoporosis, inhibition of growth, hypertension, cognitive problems, anxiety, depression, gastritis, colitis. Finally, a single study on animals has shown that a single exposure to these same drugs during brain development causes rapid brain degeneration. Despite these concerns, there is a consensus that the benefits of a single regimen of prenatal glucocorticosteroids vastly outweigh the potential risks.

The routine administration of antibiotics to all women with threatened preterm labor reduces the risk of the baby to get infected with group B streptococcus and has been shown to reduce related mortality rates.

Research reported at the 2008 conference of the Society for Maternal-Fetal Medicine suggests that administration of magnesium sulfate (Epsom salt) to women just before premature birth can cut the rate of cerebral palsy in half. While the compound is cheap and safe, it may make mothers and infants groggy, and details are pending scientific publication.

Tocolysis
Anti-contraction medications (tocolytics), such as Beta2-agonist drugs (ritodrine, terbutaline, fenoterol), calcium-channel blockers nifedipine and oxytocin antagonists (atosiban) appear only to have a temporary effect in delaying delivery. Tocolysis has not fulfilled its promise as it is rarely successful beyond 24–48 hours because current medication do not alter the fundamentals of labor activation. However, just gaining 48 hours is sufficient to allow the pregnant women to be transferred to a center specialized for management of preterm deliveries and give administered corticosteroids the possibility to reduce neonatal organ immaturity. Meta-analyses indicate that calcium-channel blockers and an oxytocin antagonist can delay delivery by 2–7 days, and β2-agonist drugs delay by 48 hours but carry more side effects. Meta-analyses of magnesium sulfate failed to support it as a tocolytic agent.

When membranes rupture prematurely, obstetrical management looks for development of labor and signs of infection. Administration of corticosteroids is indicated prior to 32 weeks gestation. Prophylactic antibiotic administration has been shown to prolong pregnancy and reduced neonatal morbidity with rupture of membranes at less than 34 weeks. Because of concern about necrotizing enterocolitis, amoxicillin or erythromycin has been recommended, but not amoxicillin + clavulanic acid (co-amoxiclav).

The routine use of cesarean section for early delivery of infants expected to have very low birth weight is controversial, and a decision concerning the route and time of delivery probably needs to be made on a case by case basis.

Neonatal care
In developed countries premature infants are usually cared for in a neonatal intensive care unit (NICU). The physicians who specialize in the care of very sick or premature babies are known as neonatologists. In the NICU, premature babies are kept under radiant warmers or in incubators (also called isolettes), which are bassinets enclosed in plastic with climate control equipment designed to keep them warm and limit their exposure to germs. Modern neonatal intensive care involves sophisticated measurement of temperature, respiration, cardiac function, oxygenation, and brain activity. Treatments may include fluids and nutrition through intravenous catheters, oxygen supplementation, mechanical ventilation support, and medications. In developing countries where advanced equipment and even electricity may not be available or reliable, simple measures such as kangaroo care (skin to skin warming), encouraging breastfeeding, and basic infection control measures can significantly reduce preterm morbidity and mortality. Bili lights may also be used to treat newborn jaundice (hyperbilirubinemia).

Prognosis
Many children will adjust well during childhood and adolescence, although a large study that followed children born between 22 and 25 weeks found some alarming results. When the children were 6 years old it was found that 46 percent had severe or moderate disabilities such as cerebral palsy, vision or hearing loss and learning problems; 34 percent were mildly disabled while 20 percent had no disabilities.12 percent had disabling cerebral palsy. For the first time this gave a real picture of what happens to children who are at the limits of viability. As survival has improved, the focus of interventions directed at the newborn has shifted to reduce long-term disabilities, particularly those related to brain injury. Some of the complications related to prematurity may not be apparent until years after the birth. A long-term study demonstrated that the risks of medical and social disabilities extend into adulthood and are higher with decreasing gestational age at birth and include cerebral palsy, mental retardation, disorders of psychological development, behavior, and emotion, disabilities of vision and hearing, and epilepsy. Standard intelligence tests showed that 41 percent of children born between 22 and 25 weeks had moderate or severe learning disabilities when compared to the test scores of a group of similar classmates who were born at full-term. It is also shown that higher levels of education were less likely to be obtained with decreasing gestational age at birth. People born prematurely may be more susceptible to developing depression as teenagers. Some of these problems can be described as being within the executive domain and have been speculated to arise due to decreased myelinization of the frontal lobes. Studies of people born premature and investigated later with MRI brain imaging, demonstrate qualitative anomalies of brain structure and grey matter deficits within temporal lobe structures and the cerebellum that persist into adolescence. Throughout life they are more likely to require services provided by physical therapists, occupational therapists, or speech therapists.

Epidemiology
In Europe and many developed countries the preterm birth rate is generally 5–9%, and in the USA it has even risen to 12–13% in the last decades. Three obstetric events precede preterm birth: spontaneous preterm births are the 40–45% preterm births that follow preterm labor and the 25–30% preterm births after premature rupture of membranes. The remainder (30–35%) are preterm births that are induced for obstetrical reasons; obstetricians may have to deliver the baby preterm because of a deteriorating intrauterine environment (i.e. infection, intrauterine growth retardation) or significant endangerment of the maternal health (i.e. preeclampsia, cancer). By gestational age, 5% of preterm births occur at less than 28 weeks (extreme prematurity), 15% at 28–31 weeks (severe prematurity), 20% at 32–33 weeks (moderate prematurity), and 60–70% at 34–36 weeks (late preterm).

As weight is easier to determine than gestational age, the World Health Organization tracks rates of low birth weight (< 2,500 grams), which occurred in 16.5 percent of births in less developed regions in 2000. It is estimated that one-third of these low birth weight deliveries are due to preterm delivery. Weight generally correlates to gestational age, however, infants may be underweight for other reasons than a preterm delivery. Neonates of low birth weight (LBW) have a birth weight of less than 2500 g (5 lb 8 oz) and are mostly but not exclusively preterm babies as they also include small for gestational age (SGA) babies. Weight-based classification further recognizes Very Low Birth Weight (VLBW) which is less than 1500 g, and Extremely Low Birth Weight (ELBW) which is less than 1000 g. Almost all neonates in these latter two groups are born preterm.

Preterm birth is a significant cost factor in healthcare, not even considering the expenses of long-term care for individuals with disabilities due to preterm birth. A 2003 study in the US determined neonatal costs to be $224,400 for a newborn at 500–700 g versus $1,000 at over 3,000 g. The costs increase exponentially with decreasing gestational age and weight. The 2007 Institute of Medicine report Preterm Birth found that the 550,000 preemies born each year in the U.S. run up about $26 billion in annual costs, mostly related to care in NICUs, but the real tab may top $50 billion.

Notable preterm births
John Matthew Duprey (born on 15 January 1996) in Burlington, Vermont was one of the earliest premature baby in Vermont. He was 87 days premature (29 weeks and 2 days.) He weighed in at 1 pound 7 ounces, but lost 1 ounce, to bring him down to 1 pound 6 ounces. He spent three months in an incubator, but he was released April 10, 1996. He survived his ordeal and so far has lived a healthy life.

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 pound 6 ounces (624 g). He survived and is quite healthy.

Amillia Taylor is also often cited as the most-premature baby. She was born on 24 October 2006 in Miami, Florida, at 21 weeks and 6 days gestation. This report has created some confusion as her gestation was measured from the date of conception (through in-vitro fertilization) rather than the date of her mother's last menstrual period making her appear 2 weeks younger than if gestation was calculated by the more common method. At birth, she was 9 in long and weighed 10 ounces (283 grams). She suffered digestive and respiratory problems, together with a brain hemorrhage. She was discharged from the Baptist Children's Hospital on 20 February 2007.

The record for the smallest premature baby to survive was held for some time by Madeline Mann, who was born at 26 weeks weighing 9.9 oz and 9.5 in long. This record was broken in September 2004 by Rumaisa Rahman, who was born in the same hospital at 25 weeks gestation. At birth, she was eight inches (20 cm) long and weighed 244 grams (8.6 ounces). Her twin sister was also a small baby, weighing 563 grams (1 pound 4 ounces) at birth. During pregnancy their mother had suffered from pre-eclampsia, which causes dangerously high blood pressure putting the baby into distress and requiring birth by caesarean section. The larger twin left the hospital at the end of December, while the smaller remained there until 10 February 2005 by which time her weight had increased to 1.18 kg. Generally healthy, the twins had to undergo laser eye surgery to correct vision problems, a common occurrence among premature babies.

The autistic savant Derek Paravicini was born at 25 weeks. The oxygen therapy given during his time in a neonatal intensive care unit rendered him blind and affected his developing brain, resulting in his severe learning disability. Furthermore Paravicini developed autism. However, he also has absolute pitch and his musical abilities developed to genius levels.

The world's smallest premature boy to survive was born in February 2009 at Children's Hospitals and Clinics of Minnesota in Minneapolis, Minnesota. Jonathon Whitehill was born at 25 weeks gestation with a weight of 310 grams (10.9 ounces). He was hospitalized in the Neonatal Intensive Care Unit for five months, and then discharged.

Historical figures who were born prematurely include Johannes Kepler (born in 1571 at 7 months gestation), Isaac Newton (born in 1643, small enough to fit into a quart mug, according to his mother), Winston Churchill (born in 1874 at 7 months gestation), and Anna Pavlova (born in 1885 at 7 months gestation).

Ethics
The transformation of medical care means that extremely premature and very ill babies have better chances of survival than ever before. But it is difficult to predict which babies will die and which will live with severe disabilities. As a consequence, families and health professionals have to make complex decisions about how much intervention is necessary or justifiable.

The most difficult decisions are about whether or not to resuscitate a premature baby and admit him or her to neonatal intensive care, or whether to withdraw intensive care and give the child palliative care.

This is discussed at great length in a report "Critical care decisions in fetal and neonatal medicine: ethical issues" produced by the London-based Nuffield Council for Bioethics.

The edge of viability
The gestational age at which a child is born plays a key part in these decisions.

22 weeks: in the UK and France babies are not normally resuscitated.

23 weeks: in Holland babies are not normally resuscitated at this age or below.

24 weeks: in most countries babies at this gestation are resuscitated.