Preterm birth

Preterm birth, also known as premature birth, is the

Preterm birth is the most common cause of death among infants worldwide.[1] About 15 million babies are preterm each year (5% to 18% of all deliveries).^[2] Late preterm birth accounts for 75% of all preterm births.^[18] This rate is inconsistent across countries. In the United Kingdom 7.9% of babies are born pre-term and in the United States 12.3% of all births are before 37 weeks gestation.^[19][20] Approximately 0.5% of births are extremely early periviable births (20–25 weeks of gestation), and these account for most of the deaths.^[21] In many countries, rates of premature births have increased between the 1990s and 2010s.^[2] Complications from preterm births resulted globally in 0.81 million deaths in 2015, down from 1.57 million in 1990.^[7][22] The chance of survival at 22 weeks is about 6%, while at 23 weeks it is 26%, 24 weeks 55% and 25 weeks about 72%.^[23] The chances of survival without any long-term difficulties are lower.^[24]

Signs and symptoms of preterm labor include four or more uterine

Preterm labor can be caused by medical conditions including infections, environmental or drug exposures, cervix insufficiency, uterine abnormalities, or amniotic fluid problems.[25] Some women require preterm labor induction for medical conditions.^[25] Other preterm births are spontaneous. In some cases, preterm labor occurs spontaneously and there is no identifiable cause.^[25] There are maternal and pregnancy-related risk factors that increase the risk of a women experiencing preterm labor.

The exact cause of spontaneous preterm birth is difficult to determine and it may be caused by many different factors at the same time as labor is a complex process.

Identifying women at high risk of giving birth early would enable the health services to provide specialized care for these women and their babies, for example a hospital with a special care baby unit such as a neonatal intensive care unit (NICU). In some instances, it may be possible to delay the birth. Risk scoring systems have been suggested as an approach to identify those at higher risk, however, there is no strong research in this area so it is unclear whether the use of risk scoring systems for identifying mothers would prolong pregnancy and reduce the numbers of preterm births or not.^[29]

Risk factors in the mother have been identified that are linked to a higher risk of a preterm birth. These include age (either very young or older),^[36] high or low body mass index (BMI),^[37][38] length of time between pregnancies,^[39] endometriosis,^[40] previous spontaneous (i.e., miscarriage) or surgical abortions,^[41][42] unintended pregnancies,^[34] untreated or undiagnosed celiac disease,^[32][4] fertility difficulties, heat exposure,^[43] and genetic variables.^[44]

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.^[36] Obesity does not directly lead to preterm birth;^[45] however, it is associated with diabetes and hypertension which are risk factors by themselves.^[36] To some degree those individuals may have underlying conditions (i.e., uterine malformation, hypertension, diabetes) that persist. Couples who have tried more than one year versus those who have tried less than one year before achieving a spontaneous conception have an adjusted odds ratio of 1.35 (95% confidence interval 1.22–1.50) of preterm birth.^[46] Pregnancies after IVF confers a greater risk of preterm birth than spontaneous conceptions after more than one year of trying, with an adjusted odds ratio of 1.55 (95% CI 1.30–1.85).^[46]

Certain ethnicities may have a higher risk as well. For example, in the U.S. and the UK, Black women have preterm birth rates of 15–18%, more than double than that of the white population. Many Black women have higher preterm birth rates due to multiple factors but the most common is high amounts of chronic stress, which can eventually lead to premature birth.^[47] Adult chronic disease is not always the case with premature birth in Black women, which makes the main factor of premature birth challenging to identify.^[47] Filipinos are also at high risk of premature birth, and it is believed that nearly 11–15% of Filipinos born in the U.S. (compared to other Asians at 7.6% and whites at 7.8%) are premature.^[48] Filipinos being a big risk factor is evidenced with the Philippines being the eighth-highest ranking in the world for preterm births, the only non-African country in the top 10.^[49] This discrepancy is not seen in comparison to other Asian groups or Hispanic immigrants and remains unexplained.^[36] Genetic make-up is a factor in the causality of preterm birth. Genetics has been a big factor into why Filipinos have a high risk of premature birth as the Filipinos have a large prevalence of mutations that help them be predisposed to premature births.^[48] An intra- and transgenerational increase in the risk of preterm delivery has been demonstrated.^[44] No single gene has been identified.

Marital status has long been associated with risks for preterm birth. A 2005 study of 25,373 pregnancies in Finland revealed that unmarried mothers had more preterm deliveries than married mothers (P=0.001).^[35] 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 to 1997 revealed less risk of preterm birth for infants with legally married mothers compared with those with common-law wed or unwed parents.^{[50][needs update]} A study conducted in Malaysia in 2015 showed a similar trend, with marital status being significantly associated with preterm birth.^[51] However, the result of a study conducted in the US showed that between 1989 and 2006, marriage became less protective of preterm births which was attributed to the changing social norms and behaviors surrounding marriage.^[52]

Medications during pregnancy, living conditions, air pollution, smoking, illicit drugs or alcohol, infection, or physical trauma may also cause a preterm birth.

Air pollution: Living in an area with a high concentration of air pollution is a major risk factor for preterm labor, including living near major roadways or highways where vehicle emissions are high from traffic congestion or are a route for diesel trucks that tend to emit more pollution.^[53][54][13]

The use of

The use of tobacco, cocaine, and excessive alcohol during pregnancy increases the chance of preterm delivery. Tobacco is the most commonly used drug during pregnancy and contributes significantly to low birth weight delivery.^[63] Babies with birth defects are at higher risk of being born preterm.^[64]

Passive smoking and/or smoking before the pregnancy influences the probability of a preterm birth. The World Health Organization published an international study in March 2014.^[65]

Presence of

Intimate violence against the mother is another risk factor for preterm birth.[67]

Physical trauma may case a preterm birth. 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.^[68] This ought not be confused with massage therapy conducted by a fully trained and certified/licensed massage therapist or by significant others trained to provide massage during pregnancy, which—in a study involving pregnant females with prenatal depression—has been shown to have numerous positive results during pregnancy, including the reduction of preterm birth, less depression, lower cortisol, and reduced anxiety.^[69] In healthy women, however, no effects have been demonstrated in a controlled study.

The frequency of infection in preterm birth is inversely related to the gestational age. Mycoplasma genitalium infection is associated with increased risk of preterm birth, and spontaneous abortion.^[70]

Infectious microorganisms can be ascending, hematogenous, iatrogenic by a procedure, or retrograde through the fallopian tubes. From the deciduae they may reach the space between the amnion and chorion, the amniotic fluid, and the fetus. A chorioamnionitis also may lead to sepsis of the mother. Fetal infection is linked to preterm birth and to significant long-term disability including cerebral palsy.^[71]

It has been reported that asymptomatic

As the condition is more prevalent in black women in the U.S. and the UK, it has been suggested to be an explanation for the higher rate of preterm birth in these populations. It is opined that bacterial vaginosis before or during pregnancy may affect the decidual inflammatory response that leads to preterm birth. The condition known as aerobic vaginitis can be a serious risk factor for preterm labor; several previous studies failed to acknowledge the difference between aerobic vaginitis and bacterial vaginosis, which may explain some of the contradiction in the results.^[72]

Untreated yeast infections are associated with preterm birth.^[73]

A review into prophylactic antibiotics (given to prevent infection) in the second and third trimester of pregnancy (13–42 weeks of pregnancy) found a reduction in the number of preterm births in women with bacterial vaginosis. These antibiotics also reduced the number of waters breaking before labor in full-term pregnancies, reduced the risk of infection of the lining of the womb after delivery (endometritis), and rates of gonococcal infection. However, the women without bacterial vaginosis did not have any reduction in preterm births or pre-labor preterm waters breaking. Much of the research included in this review lost participants during follow-up so did not report the long-term effects of the antibiotics on mothers or babies. More research in this area is needed to find the full effects of giving antibiotics throughout the second and third trimesters of pregnancy.^[74]

A number of maternal bacterial infections are associated with preterm birth including pyelonephritis, asymptomatic bacteriuria, pneumonia, and appendicitis. A review into giving antibiotics in pregnancy for asymptomatic bacteriuria (urine infection with no symptoms) found the research was of very low quality but that it did suggest that taking antibiotics reduced the numbers of preterm births and babies with low birth weight.^[75] Another review found that one dose of antibiotics did not seem as effective as a course of antibiotics but fewer women reported side effects from one dose.^[76] This review recommended that more research is needed to discover the best way of treating asymptomatic bacteriuria.^[75]

A different review found that preterm births happened less for pregnant women who had routine testing for low genital tract infections than for women who only had testing when they showed symptoms of low genital tract infections.^[77] The women being routinely tested also gave birth to fewer babies with a low birth weight. Even though these results look promising, the review was only based on one study so more research is needed into routine screening for low genital tract infections.^[77]

Also periodontal disease has been shown repeatedly to be linked to preterm birth.^[78][79] In contrast, viral infections, unless accompanied by a significant febrile response, are considered not to be a major factor in relation to preterm birth.^[36]

There is believed to be a maternal genetic component in preterm birth.^[80] Estimated heritability of timing-of-birth in women was 34%. However, the occurrence of preterm birth in families does not follow a clear inheritance pattern, thus supporting the idea that preterm birth is a non-Mendelian trait with a polygenic nature.^[81]

The absence of prenatal care has been associated with higher rates of preterm births. Analysis of 15,627,407 live births in the United States in 1995–1998 concluded that the absence of prenatal care carried a 2.9 (95%CI 2.8, 3.0) times higher risk of preterm births.^[31] This same study found statistically significant relative risks of maternal anemia, intrapartum fever, unknown bleeding, renal disease, placental previa, hydramnios, placenta abruption, and pregnancy-induced hypertension with the absence of prenatal care. All these prenatal risks were controlled for other high-risk conditions, maternal age, gravidity, marital status, and maternal education. The absence of prenatal care prior to and during the pregnancy is primarily a function of socioeconomic factors (low family income and education), access to medical consultations (large distance from the place of residence to the healthcare unit and transportation costs), quality of healthcare, and social support.^[82] Efforts to decrease rates of preterm birth should aim to increase the deficits posed by the aforementioned barriers and to increase access to prenatal care.

Fetal fibronectin (fFN) has become an important biomarker—the presence of this glycoprotein in the cervical or vaginal secretions indicates that the border between the chorion and decidua has been disrupted. A positive test indicates an increased risk of preterm birth, and a negative test has a high predictive value.^[36] 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.^[90]

Technologies under research and development to facilitate earlier diagnosis of preterm births include sanitary pads that identify biomarkers such as fFN and PAMG-1 and others, when placed into the vagina. These devices then calculate a risk of preterm birth and send the findings to a smartphone.[92] The notion that risk scoring systems are accurate in predicting preterm birth has been debated in multiple literature reviews.^[93][94]

In humans, the usual definition of preterm birth is birth before a

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.[96] Smoking bans are effective in decreasing preterm births.^[97] Different strategies are used in the administration of prenatal care, and future studies need to determine if the focus can be on screening for high-risk women, or widened support for low-risk women, or to what degree these approaches can be merged.^[96]

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 was limited.^[96] Many countries have established specific programs to protect pregnant women from hazardous or 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).

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).[101] Reducing physical activity during pregnancy has not been shown to reduce the risk of a preterm birth.^[102] Healthy eating can be instituted at any stage of the pregnancy including nutritional adjustments and consuming suggested vitamin supplements.^[96] Calcium supplementation in women who have low dietary calcium may reduce the number of negative outcomes including preterm birth, pre-eclampsia, and maternal death.^[103] The World Health Organization (WHO) suggests 1.5–2 g of calcium supplements daily, for pregnant women who have low levels of calcium in their diet.^[104] Supplemental intake of C and E vitamins have not been found to reduce preterm birth rates.^[105]

While periodontal infection has been linked with preterm birth,

Screening for asymptomatic bacteriuria followed by appropriate treatment reduces pyelonephritis and reduces the risk of preterm birth.[109] 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.^[96] Routine ultrasound examination of the length of the cervix may identify women at risk of preterm labour and tentative evidence suggests ultrasound measurement of the length of the cervix in those with preterm labor can help adjust management and results in the extension of pregnancy by about four days.^[110] Screening for the presence of fibronectin in vaginal secretions is not recommended at this time in women at low risk of preterm birth.^{[medical citation needed]}

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 therapies prior to conception, be it for asthma, diabetes, hypertension, and others.

In

A number of agents have been studied for the 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-dose aspirin was used.^[96] Even if agents such as calcium or antioxidants were able to reduce preeclampsia, a resulting decrease in preterm birth was not observed.^[96]

Reduction in activity by the mother—pelvic rest, limited work, bed rest—may be recommended although there is no evidence it is useful with some concerns it is harmful.

While antibiotics can get rid of bacterial vaginosis in pregnancy, this does not appear to change the risk of preterm birth.[116] It has been suggested that chronic chorioamnionitis is not sufficiently treated by antibiotics alone (and therefore they cannot ameliorate the need for preterm delivery in this condition).^[96]

Progestogens—often given in the form of vaginal^[117] progesterone or hydroxyprogesterone caproate—relax the uterine musculature, maintain cervical length, and possess anti-inflammatory properties; all of which invoke physiological and anatomical changes considered to be beneficial in reducing preterm birth. Two meta-analyses demonstrated a reduction in the risk of preterm birth in women with recurrent preterm birth by 40–55%.^[118][119]

Progestogen supplementation also reduces the frequency of preterm birth in pregnancies where there is a short cervix.^[120] A short cervix is one that is less than 25mm, as detected during a transvaginal cervical length assessment in the midtrimester.^[121] However, progestogens are not effective in all populations, as a study involving twin gestations failed to see any benefit.^[122] Despite extensive research related to progestogen effectiveness, uncertainties remain concerning types of progesterone and routes of administration.^[123]

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.^[120][124] 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.^[96]

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.^[125] In a hospital setting women are hydrated via intravenous infusion (as dehydration can lead to premature uterine contractions).^[126]

If a baby has cardiac arrest at birth and is less than 22 to 24 weeks gestational age, attempts at resuscitation are not generally indicated.^[127]

Severely premature infants may have underdeveloped lungs because they are not yet producing their own

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 are still some concerns about 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. A 2015 Cochrane review (updated in 2022) supports the use of repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course.^[128]

A Cochrane review from 2020 recommends the use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. Treatment with antenatal corticosteroids reduces the risk of perinatal death, neonatal death and respiratory distress syndrome and probably reduces the risk of IVH.^[129]

Concerns about adverse effects of prenatal corticosteroids include increased risk for maternal infection, difficulty with diabetic control, and possible long-term effects on neurodevelopmental outcomes for the infants. There is ongoing discussion about when steroids should be given (i.e. only antenatally or postnatally too) and for how long (i.e. single course or repeated administration). Despite these unknowns, there is a consensus that the benefits of a single course of prenatal glucocorticosteroids vastly outweigh the potential risks.^{[130][131][132]}

The routine administration of antibiotics to all women with threatened preterm labor reduces the risk of the baby being infected with group B streptococcus and has been shown to reduce related mortality rates.^[133]

When membranes rupture prematurely, obstetrical management looks for development of labor and signs of infection. Prophylactic antibiotic administration has been shown to prolong pregnancy and reduced neonatal morbidity with rupture of membranes at less than 34 weeks.^[134] Because of concern about necrotizing enterocolitis, amoxicillin or erythromycin has been recommended but not amoxicillin + clavulanic acid (co-amoxiclav).^[134]

A number of medications may be useful to delay delivery including: nonsteroidal anti-inflammatory drugs, calcium channel blockers, beta mimetics, and atosiban.^[135] Tocolysis rarely delays delivery beyond 24–48 hours.^[136] This delay, however, may be sufficient to allow the pregnant woman to be transferred to a center specialized for management of preterm deliveries and give administered corticosteroids 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.^[96][137] Magnesium sulfate does not appear to be useful to prevent preterm birth.^[138] Its use before delivery, however, does appear to decrease the risk of cerebral palsy.^[139]

The routine use of caesarean section for early delivery of infants expected to have very low birth weight is controversial,^[140] and a decision concerning the route and time of delivery probably needs to be made on a case-by-case basis.

In developed countries premature infants are usually cared for in a

Water can be carefully provided to prevent dehydration but not so much to increase risks of side effects.^[144]

In terms of respiratory support, there may be little or no difference in the risk of death or chronic lung disease between high flow nasal cannulae (HFNC) and continuous positive airway pressure (CPAP) or nasal intermittent positive pressure ventilation (NPPV).^[145] For extremely preterm babies (born before 28 weeks' gestation), targeting a higher versus a lower oxygen saturation range makes little or no difference overall to the risk of death or major disability.^[146] Babies born before 32 weeks have been shown to have a lower risk of death from bronchopulmonary dysplasia if they have CPAP immediately after being born, compared to receiving either supportive care or assisted ventilation.^[147]

There is insufficient evidence for or against placing preterm stable twins in the same cot or incubator (co-bedding).^[148]

Meeting the appropriate nutritional needs of preterm infants is important for long-term health. Optimal care may require a balance of meeting nutritional needs and preventing complications related to feeding. The ideal growth rate is not known, however, preterm infants usually require a higher energy intake compared to babies who are born at term.

The American Academy of Pediatrics recommended feeding preterm infants human milk, finding "significant short- and long-term beneficial effects," including lower rates of necrotizing enterocolitis (NEC).^[152] In the absence of evidence from randomised controlled trials about the effects of feeding preterm infants with formula compared with mother's own breast milk, data collected from other types of studies suggest that mother's own breast milk is likely to have advantages over formula in terms of the baby's growth and development.^[153][149] Milk from human donors also reduces the risk of NEC by half in very low birth rate infants and very preterm infants.^[23]

Breast milk or formula alone may not be sufficient to meet the nutritional needs of some preterm infants. Fortification of breast milk or formula by adding extra nutrients is an approach often taken for feeding preterm infants, with the goal of meeting the high nutritional demand.^[149] High quality randomized controlled trials are needed in this field to determine the effectiveness of fortification.^[154] It is unclear if fortification of breast milk improves outcomes in preterm babies, though it may speed growth.^[154] Supplementing human milk with extra protein may increase short-term growth but the longer-term effects on body composition, growth and brain development are uncertain.^[155][156] Higher protein formula (between 3 and 4 grams of protein per kilo of body weight) may be more effective than low protein formula (less than 3 grams per kilo per day) for weight gain in formula-fed low-birth-weight infants.^[157] There is insufficient evidence about the effect on preterm babies' growth of supplementing human milk with carbohydrate,^[158] fat,^[159][160] and branched-chain amino acids.^[161] Conversely, there is some indication that preterm babies who cannot breastfeed may do better if they are fed only with diluted formula compared to full strength formula but the clinical trial evidence remains uncertain.^[162]

Individualizing the nutrients and quantities used to fortify

Regarding the timing of starting fortified milk, preterm infants are often started on fortified milk/formula once they are fed 100 mL/kg of their body weight. Other some neonatal specialists feel that starting to feed a preterm infant fortified milk earlier is beneficial to improve intake of nutrients.[166] The risks of feeding intolerance and necrotising enterocolitis related to early versus later fortification of human milk are not clear.^[166] Once the infant is able to go home from the hospital there is limited evidence to support prescribing a preterm (fortified) formula.^[167]

For infants who weigh less than 1500 grams, tube feeding is usually necessary.^[151] Most often, neonatal specialists feed preterm babies intermittently with a prescribed amount of milk over a short period of time. For example, a feed could last 10–20 minutes and be given every 3 hours. This intermittent approach is meant to mimic conditions of normal bodily functions involved with feeding and allow for a cyclic pattern in the release of gastrointestinal tract hormones to promote development of the gastrointestinal system.^[151] In certain cases, continuous nasogastric feeding is sometimes preferred. There is low to very low certainty evidence to suggest that low birth weight babies who receive continuous nasogastic feeding may reach the benchmark of tolerating full enteral feeding later than babies fed intermittently and it is not clear if continuous feeding has any effect on weight gain or the number of interruptions in feedings.^[151] Continuous feeding may have little to no effect on length of body growth or head circumference and the effects of continuous feeding on the risk of developing necrotising enterocolitis is not clear.^[151]

Since preterm infants with gastro-oesophageal reflux disease do not have a fully developed antireflux mechanism, deciding on the most effective approach for nutrition is important. It is not clear if continuous bolus intragastric tube feeding is more effective compared to intermittent bolus intragastric tube feeding for feeding preterm infants with gastroesophageal reflux disease.^[168]

For infants who would benefit from intermittent bolus feeding, some infants may be fed using the "push feed" method using a syringe to gently push the milk or formula into the stomach of the infant. Others may be fed using a gravity feeding system where the syringe is attached directly to a tube and the milk or formula drips into the infant's stomach. It is not clear from medical studies which approach to intermittent bolus feeding is more effective or reduces adverse effects such as apnea, bradycardia, or oxygen desaturation episodes.^[169][170]

High-volume (more than 180 mL per kilogram per day) enteral feeds of fortified or non-fortified human breast milk or formula may improve weight gain while the pre-term infant is hospitalized, however, there is insufficient evidence to determine if this approach improves growth of the neonate and other clinical outcomes including length of hospital stay.^[149] The risks or adverse effects associated with high-volume enteral feeding of preterm infants including aspiration pneumonia, reflux, apnea, and sudden oxygen desaturation episodes have not been reported in the trials considered in a 2021 systematic review.^[149]

For preterm infants who are born after 34 weeks of gestation ("late preterm infants") who are critically ill and cannot tolerate milk, there is some weak evidence that the infant may benefit from including amino acids and fats in the intravenous nutrition at a later time point (72 hours or longer from hospital admission) versus early (less than 72 hours from admission to hospital), however further research is required to understand the ideal timing of starting intravenous nutrition.^[171]

For preterm infants in neonatal intensive care on

Imbalances of sodium (hyponatraemia and hypernatraemia) are common in babies born preterm.^[173] Hypernatraemia (sodium levels in the serum of more than 145-150 mmol/L) is common early on in preterm babies and the risk of hyponatraemia (sodium levels of less than 135 nmol/L) increases after about a week of birth if left untreated and prevention approaches are not used.^[173] Preventing complications associated with sodium imbalances is part of standard of care for preterm infants and includes careful monitoring of water and sodium given to the infant.^[173] The optimal sodium dose given immediately after birth (first day) is not clear and further research is needed to understand the idea management approach.^[173]

The Joint Committee on Infant Hearing (JCIH) state that for preterm infants who are in the neonatal intensive care unit (NICU) for a prolonged time should have a diagnostic audiologic evaluation before they are discharged from the hospital.^[174] Well babies follow a 1-2-3-month benchmark timeline where they are screened, diagnosed, and receiving intervention for a hearing loss. However, for very premature babies, it might not be possible to complete a hearing screen at one month of age due to several factors. Once the baby is stable, an audiologic evaluation should be performed. For premature babies in the NICU, auditory brainstem response (ABR) testing is recommended. If the infant does not pass the screen, they should be referred for an audiologic evaluation by an audiologist.^[174] If the infant is on aminoglycosides such as gentamicin for less than five days they should be monitored and have a follow-up 6–7 months of being discharged from the hospital to ensure there is no late onset hearing loss due to the medication.^[174]

Preterm births can result in a range of problems including mortality and physical and mental delays.^[181][182]

In the U.S. where many neonatal infections and other causes of neonatal death have been markedly reduced, prematurity is the leading cause of neonatal mortality at 25%.^[183] Prematurely born infants are also at greater risk for having subsequent serious chronic health problems as discussed below.

The earliest

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.^[186]

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 can include
  thyroid hormones, at a time when their own thyroid is unable to meet postnatal needs.^[189]
• 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 neonatal hypoglycemia, feeding difficulties, rickets of prematurity, hypocalcemia, inguinal hernia, and necrotizing enterocolitis (NEC).
• Hematologic complications include
  hyperbilirubinemia (jaundice) that can lead to kernicterus
  .
• Infection, including sepsis, pneumonia, and urinary tract infection ^[1]

The chance of survival at 22 weeks is about 6%, while at 23 weeks it is 26%, 24 weeks 55% and 25 weeks about 72% as of 2016.^[190] With extensive treatment up to 30% of those who survive birth at 22 weeks survive longer term as of 2019.^[191] The chances of survival without long-term difficulties is less.^[24] Of those who survive following birth at 22 weeks 33% have severe disabilities.^[191] In the developed world, overall survival is about 90% while in low-income countries survival rates are about 10%.^[192]

Some children will adjust well during childhood and adolescence,^[181] although disability is more likely nearer the limits of viability. A large study followed children born between 22 and 25 weeks until the age of 6 years old. Of these children, 46% had moderate to severe disabilities such as cerebral palsy, vision or hearing loss and learning disabilities, 34% had mild disabilities, and 20% had no disabilities; 12% had disabling cerebral palsy.^[193] Up to 15% of premature infants have significant hearing loss.^[194]

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.

Despite the neurosensory, mental and educational problems studied in school age and adolescent children born extremely preterm, the majority of preterm survivors born during the early years of neonatal intensive care are found to do well and to live fairly normal lives in young adulthood.[200] Young adults born preterm seem to acknowledge that they have more health problems than their peers, yet feel the same degree of satisfaction with their quality of life.^[201]

Beyond the neurodevelopmental consequences of prematurity, infants born preterm have a greater risk for many other health problems. For instance, children born prematurely have an increased risk for developing chronic kidney disease.^[202]

Preterm birth complicates 5–18% of births worldwide.^[73] In Europe and many developed countries the preterm birth rate is generally 5–9%,^[204] while in the U.S. from 2007 to 2022 the rate fluctuated from 9.6 to 10.5 per cent.^[205]

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% of births in less developed regions in 2000.^[206] 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 2,500 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 1,500 g, and Extremely Low Birth Weight (ELBW) which is less than 1,000 g.^[207] Almost all neonates in these latter two groups are born preterm.

About 75% of nearly a million deaths due to preterm delivery would survive if provided warmth, breastfeeding, treatments for infection, and breathing support.^[192] Complications from preterm births resulted in 740,000 deaths in 2013, down from 1.57 million in 1990.^[22]

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 U.S. 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.^[208] The 2007 Institute of Medicine report Preterm Birth^[209] found that the 550,000 premature babies born each year in the U.S. run up about $26 billion in annual costs, mostly related to care in neonatal intensive care units, but the real tab may top $50 billion.^[210]

James Elgin Gill (born on 20 May 1987 in Ottawa, Ontario, Canada) was the earliest premature baby in the world, until that record was broken in 2004. He was 128 days premature, 21 weeks 5 days gestation, and weighed 624 g (1 lb 6 oz). He survived.^[211][212]

In 2014, Lyla Stensrud, born in San Antonio, Texas, U.S., became the youngest premature baby in the world. She was born at 21 weeks 4 days and weighed 410 grams (less than a pound). Kaashif Ahmad resuscitated the baby after she was born. As of November 2018, Lyla was attending preschool. She had a slight delay in speech, but no other known medical issues or disabilities.^[213]

Amillia Taylor is also often cited as the most premature baby.^[214] She was born on 24 October 2006 in Miami, Florida, U.S., at 21 weeks and 6 days' gestation.^[215] 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 23 cm (9 in) long and weighed 280 g (10 oz).^[214] She had digestive and respiratory problems, together with a brain hemorrhage. She was discharged from the Baptist Children's Hospital on 20 February 2007.^[214]

The record for the smallest premature baby to survive was held for a considerable amount of time by Madeline Mann, who was born in 1989 at 26 weeks, weighing 280.0 g (9.875 oz) and measuring 24 cm (9.5 in) long.^[216] This record was broken in September 2004 by Rumaisa Rahman, who was born in the same hospital, Loyola University Medical Center in Maywood, Illinois.^[217] at 25 weeks' gestation. At birth, she was 20 cm (8 in) long and weighed 261 g (9.2 oz).^[218] Her twin sister was also a small baby, weighing 563 g (1 lb 3.9 oz) at birth. During pregnancy their mother had pre-eclampsia, 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 (2 lb 10 oz).^[219] Generally healthy, the twins had to undergo laser eye surgery to correct vision problems, a common occurrence among premature babies.

In May 2019, Sharp Mary Birch Hospital for Women & Newborns in San Diego announced that a baby nicknamed "Saybie" had been discharged almost five months after being born at 23 weeks' gestation and weighing 244 g (8.6 oz). Saybie was confirmed by Dr. Edward Bell of the University of Iowa, which keeps the Tiniest Babies Registry, to be the new smallest surviving premature baby in that registry.^[220]

Born in February 2009, at

Richard Hutchinson was born at Children's Hospitals and Clinics of Minnesota in Minneapolis, Minnesota, on June 5, 2020, at 21 weeks 2 days gestation. At birth he weighed 340 g (12 oz). He remained hospitalized until November 2020, when he was then discharged.[222]^[223]

On 5 July 2020 Curtis Means was born at the University of Alabama at Birmingham hospital at 21 weeks 1 day, and weighed 420 g (15 oz). He was discharged in April 2021. As of March 2023^[update], he is the current world record holder.^[224]

Historical figures who were born prematurely include Johannes Kepler (born in 1571 at seven months' gestation), Isaac Newton (born in 1642, small enough to fit into a quart mug, according to his mother), Winston Churchill (born in 1874 at seven months' gestation), and Anna Pavlova (born in 1885 at seven months' gestation).^[225]

During the COVID-19 pandemic, a drastic drop in the rate of premature births has been reported in many countries, ranging from a 20% reduction to a 90% drop in the starkest cases. Studies in Ireland and Denmark first noticed the phenomenon, and it has been confirmed elsewhere. There is no universally accepted explanation for this drop as of August 2020. Hypotheses include additional rest and support for expectant mothers staying at home, less air pollution due to shutdowns and reduced car fumes, and reduced likelihood of catching other diseases and viruses in general due to the lockdowns.^[226]

Brain injury is common among preterms, ranging from

The evidence to support the use of osteopathic manipulations to provide benefit in neonatal care is weak.^[245][246]

• World Prematurity Day