Preterm birth

Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks' gestational age, as opposed to the usual about 40 weeks.[1] These babies are known as preemies or premmies.[1] Symptoms of preterm labor include uterine contractions which occur more often than every ten minutes or the leaking of fluid from the vagina.[8] Premature infants are at greater risk for cerebral palsy, delays in development, hearing problems and sight problems.[1] The earlier a baby is born, the greater these risks will be.[1]

Preterm birth
Other names	Premature birth, preemies, premmies
Intubated preterm baby in an incubator
Specialty	Obstetrics, pediatrics
Symptoms	Birth of a baby at younger than 37 weeks' gestational age[1]
Complications	Cerebral palsy, delays in development, hearing problems, sight problems[1]
Causes	Often unknown[2]
Risk factors	Diabetes, high blood pressure, being pregnant with more than one baby, obesity or underweight, a number of vaginal infections, celiac disease, tobacco smoking, psychological stress[2][3][4]
Prevention	Progesterone[5]
Treatment	Corticosteroids, keeping the baby warm through skin-to-skin contact, supporting breastfeeding, treating infections, supporting breathing[2][6]
Frequency	~15 million a year (12% of deliveries)[2]
Deaths	805,800[7]

The cause of preterm birth is often not known.[2] Risk factors include diabetes, high blood pressure, being pregnant with more than one baby, being either obese or underweight, a number of vaginal infections, air pollution including tobacco smoking, and psychological stress.[2][3][9] It is recommended that labor not be medically induced before 39 weeks unless required for other medical reasons.[2] The same recommendation applies to cesarean section.[2] Medical reasons for early delivery include preeclampsia.[10]

In those at risk, the hormone progesterone, if taken during pregnancy, may prevent preterm birth.[5] Evidence does not support the usefulness of bed rest.[5][11] It is estimated that at least 75% of preterm infants would survive with appropriate treatment, and the survival rate is highest among the infants born the latest.[2] In women who might deliver between 24 and 37 weeks, corticosteroids improve outcomes.[6][12] A number of medications, including nifedipine, may delay delivery so that a mother can be moved to where more medical care is available and the corticosteroids have a greater chance to work.[13] Once the baby is born, care includes keeping the baby warm through skin-to-skin contact, supporting breastfeeding, treating infections and supporting breathing.[2]

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] In the United Kingdom they are about 7.9% and in the United States they are about 12.3% of all births.[14][15] Approximately 0.5% of births are extremely early periviable births, and these account for most of the deaths.[16] In many countries, rates of premature births have increased between the 1990s and 2010s.[2] Complications from preterm births resulted in 0.81 million deaths in 2015 down from 1.57 million in 1990.[7][17] 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%.[18] The chances of survival without any long-term difficulties are lower.[19]

Signs and symptoms

A new mother holds her premature baby at Kapiolani Medical Center NICU in Honolulu, Hawaii

A preterm birth can be brought on by being induced, or can occur spontaneously. Preterm births can cause a range of problems.[20][21]

The main categories of causes of preterm birth are preterm labor induction and spontaneous preterm labor. Signs and symptoms of preterm labor include four or more uterine contractions in one hour. In contrast to false labour, 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.

A review into using uterine monitoring at home to detect contractions and possible preterm births in women at higher risk of having a preterm baby found that it did not reduce the number of preterm births.[22] The research included in the review was poor quality but it showed that home monitoring may increase the number of unplanned antenatal visits and may reduce the number of babies admitted to special care when compared with women receiving normal antenatal care.[22]

Complications

Mortality and morbidity

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%.[23] 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, the limit of viability has reduced to approximately 24 weeks.[24][25] Most newborns who die, and 40% of older infants who die, were born between 20 and 25.9 weeks (gestational age), during the second trimester.[16]

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.[26]

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),[27] developmental disability, transient hyperammonemia of the newborn, cerebral palsy and intraventricular hemorrhage, the latter affecting 25% of babies born preterm, usually before 32 weeks of pregnancy.[28] Mild brain bleeds usually leave no or few lasting complications, but severe bleeds often result in brain damage or even death.[28] Neurodevelopmental problems have been linked to lack of maternal thyroid hormones, at a time when their own thyroid is unable to meet postnatal needs.[29]
• 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 anemia of prematurity, thrombocytopenia, and hyperbilirubinemia (jaundice) that can lead to kernicterus.
• Infection, including sepsis, pneumonia, and urinary tract infection

A study of 241 children born between 22 and 25 weeks who were currently of school age found that 46 percent had severe or moderate disabilities such as cerebral palsy, vision or hearing loss and learning problems. Thirty-four percent were mildly disabled and 20 percent had no disabilities, while 12 percent had disabling cerebral palsy.[30][31] Up to 15 out of 100 premature infants have significant hearing loss.[32]

Risk factors

The exact cause of preterm birth is difficult to determine and it may be multi-factorial. 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 (placental abruption), decidual bleeding, and intrauterine inflammation/infection.[33]

Identifying women at high risk of giving birth early would enable the health services to provide specialized care for these women to delay the birth or make sure they are in the best place to give birth (for example a hospital with a special care baby unit). Risk scoring systems have been suggested as a possible way of identifying these women. However, there is no research in this area so it is unclear whether the risk scoring systems would prolong pregnancy and reduce the numbers of preterm births or not.[34]

Maternal factors

Risk factor	Relative risk[35]	95% confidence interval[35]
Fetal fibronectin	4.0	2.9–5.5
Short cervical length	2.9	2.1–3.9
Chlamydia	2.2	1.0–4.8
Low socio-economic status	1.9	1.7–2.2
Large or small pregnancy weight gain	1.8	1.5–2.3
Short maternal height	1.8	1.3–2.5
Periodontitis	1.6	1.1–2.3
Celiac disease	1.4[36]	1.2–1.6[36]
Asymptomatic bacteriuria	1.1	0.8–1.5
High or low BMI	0.96	0.66–1.4
	odds ratio
History of spontaneous preterm birth	3.6	3.2–4.0
Bacterial vaginosis	2.2	1.5–3.1
Black ethnicity/race	2.0	1.8–2.2
Filipino ancestry[37]	1.7	1.5–2.1
Unwanted pregnancy[38]^:1	1.5	1.41-1.61
Unintended pregnancy[38]^:1	1.31	1.09-1.58
Being single/unmarried[39]	1.2	1.03–1.28

Percentage premature births in England and Wales 2011, by age of mother and whether single or multiple birth.

A number of factors have been identified that are linked to a higher risk of a preterm birth such as being less than 18 years of age.[40] Maternal height and weight can play a role.[41]

Further, 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.[42] Adult chronic disease isn't always the case with premature birth in Black women, which makes the main factor of premature birth challenging to identify.[42] 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.[43] Filipinos being a big risk factor is evidenced with the Philippines being the 8th highest ranking in the world for preterm births, the only non-African country in the top 10.[44] This discrepancy is not seen in comparison to other Asian groups or Hispanic immigrants and remains unexplained.[40]

Pregnancy interval makes a difference as women with a six-month span or less between pregnancies have a two-fold increase in preterm birth.[45] 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.[40]

A history of spontaneous (i.e., miscarriage) or surgical abortion has been associated with a small increase in the risk of preterm birth, with an increased risk with increased number of abortions, although it is unclear whether the increase is caused by the abortion or by confounding risk factors (e.g., socioeconomic status).[46] Increased risk has not been shown in women who terminated their pregnancies medically.[47] Pregnancies that are unwanted or unintended are also a risk factor for preterm birth.[38]

Adequate maternal nutrition is important. Women with a low BMI are at increased risk for preterm birth.[48] Further, women with poor nutrition 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.[49] Obesity does not directly lead to preterm birth;[50] however, it is associated with diabetes and hypertension which are risk factors by themselves.[40] To some degree those individuals may have underlying conditions (i.e., uterine malformation, hypertension, diabetes) that persist.

Women with celiac disease have an increased risk of the development of preterm birth.[36] The risk of preterm birth is more elevated when celiac disease remains undiagnosed and untreated.[4]

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).[39] 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.[51]

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.[43] An intra- and transgenerational increase in the risk of preterm delivery has been demonstrated.[52] No single gene has been identified.

Subfertility is associated with preterm birth. Couples who have tried more than 1 year versus those who have tried less than 1 year before achieving a spontaneous conception have an adjusted odds ratio of 1.35 (95% confidence interval 1.22-1.50) of preterm birth.[53] Pregnancies after IVF confers a greater risk of preterm birth than spontaneous conceptions after more than 1 year of trying, with an adjusted odds ratio of 1.55 (95% CI 1.30-1.85).[53]

Exposure to heat also appear to increase the risk of preterm birth, with this occurring in about 25,000 pregnancies per year.[54]

Factors during pregnancy

Air pollution increases the risk of preterm birth.[9] One study attributed air pollution to 18% of premature births globally.[55] The countries with the highest air pollution associated preterm births were in South and East Asia, the Middle East, North Africa, and West sub-Saharan Africa. Living in an area with a high concentration of air pollution is a major risk factor, 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.[56][57]

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. Often labor has to be induced for medical reasons; such conditions include high blood pressure,[58] pre-eclampsia,[59] maternal diabetes,[60] asthma, thyroid disease, and heart disease.

In a number of women anatomical issues prevent the baby from being carried to term. Some women have a weak or short cervix[58] (the strongest predictor of premature birth)[61][62][63] 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 conditions is linked to a higher preterm birth rate.[64] Women with abnormal amounts of amniotic fluid, whether too much (polyhydramnios) or too little (oligohydramnios), are also at risk.[40] The mental status of the women is of significance. Anxiety[65] and depression have been linked to preterm birth.[40]

The use of tobacco, cocaine, and excessive alcohol during pregnancy increases the chance of preterm delivery. Tobacco is the most commonly abused drug during pregnancy and contributes significantly to low birth weight delivery.[66] Babies with birth defects are at higher risk of being born preterm.[67]

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.[68]

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.[69]

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.[70]

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.[71] 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.[72]

Infection

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.[73]

Infectious microorganisms can be 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 the fetus. A chorioamnionitis also may lead to sepsis of the mother. Fetal infection is linked to preterm birth and to significant long-term handicap including cerebral palsy.[74]

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.

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 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.[75]

Untreated yeast infections are associated with preterm birth.[76]

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.[77]

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.[78] 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.[79] This review recommended that more research is needed to discover the best way of treating asymptomatic bacteriuria.[78]

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.[80] 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.[80]

Also periodontal disease has been shown repeatedly to be linked to preterm birth.[81][82] In contrast, viral infections, unless accompanied by a significant febrile response, are considered not to be a major factor in relation to preterm birth.[40]

Genetics

There is believed to be a maternal genetic component in preterm birth.[83] 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.[84]

Diagnosis

Placental alpha microglobulin-1

Placental alpha microglobulin-1 (PAMG-1) has been the subject of several investigations evaluating its ability to predict imminent spontaneous preterm birth in women with signs, symptoms, or complaints suggestive of preterm labor.[85][86][87][88][89][90] In one investigation comparing this test to fetal fibronectin testing and cervical length measurement via transvaginal ultrasound, the test for PAMG-1 (commercially known as the PartoSure test) has been reported to be the single best predictor of imminent spontaneous delivery within 7 days of a patient presenting with signs, symptoms, or complaints of preterm labor. Specifically, the PPV, or positive predictive value, of the tests were 76%, 29%, and 30% for PAMG-1, fFN and CL, respectively (P < 0.01).[91]

Fetal fibronectin

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 deciduas has been disrupted. A positive test indicates an increased risk of preterm birth, and a negative test has a high predictive value.[40] 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.[92]

Ultrasound

Obstetric ultrasound has become useful in the assessment of the cervix in women at risk for premature delivery. A short cervix preterm is undesirable: A cervical length of less than 25 mm at or before 24 weeks of gestational age is the most common definition of cervical incompetence.[93]

Classification

Stages in prenatal development, with weeks and months numbered from last menstruation.

In humans, the usual definition of preterm birth is birth before a gestational age of 37 complete weeks.[94] 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 mature in the womb; because of this, many premature babies spend the first days and weeks of their lives on ventilators. Therefore, a significant overlap exists between preterm birth and prematurity. Generally, preterm babies are premature and term babies are mature. Preterm babies born near 37 weeks often have no problems relating to prematurity if their lungs have developed adequate surfactant, which allows the lungs to remain expanded between breaths. Sequelae of 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.

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.[95] Smoking bans are effective in decreasing preterm births.[96]

Before pregnancy

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.[95] 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).[97] Also, night work has been linked to preterm birth.[98] Health policies that take these findings into account can be expected to reduce the rate of preterm birth.[95] 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.[99][100][101] Reducing smoking is expected to benefit pregnant women and their offspring.[95]

During pregnancy

Healthy eating can be instituted at any stage of the pregnancy including nutritional adjustments, use of vitamin supplements, and smoking cessation.[95] Calcium supplementation in women who have low dietary calcium may reduce the number of negative outcomes including preterm birth, pre-eclampsia, and maternal death.[102] The World Health Organization (WHO) suggests 1.5–2 g of calcium supplements daily, for pregnant women who have low levels calcium in their diet.[103] Supplemental intake of C and E vitamins have not been found to reduce preterm birth rates.[104] 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.[95] While periodontal infection has been linked with preterm birth, randomized trials have not shown that periodontal care during pregnancy reduces preterm birth rates.[95]

Additional support during pregnancy does not appear to prevent low birthweight or preterm birth.[105]

Screening of low risk women

Screening for asymptomatic bacteriuria followed by appropriate treatment reduces pyelonephritis and reduces the risk of preterm birth.[106] 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.[95] Routine ultrasound examination of the length of the cervix identifies patients at risk, but cerclage is not proven useful, and the application of a progestogen is under study.[95] 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.[107][108]

Cervical assessment by ultrasound

There is tentative evidence that 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 4 days.[109]

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

Multiple pregnancies

In multiple pregnancies, which often result from use of assisted reproductive technology, there is a high risk of preterm birth. Selective reduction is used to reduce the number of fetuses to two or three.[110][111][112]

Reducing indicated preterm birth

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.[95] Even if agents such as calcium or antioxidants were able to reduce preeclampsia, a resulting decrease in preterm birth was not observed.[95]

Reducing spontaneous preterm birth

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.[113] Increasing medical care by more frequent visits and more education has not been shown to reduce preterm birth rates.[105] 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,[114] and further studies are in the making.

Antibiotics

While antibiotics can get rid of bacterial vaginosis in pregnancy, this does not appear to change the risk of preterm birth.[115] 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).[95]

Progestogens

Progestogens, often given in the form of progesterone or 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 reduction in the risk of preterm birth in women with recurrent preterm birth by 40–55%.[116][117]

Progestogen supplementation also reduces the frequency of preterm birth in pregnancies where there is a short cervix.[118] However, progestogens are not effective in all populations, as a study involving twin gestations failed to see any benefit.[119]

Cervical cerclage

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.[118][120] 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.[95]

Management

Preterm birth at 32 weeks and 4 days with a weight of 2,000 g attached to medical equipment

About 75% of nearly a million deaths due to preterm deliver would survive if provided warmth, breastfeeding, treatments for infection, and breathing support.[121] If a baby has cardiac arrest at birth and is before 23 weeks or less than 400 g attempts at resuscitation are not indicated.[122]

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.[123] In a hospital setting women are hydrated via intravenous infusion (as dehydration can lead to premature uterine contractions).[124]

Steroids

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 baby.[12] Steroid use up to 37 weeks is also recommended by the American Congress of Obstetricians and Gynecologists.[12] Typical glucocorticoids that would be administered in this context are betamethasone or dexamethasone, often when the pregnancy 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 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 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.[125]

Beside reducing respiratory distress, other neonatal complications are reduced by the use of glucocorticosteroids, namely intraventricular bleeding, necrotising enterocolitis, and patent ductus arteriosus.[126] A single course of antenatal corticosteroids could be considered routine for preterm delivery, but there are some concerns about applicability of this recommendation to low-resource settings with high rates of infections.[126] It remains unclear whether one corticosteroid (or one particular regimen) has advantages over another.[127]

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.[128][129][130]

Antibiotics

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.[131]

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.[132] Because of concern about necrotizing enterocolitis, amoxicillin or erythromycin has been recommended, but not amoxicillin + clavulanic acid (co-amoxiclav).[132]

Tocolysis

A number of medications may be useful to delay delivery including: nonsteroidal anti-inflammatory drugs, calcium channel blockers, beta mimetics, and atosiban.[133] Tocolysis rarely delays delivery beyond 24–48 hours.[134] 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.[95][135] Magnesium sulfate does not appear to be useful to prevent preterm birth.[136] Its use before delivery, however, does appear to decrease the risk of cerebral palsy.[137]

Mode of delivery

The routine use of caesarean section for early delivery of infants expected to have very low birth weight is controversial,[138] and a decision concerning the route and time of delivery probably needs to be made on a case-by-case basis.

Neonatal care

Incubator for preterm baby

After delivery, plastic wraps or warm mattresses are useful to keep the infant warm on their way to the neonatal intensive care unit (NICU).[139] In developed countries premature infants are usually cared for in an 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,[140] 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).

Water can be carefully provided to prevent dehydration but no so much to increase risks of side effects.[141]

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).[142] 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.[143] Babies born before 32 weeks' probably 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.[144]

One review found that when premature infants are given osteopathic manipulations, they are less likely to require as lengthy of a hospital stay than if they are not manipulated.[145]

There is insufficient evidence for or against placing preterm stable twins in the same cot or incubator (co-bedding).[146]

Nutrition

In a 2012 policy statement, 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).[147] 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.[148] It is unclear if fortification of breast milk improves outcomes in preterm babies, though it may speed growth.[149] 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.[150] When a mother's breastmilk is not available, formula is probably better than donor breast milk for preterm babies in terms of weight gain, linear growth and head growth but there may be little or no difference in terms of neurodevelopmental disability, death or necrotising enterocolitis.[151] 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.[152] There is limited evidence to support prescribing a preterm formula for the preterm babies after hospital discharge.[153]

Hearing assessment

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.[154] Well babies follow a 1-2-3 month benchmark timeline where they are screened, diagnosed, and receiving intervention for a hearing loss. However, 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 doesn't pass the screen, they should be referred for an audiologic evaluation by an audiologist.[154] 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.[154]

Prognosis

Preterm infants survival rates[155][156][157][158][159][160]

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.[18] With extensive treatment up to 30% of those who survive birth at 22 weeks survive longer term as of 2019.[161] The chances of survival without long-term difficulties is less.[19] Of those who survival following birth at 22 weeks 33% have severe disabilities.[161] In the developed world overall survival is about 90% while in low-income countries survival rates are about 10%.[121]

Some children will adjust well during childhood and adolescence,[20] 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 percent had moderate to severe disabilities such as cerebral palsy, vision or hearing loss and learning disabilities, 34 percent had mild disabilities, and 20 percent had no disabilities. Twelve percent had disabling cerebral palsy.[31]

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.[20] 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, intellectual disability, disorders of psychological development, behavior, and emotion, disabilities of vision and hearing, and epilepsy.[162] 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.[31] It is also shown that higher levels of education were less likely to be obtained with decreasing gestational age at birth.[162] People born prematurely may be more susceptible to developing depression as teenagers.[163] 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.[164] 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.[165] Throughout life they are more likely to require services provided by physical therapists, occupational therapists, or speech therapists.[20]

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.[166] 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.[167]

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.[168]

Epidemiology

Disability-adjusted life year for prematurity and low birth weight per 100,000 inhabitants in 2004.[169]

  no data

  less than 120

  120-240

  240-360

  360-480

  480-600

  600-720

  720-840

  840-960

  960-1080

  1080-1200

  1200-1500

  more than 1500

Preterm birth complicates the births of infants worldwide affecting 5% to 18% of births.[76] 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.[170]

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.[171] 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 1,500 g, and Extremely Low Birth Weight (ELBW) which is less than 1,000 g.[172] Almost all neonates in these latter two groups are born preterm.

Complications from preterm births resulted in 740,000 deaths in 2013, down from 1.57 million in 1990.[17]

Society and culture

Economics

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.[173] The 2007 Institute of Medicine report Preterm Birth[174] 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.[175]

Notable cases

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 and 5 days' gestation) and weighed 1 pound 6 ounces (624 g). He survived.[176][177]

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.[178]

Amillia Taylor is also often cited as the most premature baby.[179] She was born on 24 October 2006 in Miami, Florida, U.S. at 21 weeks and 6 days' gestation.[180] 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.[163] At birth, she was 9 inches (22.9 cm) long and weighed 10 ounces (280 g).[179] She suffered digestive and respiratory problems, together with a brain hemorrhage. She was discharged from the Baptist Children's Hospital on 20 February 2007.[179]

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 9.9 ounces (280 g) and measuring 9.5 inches (241.3 mm) long.[181] This record was broken in September 2004 by Rumaisa Rahman, who was born in the same hospital, Loyola University Medical Center in Maywood, Illinois.[182] at 25 weeks' gestation. At birth, she was 8 inches (200 mm) long and weighed 261 grams (9.2 oz).[183] Her twin sister was also a small baby, weighing 563 grams (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 (2.6 lb).[184] 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 grams (8.6 oz). Saybie was confirmed by Dr. Edward Bell of the University of Iowa to be the new smallest surviving premature baby.[185]

The world's smallest premature boy to survive was born in February 2009 at Children's Hospitals and Clinics of Minnesota in Minneapolis, Minnesota, U.S. Jonathon Whitehill was born at 25 weeks' gestation with a weight of 310 grams (11 oz). He was hospitalized in a neonatal intensive care unit for five months, and then discharged.[186]

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).[187]

Effect of the coronavirus pandemic

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 to catch other diseases and viruses in general due to the lockdowns.[188]

Neurological research

Brain injury is common among preterms, ranging from white matter injury to intraventricular and cerebellar haemorrhages [189]. The characteristic neuropathology of preterms has been described as the “encephalopathy of prematurity” [190]. The number of preterms that receive special education is doubled compared to the general population. School marks are lower and so are verbal learning, executive function, language skills, and memory performance scores [191] [192] [193] [194], as well as IQ scores [195] [196] [197] [198] [199] [200] [201]. Behaviourally, adolescents who were born very preterm and/or very low birth weight have similar self-reports of quality of life, health status and self-esteem as term controls [202] [203] [204] [205].

Various structural magnetic resonance studies found consistent reductions in whole brain volume [206] [207] [208] [209] [210]. The extensive list of particular regions with smaller volumes compared to controls includes many cortical areas (temporal, frontal, parietal, occipital and cingulate), the hippocampal regions, thalamus, basal ganglia, amygdala, brain stem, internal capsule, corpus callosum and cerebellum. Brain volume reduction seems to be present throughout the whole brain. In contrast, larger volumes were found in some of the same areas including medial/anterior frontal, parietal and temporal cortex, cerebellum, middle temporal gyrus, parahippocampal gyrus, and fusiform gyrus, as well as larger lateral ventricles on average [211]. The cause of these inconsistencies are unknown. Additionally, reductions in cortical surface area/cortical thickness were found in the temporal lobes bilaterally and in left frontal and parietal areas [212] [213]. Thicker cortex was found bilaterally in the medial inferior and anterior parts of the frontal lobes and in the occipital lobes. Gestational age was positively correlated with volumes of the temporal and fusiform gyri and sensorimotor cortex bilaterally, left inferior parietal lobule, brain stem, and various white matter tracts, as well as specific positive associations with the cerebellum and thalamus. Several structural brain alterations have been linked back to cognitive and behavioural outcome measures. For example, total brain tissue volume explained between 20-40% of the IQ and educational outcome differences between extremely preterm born adolescents and control adolescents [214] [215] . In another study, a 25% quartile decrease in white matter values in middle temporal gyrus was associated with a 60% increase in the risk of cognitive impairment [216]. Nosarti and colleagues previously hypothesised that maturational patterns in preterm brains were consistent with the age-related stages typically observed in younger subjects. Their most recent study suggests however, that their trajectory may not only be delayed but also fundamentally distinctive. Since both smaller and larger regional volumes were found in very preterm individuals compared to controls [217].

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External links

Classification	D ICD-10: O60.1, P07.3 ICD-9-CM: 644, 765 MeSH: D047928 DiseasesDB: 10589
External resources	MedlinePlus: 001562 eMedicine: ped/1889