Background
Preterm birth, defined as birth between 20 0/7 and 36 6/7 weeks of gestation, is the leading cause of neonatal mortality in nonanomalous fetuses and is the leading cause of long-term neurodevelopmental impairment. [1, 2, 3] It is estimated that 15 million preterm births occur globally each year. [4, 5, 6] Despite considerable investment in research and strategies to prevent preterm birth, little impact has been made on this goal, and there have not been substantial changes in the rates of preterm birth over the past decade. [1, 5]
Preterm birth is categorized based on gestational age at delivery. Births occurring between 34 weeks and 36 weeks and 6 days are classified as late preterm births, whereas those between 32 weeks and 33 weeks and 6 days are referred to as moderate preterm births. [4] Births occurring before 32 weeks are categorized as early preterm births. In the United States, the majority of preterm births (approximately 71%) fall under the late preterm category, whereas about 16% occur before 32 weeks. [4]
Preterm birth may be spontaneous or medically indicated. [7, 8, 9] In spontaneous preterm birth (representing approximately two-thirds of preterm births), painful contractions and progressive cervical effacement and dilation lead to early delivery, whereas in medically indicated preterm birth, the patient is delivered early due to complications of pregnancy or medical conditions in which the risk to the mother or fetus of continuing with the pregnancy is greater than the risk of delivery at that gestational age. [9]
This article deals primarily with spontaneous preterm birth. However, there is some overlap between the conditions, and individuals who have one of these subtypes of preterm birth have increased risks both for recurrence and for the other subtype. [8, 9]
Pathophysiology
Over the past decades, extensive research into preterm labor and preterm delivery has shown that, rather than being a single condition, preterm labor is a syndrome with multiple distinct causes, all culminating in a common pathway characterized by painful uterine contractions, cervical dilation, and vaginal delivery. [10] Some mechanisms that have been shown to result in preterm labor and preterm delivery include the following:
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Decidual hemorrhage and placental abruption
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Uterine overdistension such as from multiple gestations or polyhydramnios
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Cervical insufficiency
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Uterine distortion
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Maternal inflammation/stress
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Uteroplacental insufficiency
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Intrauterine infection and inflammation
Decidual hemorrhage and placental abruption
Bleeding in pregnancy has been shown to be a strong risk factor for preterm labor and delivery. Thrombin is a powerful uterotonic agent. In addition, bleeding greatly increases the risk for degradation and rupture of the membranes. It has been estimated that abruption contributes to at least 20% of spontaneous preterm births.
Uterine overdistension
Uterine overdistension, such as from multiple gestations or polyhydramnios, significantly increases the risk of uterine contractions, cervical dilation, and preterm delivery. The higher incidence of preterm delivery in multifetal pregnancies is primarily attributed to uterine overdistension. This understanding forms the rationale for multifetal reduction in higher-order multifetal pregnancies.
In some cases of multifetal pregnancies, the early spontaneous delivery of one or more fetuses alleviates uterine overdistension, often halting preterm labor and prolonging gestation for the remaining fetuses—a phenomenon known as delayed interval delivery. [11]
A similar mechanism underlies the increased risk of preterm delivery in patients with uterine anomalies, such as a bicornuate or unicornuate uterus, uterus didelphys, or septate uterus. [12, 13] These anomalies reduce uterine capacity, leading to earlier overdistension. For example, in patients with a bicornuate uterus, the classic presentation before the advent of ultrasonography was recurrent preterm birth, with gestational ages progressively increasing in subsequent pregnancies due to the "stretching" of the uterus with each pregnancy.
Cervical insufficiency
In some pregnancies, cervical insufficiency (previously called “cervical incompetence”) can lead to early painless cervical dilation, often resulting in premature rupture of membranes—particularly during the second trimester—and spontaneous preterm birth. [14] True cervical insufficiency may arise from trauma, such as cervical lacerations sustained during spontaneous or instrumental vaginal delivery, or from cervical surgery, including extensive cervical cone biopsy or trachelectomy.
Congenital cervical insufficiency can also occur in patients with connective tissue disorders, such as Marfan syndrome and Ehlers-Danlos syndrome. However, the term “cervical insufficiency” is somewhat nonspecific and implies an inherent “weakness” of the cervix. [14] In reality, a significant proportion of patients with spontaneous, painless cervical dilation do not have a structurally weak cervix. Instead, cervical softening and dilation are often caused by intrauterine infection.
Uterine distortion
In some cases, preterm delivery associated with uterine anomalies may result from uterine overdistension. However, additional mechanisms may contribute, particularly in patients with distorted uterine cavities, such as those with uterine fibroids.
Maternal inflammation/stress
Maternal inflammation and stress have been strongly implicated in spontaneous preterm labor and birth, even in the absence of intrauterine infection.
Uteroplacental insufficiency
Uteroplacental insufficiency and the syndrome known as “ischemic placental disease” encompass conditions such as early-onset preeclampsia, severe early-onset fetal growth restriction, and placental abruption. These conditions often overlap, and while they frequently result in medically indicated preterm births, they also carry an increased risk of spontaneous preterm birth.
Intrauterine infection and inflammation
Intrauterine infection has emerged as an important cause of spontaneous preterm birth and may contribute to at least 25-40% of preterm births. [15, 16, 17] The inciting agents are mainly Ureaplasma urealyticum and Mycoplasma hominis. The majority of these infections are subclinical with evidence of infection appearing only on evaluation of the amniotic fluid. Bacterial vaginosis has also been strongly implicated in preterm birth. [18]
Finally, the fetus plays a role in the initiation of labor. In a simplistic sense, the fetus recognizes a hostile intrauterine environment and precipitates labor by premature activation of a fetal-placental parturition pathway.
Epidemiology and Risk Factors
In the United States, preterm birth complicates approximately 10.4% of pregnancies. This incidence has not changed substantially over the past several decades. [1] Risk factors for preterm birth include a history of prior preterm birth, multifetal gestations, African descent/Black race, lower socioeconomic status and socioeconomic deprivation, smoking, drug use, short interpregnancy interval, low and high maternal ages, single marital status, congenital uterine anomalies, and low prepregnancy weight. [4, 12, 19, 20, 21, 22] Interestingly, obesity appears to be associated with a lower risk of spontaneous preterm birth, but it increases the risks for medically indicated preterm birth. [19] Of concern is the considerable disparity in preterm birth, with non-Hispanic Blacks having double the preterm birth rates of non-Hispanic Whites. [23, 24]
Genetic factors appear to increase the risk for preterm birth. [25, 26] Some studies have found increased risks for preterm birth among women who themselves were born preterm. [27] However, other researchers have found this effect only in non-Hispanic Black women. [28] In addition, women who have first-degree relatives who delivered preterm are more likely to deliver preterm. [29]
Early studies indicated that periodontal disease in pregnancy is associated with preterm birth. [30] However, results of subsequent studies have conflicted with that finding and have not shown that treating periodontal disease in pregnancy reduces the incidence of preterm birth. [31, 32]
Consequences of Preterm Birth
Preterm birth has significant short- and long-term implications for the infant and is a leading cause of neonatal morbidity and mortality, with long-term morbidity that is often lifelong and associated with a shortened lifespan. [2, 33, 34] Common short-term complications include respiratory distress syndrome, intraventricular hemorrhage, neonatal jaundice, necrotizing enterocolitis, sepsis, and prolonged neonatal intensive care unit admissions. Long-term sequelae often involve neurodevelopmental impairment, such as cerebral palsy, blindness, deafness, and chronic lung diease. [33, 35] With increasing gestational age at delivery, the rates of these sequelae drop considerably. [36] Beyond the medical outcomes, preterm birth imposes a profound psychosocial burden on parents and families and results in immense economic costs to society.
Neonatal outcomes following preterm birth
With each additional week of gestational age at delivery, both short- and long-term outcomes significantly improve for the child. Between 23 and 26 weeks of gestation, it is estimated that each additional day increases survival rates by 1-3%. Therefore, strategies that effectively prolong gestation are likely to be associated with better neonatal outcomes.
The following table depicts survival, major short-term morbidity, and intact long-term survival by gestational age. [37]
Table. Neonatal Morbidity and Mortality by Gestational Age (Open Table in a new window)
Gestational Age, wk |
Survival |
Respiratory Distress Syndrome |
Intraventricular Hemorrhage |
Sepsis |
Necrotizing Enterocolitis |
Intact |
24 |
40% |
70% |
25% |
25% |
8% |
5% |
25 |
70% |
90% |
30% |
29% |
17% |
50% |
26 |
75% |
93% |
30% |
30% |
11% |
60% |
27 |
80% |
84% |
16% |
36% |
10% |
70% |
28 |
90% |
65% |
4% |
25% |
25% |
80% |
29 |
92% |
53% |
3% |
25% |
14% |
85% |
30 |
93% |
55% |
2% |
11% |
15% |
90% |
31 |
94% |
37% |
2% |
14% |
8% |
93% |
32 |
95% |
28% |
1% |
3% |
6% |
95% |
33 |
96% |
34% |
0% |
5% |
2% |
96% |
34 |
97% |
14% |
0% |
4% |
3% |
97% |
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Algorithm for use of progestogens in prevention of PTB in clinical care. <sup>aIf TVU CL screening is performed; <sup>b17P 250 mg intramuscularly every week from 16-20 weeks to 36 weeks; <sup>ceg, daily 200-mg suppository or 90-mg gel from time of diagnosis of short CL to 36 weeks. CL, cervical length; PTB, preterm birth; 17P, 17-alpha-hydroxy-progesterone caproate; TVT, transvaginal ultrasound. Reprinted from Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. <I>Am J Obstet Gynecol<I>. 2012 May; 206(5):376-86, with permission from Elsevier.
Tables
Gestational Age, wk |
Survival |
Respiratory Distress Syndrome |
Intraventricular Hemorrhage |
Sepsis |
Necrotizing Enterocolitis |
Intact |
24 |
40% |
70% |
25% |
25% |
8% |
5% |
25 |
70% |
90% |
30% |
29% |
17% |
50% |
26 |
75% |
93% |
30% |
30% |
11% |
60% |
27 |
80% |
84% |
16% |
36% |
10% |
70% |
28 |
90% |
65% |
4% |
25% |
25% |
80% |
29 |
92% |
53% |
3% |
25% |
14% |
85% |
30 |
93% |
55% |
2% |
11% |
15% |
90% |
31 |
94% |
37% |
2% |
14% |
8% |
93% |
32 |
95% |
28% |
1% |
3% |
6% |
95% |
33 |
96% |
34% |
0% |
5% |
2% |
96% |
34 |
97% |
14% |
0% |
4% |
3% |
97% |
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- Overview
- Treatment
- Goals of Management
- Preconception Strategies to Reduce Risk of Preterm Delivery
- Prediction and Risk Assessment for Preterm Delivery
- Prevention of Preterm Delivery in Patients at Risk
- Diagnosis and Management of the Symptomatic Patient With Preterm Labor
- Preterm Birth at the Limits of Viability
- Delivery
- Conclusion
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- Medication
- Tables
- References