Vincenzo Berghella and Eduardo da Fonseca
Definition, impact, and incidence
Every 30 seconds a baby dies from being born too soon. The definition of preterm birth (PTB) is birth before 37 weeks. Usually this implies a birth ≥20 weeks, but the earlier cutoff in gestational age varies by countries. This leads to an effect on incidences of PTB in different countries. The World Health Organization (WHO) estimates that there are about 15 million annually in the world, and that over 1 million babies die of PTB (1). In fact, in terms of years-of-life lost, as PTB “kills” the youngest humans, it might represent the deadliest of all diseases.
Prediction of preterm birth
To prevent PTB, prediction is most important. Prediction is best accomplished by review of risk factors for PTB. A list of risk factors is shown in Table 5.1 (2). We advocate that all of these risk factors be reviewed with the patient, preferably before conception, as many (e.g., smoking, diabetes, etc.) should be managed aggressively pre-pregnancy.
Table 5.1 Risk factors for preterm birth (PTB)
•Prior obstetrics/gynecological history
•Cervical surgery (e.g., cone biopsy, loop electrosurgical excision procedure [LEEP], etc.)
•Multiple dilations and evacuations (D&Es)
•<17, >35 years of age
•Less education (e.g., <12 grades)
•Single marital status
•Lower socioeconomic status
•Short interpregnancy interval (e.g., <6 months)
•Other social factors (e.g., poor access to care, physical abuse, acculturation)
•Nutritional status/physical activity
•Body mass index <19, or pre-pregnancy weight <50 kg (<120 lb)
•Poor nutritional status
•Long working hours (e.g., >80/week)
•Hard physical labor (e.g., shift work, standing >8 hours)
•Current pregnancy characteristics
•Assisted reproductive techniques (e.g., in vitro fertilization [IVF])
•Fetal disease (e.g., chromosome anomaly, structural abnormality, growth restriction, death, etc.)
•Vaginal bleeding (e.g., first and second trimester, placenta previa, abruption)
•Poly- or oligohydramnios
•Maternal medical conditions (e.g., hypertension, diabetes, thyroid disease, asthma, etc.)
•Maternal abdominal surgery
•Psychological (e.g., stress, depression)
–Smoking (e.g., tobacco)
–Heavy alcohol consumption
–Urinary tract infection (e.g., asymptomatic bacteriuria, pyelonephritis)
–Severe viral infections
•Short cervical length (CL) between 14 and 28 weeks
•Positive fetal fibronectin between 22 and 34 weeks
In bold in Table 5.1 are the three risk factors that are currently most used for clinical management: prior PTB, multiple gestations, and short cervical length (CL).
Genetics and preterm birth
There are several recent studies and reviews on possible genetic etiologies, or at least associations, with PTB (3–5). These in general confirm the different pathways associated so far with PTB and risk factors. For example, a recent review highlighted genetic variants detected by whole exome (or genome in some cases) sequencing (WES) pointing to the negative regulation (dampening) of the innate immune response (e.g., CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (e.g., DEFB1, MBL2) associated with PTB (3). These genetic associations support the concept that PTB, at least in part, has an inflammatory etiology, which can be induced either by pathogens (i.e., intra-amniotic infection) or “danger signals” (e.g., alarmins) released during cellular stress or necrosis (i.e., sterile intra-amniotic inflammation) (3). PTB has a polygenic basis that involves mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. WES is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous PTB (3).
Another association is with genetic issues related to hormones as estrogen and progesterone, or other pathways for PTB, such as variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci, which are associated with gestational duration, and variants at the EBF1, EEFSEC, and AGTR2 loci, associated with PTB (4). Genetics and genomics also have a role in pharmacogenomics, e.g., how a pregnant woman “reacts” to a certain pharmacologic intervention, such as progesterone for prevention of PTB, for example. Genotype may influence the response to commonly used therapeutics administered for PTB prevention and treatment (5).
Prevention of preterm birth
Prevention of PTB can be divided into primary, secondary, or tertiary prevention. Primary prevention involves interventions that can be applied to all women.
Table 5.2 lists some selected examples of prevention strategies tentatively aimed at primary prevention of preterm birth in the general population. These are extremely important and are best implemented though a preconception visit (2).
Table 5.2 Selected examples of prevention strategies tentatively aimed at primary prevention of preterm birth in the general population
Pre-pregnancy (in early pregnancy if not already done)
•Preconception care with visit
•Aiming for desirable interpregnancy interval (18–24 months)
•Decrease unplanned and undesired pregnancy, family planning
•Minimize uterine instrumentation, decrease abortions
•Having normal body mass index (BMI) by diet and proper weight gain
•Avoiding maternal weight <120 pounds or BMI <19 kg/m2
•Avoiding multiple gestations
•Avoiding extremes of age
•Avoiding illicit drug and alcohol use
•Prevent sexually transmitted diseases
Pregnancy (all above, plus)
•Avoiding prolonged standing, long work hours, shift work
•Minimizing allostatic load (stress)
•Appropriate weight gain and exercise