Rising preterm birth rates: Time to double down on our efforts

Dr Lockwood, editor in chief, is Senior Vice President, USF Health, and Dean, Morsani College of Medicine, University of South Florida, Tampa. He can be reached at DrLockwood@advanstar.com.

The Centers for Disease Control and Prevention (CDC) preliminary report of 2015 birth outcomes contains some heartening news.¹ The birth rate for teenagers aged 15 to 19 years continues to fall, dropping 8% in just 1 year, 46% since 2007 and 64% since its peak rate in 1991. And while the decrease wasn’t of the same magnitude, cesarean delivery rates also fell for the third year in a row to 32% from 32.2%. Moreover, the cesarean rate for low-risk women (ie, nulliparas with singleton fetuses in vertex presentations at term) dropped to 25.7% from 26.0%.

Unfortunately, after nearly a decade of declines, the US preterm birth (PTB) rate rose from 9.57% in 2014 to 9.62% in 2015. Interestingly, this increase was largely confined to late (34 to 36 weeks) PTBs, which increased from 6.82% to 6.87%. The increase was also fueled by a widening of the already serious racial disparity in PTBs. Rates increased among non-Hispanic black women from 13.23% to 13.39% while declining among non-Hispanic whites from 8.91% to 8.88%. While all these changes are small, they should be a wake-up call to reinvigorate our efforts to fully implement proven strategies to reduce PTBs.

Do what works to prevent excess preterm births

The March of Dimes has been strongly advocating 7 strategies to reduce PTBs; my version of these interventions include:

• Reducing non-medically indicated deliveries prior to 39 weeks. It is unclear whether the current modest increase in late PTBs, especially among African-American women, reflects a loosening of our collective resolve to vanquish truly elective preterm deliveries or an increase in bona fide medically indicated PTBs. Given changing maternal demographics, I suspect the latter. Birth rates are declining not just among teenagers but also among women aged 20 to 24 years, who experienced a 3% decline from 2014 and a 27% drop since 2007. Conversely, birth rates are up among women aged 35 to 39 years, rising 1% since 2014 and 13% since 2013. There were also more births to women aged 40 to 49 years last year. In a large cohort study, Khalil and colleagues noted that, after adjusting for other confounders, maternal age ≥40 years increased the occurrence of preeclampsia (odds ratio [OR] of 1.49; 95% CI: 1.22–1.82), gestational diabetes (OR of 1.88; 95% CI: 1.55–2.29), and small-for-gestational-age infants (OR of 1.46; 95% CI: 1.27–1.69), all risk factors for indicated PTB.²  Interestingly, this “advanced” maternal age was not associated with increases in spontaneous PTB. Weight tends to increase with age, and obesity, especially when body mass indices (BMIs) reach or exceed 40, is a risk factor for both medically indicated and, to a lesser extent, spontaneous PTB.³

Thus, the aging of our maternity wards, combined with the ongoing obesity epidemic, could certainly help account for a rise in indicated PTBs. The observed increase in racial disparity may either parallel these secular trends or be an independent contributor. Clearly we should avoid performing truly elective PTBs but a reduction in indicated PTBs will take a concerted societal effort to encourage women to reduce preconception weight and excess gestational weight gain through diet and exercise. It will also necessitate more aggressive blood pressure and glucose control among hypertensive and diabetic patients, respectively, both prior to and during pregnancy. Finally, it may also be time to for an honest discussion with younger women about the benefits of planning pregnancies between the ages of 25 and 35 years.

• Increasing use of low-dose aspirin in women at risk for preeclampsia. As noted, increasing maternal age and obesity are both risk factors for preeclampsia.³ Preeclampsia is, in turn, a major risk factor for indicated PTBs. It is known that low-dose aspirin therapy, ideally started at the end of the first trimester, decreases the occurrence of preeclampsia by 24%, intrauterine growth restriction (IUGR) by 20%, and PTB by 14%.⁴ Thus, the US Preventive Services Task Force (USPSTF) recommends use of low-dose aspirin (81 mg/day) after 12 weeks’ gestation in women who are at high risk for preeclampsia.⁴  Patients are considered to be at high risk for preeclampsia if they have one or more of the following features: prior preeclampsia, multiple gestation, chronic hypertension, type 1 or 2 diabetes, renal disease, and autoimmune diseases such as lupus or antiphospholipid antibodies. The USPSTF also recommends considering low-dose aspirin if a patient has several moderate risk factors, including nulliparity, BMI >30, first-degree relative with a history of preeclampsia, African-American race, low socioeconomic status, age ≥35 years, prior IUGR or other adverse pregnancy outcome, and >10-year inter-pregnancy interval.

• Reducing smoking in pregnancy. Between 2000 and 2010 there was a modest drop in the prevalence of smoking during pregnancy from 13.3% to 12.3%, however, smoking still accounts for 5% to 8% of PTBs.⁵ Increasing smoke-free zones, raising cigarette taxes, and implementing aggressive public awareness campaigns have shown success but these efforts must continue.⁵ In addition, we need to be more aggressive in our counseling and efforts to assist patients in stopping tobacco use.

• Reducing multiple births through assisted reproductive technologies (ART). The majority of higher-order multiple gestations now result from ovulation induction and super-ovulation medical therapy rather than in vitro fertilization (IVF).⁶  However, while most twins are naturally conceived or result from ovulation induction, IVF does significantly contribute to our high US twin gestation rate, which currently stands at 33.9 per 1000 births.⁷ Thus, ob/gyns should preferentially refer their patients to IVF practices with lower multiple gestation rates and/or those that favor use of single embryo transfers (SETs) whenever feasible because this strategy has been shown to reduce the risk of multiple pregnancy without a substantial decrement in live born rates.^8,9 Moreover, insurance companies should preferentially reimburse SET cycles. Finally, selecting a single euploid embryo to transfer based on preimplantation comprehensive chromosomal screening using trophectoderm biopsy, newer genetic testing methods, and cryopreservation of tested blastocysts with subsequent SET may represent the long-term solution to ART-associated multiple gestations.

• Encouraging women to prolong inter-pregnancy intervals to >18 months. There is a nearly 4-fold increase in spontaneous early PTBs among women whose interval between a prior delivery and the last menstrual period preceding their next pregnancy is ≤6 months.¹⁰ The mechanism(s) for this association remain unproven but could include persistent inflammation and nutritional deficiency. In a retrospective cohort study of 111,948 women seen at least once by a provider within 18 months of delivery, every month of contraception coverage reduced the risks of PTB by 1.1% (OR of 0.989; 95%CI: 0.986–0.993).¹¹  Moreover, provision of long-acting reversible contraception (LARC) in the immediate postpartum period has been shown to increase contraception use at 6 and 12 months, thus decreasing the incidence of unintended pregnancy during this time.¹² This approach may be one of the most effective single strategies we can employ to reduce PTBs, although it will have less applicability in older women who are approaching the limits of fecundity but want to have more children. 

• Increasing use of 17 α-hyroxyprogesterone caproate (17-OHP) in women with prior spontaneous PTB. The original NICHD Maternal-Fetal Medicine Units Network study randomized 459 women with a history of spontaneous singleton preterm delivery to weekly intramuscular injections of 17-OHP versus placebo from 16 to 20 weeks until 36 weeks and demonstrated a reduction in births before 37 weeks (relative risk [RR] of 0.66; 95% CI: 0.54–0.81), 35 weeks (RR 0.67; 95% CI: 0.48–0.93), and 32 weeks (RR 0.58; 95% CI: 0.37–0.91).¹³  Meta-analysis of 36 trials of either 17-OHP or vaginal progesterone versus placebo in women with a history of spontaneous PTB demonstrates that progesterone reduces perinatal mortality (risk ratio [RR] of 0.50; 95% CI: 0.33–0.75), births <37 weeks (RR 0.55; 95% CI: 0.42–0.74), births <34 weeks (RR 0.31; 95% CI: 0.14–0.69), assisted neonatal ventilation (RR 0.40; 95% CI: 0.18–0.90), necrotizing enterocolitis (RR 0.30; 95% CI: 0.10–0.89), and admission to a neonatal intensive care unit (RR 0.24; 95% CI: 0.14–0.40).¹⁴ Thus, I contend that all patients with prior spontaneous PTB should be offered weekly 17-OHP injections, and if not available, vaginal progesterone from 16 to 36 weeks.

• Implementing universal screening for short cervices and intervening with vaginal progesterone or cerclage as indicated. Consensus has not been reached on the utility of universal cervical length screening at mid-gestation, or on at what gestational age to initiate the process or even what cervical length cut-off to use. However, there is evidence that vaginal progesterone therapy (via 90-mg gel or 200-mg suppository) reduces PTB in women with shortened cervices (≤20 mm) before 24 weeks who have no history of spontaneous PTB.¹⁴ Moreover, there is also evidence that either placement of a cerclage or the addition of vaginal progesterone in women found to have a shortened cervix (15 to 20 mm) at mid-gestation and who had a prior PTB will lower recurrence rates.¹⁵ Nonetheless, the Society for Maternal-Fetal Medicine has opined that universal cervical length screening is “reasonable.”¹⁶ Indeed, an abstract presented at this year’s ACOG Annual Clinical Meeting reported that 68% of centers with MFM fellowships had implemented cervical length screening.¹⁷ However, neither intervention is helpful in multiple gestations or following preterm fetal membrane rupture. Moreover, weekly 17-OHP does not appear to reduce PTB in nulliparous women with short cervices.¹⁸

One cautionary note comes from the recent UK OPPTIMUM trial.¹⁹ This was a complex double-blind trial in which women were randomized to vaginal progesterone (200 mg per day) (n=618) versus placebo (n=1228) from 22–24 to 34 weeks if they had a prior PTB at ≤34 weeks, or a cervical length ≤25 mm, or a positive fetal fibronectin test combined with other clinical risk factors for PTB. The authors noted that progesterone did not affect the primary obstetric outcome of fetal death or birth <34 weeks (adjusted OR of 0.86, 95% CI: 0.61–1.22) or a composite neonatal outcome (OR 0.62; 95%CI: 0.38–1.03). However, this study mixed various risk categories and may have been underpowered for these outcomes. Also the presence of an elevated fetal fibronectin suggests that pro-parturition inflammatory processes may well have been under way by the time progesterone therapy was initiated. This is important because we have shown that both abruption (via thrombin) and infection (via interleukin-1β) are associated with significant down-regulation of decidual cell progesterone receptor levels^20,21 and in the absence of its receptor even pharmacologic levels of progesterone will be ineffective.

Given these studies I would contend that progesterone therapy is best started early and, ideally prophylactically. Thus, I would recommend 17-OHP starting at 16 weeks in women with prior PTBs and high-dose vaginal progesterone for asymptomatic women with shortened cervix ≤20 mm, ideally started at 10 to 22 weeks, but certainly no later than 24 weeks and only if there is no evidence of infection or active abruption.

Take-home message

The recent national uptick in PTB rates may reflect the aging of our maternity population with its attendant accumulation of comorbidities triggering indicated PTBs. However, this increase should be a reminder that we must all do our best to optimize our patients’ lifestyle choices, BMI, fitness levels, and medical regimens prior to conception to reduce indicated PTBs. We should also fully employ the 7 practices described above that are known to reduce PTB rates. Our struggle against PTB is far from over and now is the time to redouble our efforts.

References

Hamilton BE, Martin JA, Osterman MJ. Births: Preliminary Data for 2015. Natl Vital Stat Rep. 2016;65(3):1-15.

Khalil A, Syngelaki A, Maiz N, Zinevich Y, Nicolaides KH. Maternal age and adverse pregnancy outcome: a cohort study. Ultrasound Obstet Gynecol. 2013;42(6):634-643.

Lutsiv O, Mah J, Beyene J, McDonald SD. The effects of morbid obesity on maternal and neonatal health outcomes: a systematic review and meta-analyses. Obes Rev. 2015;16(7):531-546.

LeFevre ML; U.S. Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;161(11):819-826.

Centers for Disease Control and Prevention. Trends in Smoking Before, During, and After Pregnancy-Pregnancy Risk Assessment Monitoring System, United States, 40 Sites, 2000–2010. http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6206a1.htm. Accessed June 22, 2016.

Practice Committee of American Society for Reproductive Medicine. Multiple gestation associated with infertility therapy: an American Society for Reproductive Medicine Practice Committee opinion. Fertil Steril. 2012;97(4):825-834.

Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: Final Data for 2014. Natl Vital Stat Rep. 2015;64(12):1-64.

Ryan GL, Sparks AE, Sipe CS, et al. A mandatory single blastocyst transfer policy with educational campaign in a United States IVF program reduces multiple gestation rates without sacrificing pregnancy rates. Fertil Steril. 2007;88(2):354-360.

Kresowik JD, Stegmann BJ, Sparks AE, Ryan GL, van Voorhis BJ. Five years of a mandatory single-embryo transfer (mSET) policy dramatically reduces twinning rate without lowering pregnancy rates. Fertil Steril. 2011;96(6):1367-1369.

Rodrigues T, Barros H. Short interpregnancy interval and risk of spontaneous preterm delivery. Eur J Obstet Gynecol Reprod Biol. 2008;136(2):184-188.

Rodriguez MI, Chang R, Thiel de Bocanegra H. The impact of postpartum contraception on reducing preterm birth: findings from California. Am J Obstet Gynecol. 2015;213(5):703.e1-6.

Goldthwaite LM, Shaw KA. Immediate postpartum provision of long-acting reversible contraception. Curr Opin Obstet Gynecol. 2015;27(6):460-464.

Meis PJ, Klebanoff M, Thom E, et al. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-2385. Erratum in: N Engl J Med. 2003;349(13):1299.

Dodd JM, Jones L, Flenady V, Cincotta R, Crowther CA.Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev. 2013;(7):CD004947.

Conde-Agudelo A, Romero R, Nicolaides K, et al. Vaginal progesterone vs. cervical cerclage for the prevention of preterm birth in women with a sonographic short cervix, previous preterm birth, and singleton gestation: a systematic review and indirect comparison metaanalysis. Am J Obstet Gynecol. 2013;208(1):42.e1-42.e18.

Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol. 2012;206(5):376-386. Erratum in: Am J Obstet Gynecol. 2013;208(1):86.

Khalifeh A, Quist-Nelson J, Berghella V. Current implementation of universal cervical length screening for preterm birth prevention in the United States. Obstet Gynecol 2016;127(5 supplement):7S.

Grobman WA, Thom EA, Spong CY, et al. 17 alpha-hydroxyprogesterone caproate to prevent prematurity in nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol. 2012;207(5):390.e1-8.

Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387(10033):2106-2116.

Lockwood CJ, Kayisli UA, Stocco C, et al. Abruption-induced preterm delivery is associated with thrombin-mediated functional progesterone withdrawal in decidual cells. Am J Pathol. 2012;181(6):2138-2148.

Guzeloglu-Kayisli O, Kayisli UA, Semerci N, et al. Mechanisms of chorioamnionitis-associated preterm birth: interleukin-1β inhibits progesterone receptor expression in decidual cells. J Pathol. 2015;237(4):423-434.