![ORCID Icon]({"type":"image","src":"/templates/jsp/_style2/_tandf/images/orcid.svg"} "ORCID Icon"){kind=small}
https://orcid.org/0000-0002-8531-7124
Introduction
The lowest incidence of perinatal morbidity and mortality occurs around 39–40 weeks. Therefore, a policy of elective induction of uncomplicated singleton once pregnancy reaches full‐term become caught the attention of many scientists. Finally, a large, randomized trial (ARRIVE trial) was performed to compare elective induction of labor (IOL) between 39 + 0 weeks and 39 + 4 weeks with expectant management, in nulliparous, low-risk women without medical indications. Elective IOL failed to improve neonatal well-being which was measured through a composite outcome including perinatal mortality, need for respiratory support, umbilical cord acidemia. Among secondary outcomes, authors observed a significant reduction of both cesarean deliveries (CD) and hypertensive disorders of pregnancy (HDP) in women receiving IOL compared to those randomized to expectant management [1].
Based on these results, SMFM state that “It is reasonable to offer elective induction of labor to low-risk nulliparous women ≥39 weeks 0 days of gestation. Providers who choose this approach should ensure that women meet eligibility criteria of the ARRIVE trial” [2]. It remains uncertain, however, if such policy is transferable and would be beneficial to other countries outside United States, namely to Europe where the population characteristics, the perinatal mortality and the socio-cultural environment could be very different. Therefore, we analyze here some of the above conditions.
Population
It is increasingly common for European women to delay childbearing. The mean age of European mothers overall is 29.5 years, with Italy, Spain and Greece being the nations with higher figures [3]. Italian women give birth to their first child at a median age of 31 (Table 1). Notably, 10.2% of nulliparous women are aged 40 years and beyond at their first delivery [4]. These numbers are far above respect with women enrolled in ARRIVE Trial whose median age was 24. Aside from the impact of an ageing population on the economics and burdens of society [5], age is positively associated with both occurrence of stillbirths (SB) and CD rate [6,7].
Table 1. Comparison characteristics between ARRIVE trial and European population.
Looking at body composition, EU and US differences are even more remarkable. The vast majority of women included in the ARRIVE trial is obese contrarily to European women where BMI ≥30 ranged 7.8%–25.5%. In continental Europe, the maximal prevalence was 14.8%, referred to German pregnant women [8] (Table 1). Obesity is well known to complicate pregnancy and parturition. An increased risk for Gestational Diabetes, SB, HPD, Premature delivery and CD has been described as strongly associated with increasing BMI categories [9]. Several factors have been found causally associated including low-risk inflammation, insulin resistance, oxidative stress and so on [10,11].
Also socio-economic and cultural characteristics of the women randomized in the ARRIVE Trial are dissimilar from those living in western European nations. While in the latter not less than 90% benefit of a full coverage for their perinatal cares, commonly offered by National Health Systems (with differences among them) [12], it is noteworthy that >50% of women of the ARRIVE trial does not have a private insurance, therefore receiving Medicaid assistance, a health coverage of pregnancy and childbearing for lower income women [13].
As far as family status, a diffused homogeneous situation in the different European countries is that half of the women are married while another 30% live in a couple “de facto” allowing almost the 90% of women living with a partner whereas this occurred only in <60% of women in the ARRIVE trial. It is known that single mothers are prone to unhealthy habits like smoking, poor quality diet, sedentary life, etc. [14]. Such lifestyles associated with scarce health coverage expose those women to the adverse perinatal outcomes that have been repeatedly reported in disadvantaged populations [15,16].
Outcomes
Perinatal mortality
The primary outcome of the ARRIVE trial is a composite of perinatal death plus severe neonatal complications that occurred in 4.3% of the neonates in the IOL arm and in 5.4% in the expectant-management arm (relative risk, 0.80; 95% CI, 0.64 to 1.00; p = .049). The rate of the primary (composite) outcome was higher than the authors’ estimate (3.5%), on which the sample size was calculated (n = 6000) to highlight a difference between the groups. Therefore, if there had been a difference, it would have recognized. The high rate of the primary outcome (5.4%) is most likely a sign that the study population is not at low risk. However, Po’ et al. performed a theoretical exercise where they simulated the effects of IOL once applied to the entire US population. According to vital statistics data from Live Birth and Fetal Death certificates of the period 2014–2016, the risk of stillbirth (SB) beyond 39 weeks is 0.6/1000 hence they conclude that every 1675 IOL during that period 1 SB case would be prevented [17].
The rate of SB in West European countries is 4.3 per 1000 total births in France, 3.1‰ in Greece, 3.0‰ in United Kingdom, 2.7‰ in Germany and under 2.5‰ in all other countries [18], lower than the one reported in the United States (6.0‰) [19]. However, extracting data from the perinatal registry of Emilia Romagna (2014–2019) we found the same risk of SB beyond 39 weeks. Hence, a similar benefit could be expected in our population too.
Cesarean delivery
IOL arm showed a significantly lower CD rate than the expectant-management group (18.6% vs. 22.2%; relative risk, 0.84; 95% CI, 0.76 to 0.93; p < .001) in the ARRIVE trial. This is not unexpected since the progression of gestation is associated with increasing maternal (and fetal) morbidity. Indeed, the expectant management arm (14.1%) reported a significantly higher prevalence of HDP than the IOL arm (9.1%). Obesity per sé could explain such a trend since the strong association between fat mass and the development of hypertension and Preeclampsia (PE) [20]. Despite advanced maternal age in Europe, pregnant women appear to be less obese, determining the lower prevalence of HDP found in European countries (5.2%) [21] respect with United States (10%) [22].
There are few data on CD rate in the specific population we are considering, that is, nulliparous, singleton, low-risk, spontaneous labor >39 weeks. Those women are similar to the Robson class I category which, however, also include early-term deliveries at 37 and 38 weeks. According to an international comparison of 2009 including six EU countries, CD in class I ranged 5.7–20.6% [23]. In Italy, one of the countries in the top ten ranking for CD, analysis of the last 2017 birth registry reported a CD rate of 13.3% in the Robson class I [4]. A deep analysis of Birth certificates from Emilia Romagna allows us to describe the same population as included in the ARRIVE Trial. As already reported [10], the rate of CD progressively increase from 39 to 42+ weeks, either in spontaneous labors (from 7.0 to 12.7%) and in labors induced upon medical indication (from 18.4 to 28.4%). However, the overall CD rate since 39 weeks or since 40 weeks is markedly lower than that reported in the two arms of the ARRIVE trial (Figure 1).
Published online:
26 November 2020Figure 1. Cesarean Section rates in induced and spontaneous labors. Data from Emilia-Romagna perinatal registry (2016–2018).
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/ijmf20/0/ijmf20.ahead-of-print/14767058.2020.1849128/20201126/images/medium/ijmf_a_1849128_f0001_c.jpg"})
Figure 1. Cesarean Section rates in induced and spontaneous labors. Data from Emilia-Romagna perinatal registry (2016–2018).
Factors affecting CD are several and must be evaluated in complex personal bio-psycho-social dimensions.
Conclusion
In summary, European populations look very different respect with those randomized in the ARRIVE trial. They are older but considerably thinner, develop less HPD, benefit more from family and social support being also managed by a markedly different perinatal organization. Besides, neonatal outcomes in the US population are worse than in other advanced countries [24]. Therefore, the baseline risk of perinatal adverse outcomes (primary outcome) is lower and so are the expected benefits of the intervention in Europe. Along with that, fewer are also the expected benefits on the CD rate.
Moreover, the advantage of an elective IOL since 39 weeks, demonstrated by the trial, is a CD reduction of 3.6 points in women developing Hypertensive Disorders (11.5% of cases), with a baseline CD rate of 20%. However, the lowest rate of CD reported in IOL arm was several points higher than the CD rate occurring with a policy of expectant management associated with a selective IOL, performed upon medical indication (Figure 1). This is the policy actually ongoing in many European countries.
The last consideration, certainly not least for importance, is related to the attitude women have versus childbirth. In most parts of the cultures, childbirth is a liminality, a passage of persona/social status and according to a recent qualitative review “what matters to most women was a positive experience (of childbirth), […] Most wanted a physiological labor and birth, while acknowledging that birth can be unpredictable and frightening” [25]. These beliefs give reason as to why 73% of the >22,000 eligible women refused randomization in the ARRIVE Trial.
In conclusion, we should be grateful to our American colleagues for highlighting several concepts and rebutting some myths like “IOL is associated with more CD”. However, it seems unlikely that elective IOL at 39th week, in low-risk women would provide benefits in most European countries, changing our policy of expecting labor onset (at least untill 41 weeks) and performing selective IOL upon medical indication.
| ARRIVE trial | European population | |
|---|---|---|
| Age (yrs) at first delivery | ||
| Median | 24 | 31a |
| Interquartile range | 21–28 | 28−33 |
| Age ≥35 yr | 4.0% | Age 30−39 yr − (59.5%) Age ≥ 40 yr − (10.2%) |
| Pre-pregnancy BMI | ||
| Median | 30.5 | 21.7b |
| Interquartile range | 27.3–35.0 | 18.5−24.9 |
| BMI ≥30 | 53% | 14.4% |
| Private insurance for prenatal care | 44.9% | <10%c |
| Family status Married or living with a partner | 59% | 87%d |
aData from Italian perinatal registry 2017.
bData from EuroPeristat 2015.
cEurohealth 2020.
dData from Finland perinatal registry 2018.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Conference
This topic was orally presented at the 6th edition of the BIRTH 2020 – Clinical Challenges in Labor and Delivery.
References
- GrobmanWA, RiceMM, ReddyUM, et al. Labor induction versus expectant management in low-risk nulliparous women. N Engl J Med. 2018;379(6):513–523. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- SMFM statement on elective induction of labor in low-risk nulliparous women at term: the ARRIVE trial. Am J Obstet Gynecol 2019;221(1):B2–B4. [Web of Science ®], [Google Scholar]
- Health Programme of the European Union . Euro-Peristat [Internet]. 2017. Available from: https://www.europeristat.com/. [Google Scholar]
- Italian Ministry of Health – Health Information System and Statistics. Childbirth Assistance Certificate (CeDAP) . Analysis of the birth event; 2017. Available from: http://www.salute.gov.it/statistiche. [Google Scholar]
- ChristensenK, DoblhammerG, RauR, et al. Ageing populations: the challenges ahead. Lancet. 2009;374(9696):1196–1208. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- SalihuHM, WilsonRE, AlioAP, et al. Advanced maternal age and risk of antepartum and intrapartum stillbirth. J Obstet Gynaecol Res. 2008;34(5):843–850. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- BayrampourH, HeamanM. Advanced maternal age and the risk of cesarean birth: a systematic review. Birth. 2010;37(3):219–226. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- ZeitlinJ, MohangooA, CuttiniM. The European Perinatal Health Report: comparing the health and care of pregnant women and newborn babies in Europe. J Epidemiol Community Heal. 2009;63(9):681–682. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- OvesenP, RasmussenS, KesmodelU. Effect of prepregnancy maternal overweight and obesity on pregnancy outcome. Obstet Gynecol. 2011;118(2, Part 1):305–312. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Fernández-SánchezA, Madrigal-SantillánE, BautistaM, et al. Inflammation, oxidative stress, and obesity. Int J Mol Sci. 2011;12(5):3117–3132. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- ShoelsonSE, HerreroL, NaazA. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132(6):2169–2180. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- European observatory on health systems and policies . Eurohealth. 2020. Available from: https://www.euro.who.int/en/about-us/partners/observatory [Google Scholar]
- WherryLR. State medicaid expansions for parents led to increased coverage and prenatal care utilization among pregnant mothers. Health Serv Res. 2018;53(5):3569–3591. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- FarbuJ, HaugenM, MeltzerHM, et al. Impact of singlehood during pregnancy on dietary intake and birth outcomes – a study in the Norwegian Mother and Child Cohort Study. BMC Pregnancy Childbirth. 2014;14(1):396 [Crossref], [PubMed], [Google Scholar]
- GavinAR, NuriusP, Logan-GreeneP. Mediators of adverse birth outcomes among socially disadvantaged women. J Womens Health. 2012;21(6):634–642. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- LarsonCP. Poverty during pregnancy: its effects on child health outcomes. Paediatr Child Health. 2007;12(8):673–677. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- Po'G, OliverEA, ReddyUM, et al. The impact of induction of labor at 39 weeks in low-risk women on the incidence of stillbirth. Am J Obstet Gynecol. 2020;222(1):88–90. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- United Nations Inter-agency Group for Child Mortality Estimation (UN IGME ). A neglected tragedy: the global burden of stillbirths. 2020. Available from: https://www.unicef.org/reports/neglected-tragedy-global-burden-of-stillbirths-2020 [Google Scholar]
- PruittSM, HoyertDL, AndersonKN, et al. Racial and ethnic disparities in fetal deaths – United States, 2015–2017. Morb Mortal Wkly Rep. 2020;69(37):1277–1282. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- GaillardR, SteegersEA, HofmanA, et al. Associations of maternal obesity with blood pressure and the risks of gestational hypertensive disorders. The Generation R study. J Hypertens. 2011;29(5):937–944. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- RobertsCL, FordJB, AlgertCS, et al. Population-based trends in pregnancy hypertension and pre-eclampsia: an international comparative study. BMJ Open. 2011;21(1):e000101. [Crossref], [Google Scholar]
- AronowWS. Hypertensive disorders in pregnancy. Ann Transl Med. 2017;5(12):266–266. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]
- BrennanDJ, RobsonMS, MurphyM, et al. Comparative analysis of international cesarean delivery rates using 10-group classification identifies significant variation in spontaneous labor. Am J Obstet Gynecol. 2009;201(3):308.e1–308.e8. [Crossref], [Web of Science ®], [Google Scholar]
- National Research Council and Institute of Medicine. U.S. health in international perspective. Washington (DC): National Academies Press; 2013. p. 61. [Google Scholar]
- DowneS, FinlaysonK, OladapoO, et al. What matters to women during childbirth: a systematic qualitative review. PLoS One. 2018;13(4):e0194906. [Crossref], [PubMed], [Web of Science ®], [Google Scholar]