Universal cervical‐length screening and vaginal progesterone prevents early preterm births, reduces neonatal morbidity and is cost saving: doing nothing is no longer an option (2011)

In a paper in this issue of the Journal, Hassan et al.1 address the question as to whether the incidence of spontaneous preterm birth (PTB), which has been rising inexorably over the past 30 years, can be reduced. The authors demonstrate that, by screening all singleton pregnancies, a group of women at high risk for spontaneous PTB can be identified in the middle trimester by transvaginal measurement of the cervix and that gestation can be prolonged and neonatal morbidity lessened in this high-risk group by daily vaginal progesterone therapy. Furthermore, the treatment is well accepted by the patients and has no known side effects. Also in this issue, Werner et al.2 calculate that this program, and a similar one published previously3, are cost saving. In this Editorial I will give briefly some of the background to this far-reaching plan which, in modern parlance, is a game-changer. Preterm delivery, with its collateral effects on neonatal mortality, short- and long-term infant morbidity and astronomical healthcare costs, is the foremost problem in modern obstetrics. In spite of advances in obstetric care, the rate of prematurity has not decreased over the past 40 years and in developed countries there has been an increase, possibly as a result of assisted reproductive technology (ART) programs. The current frequency of PTBs is 12.5% in the USA and 5–9% in European and other developed countries4. Spontaneous PTB, with or without prior rupture of the membranes (PPROM), accounts for two-thirds of PTBs, with the remainder occurring as a result of obstetrically indicated preterm delivery due to conditions such as pre-eclampsia and intrauterine growth restriction (IUGR)4. Prematurity remains a leading cause of neonatal morbidity and mortality in developed countries, accounting for 60–80% of deaths of infants without congenital anomalies. Greater attention is now being focused on very PTBs < 32 weeks' gestation, because, although this group represents only 1–2% of all deliveries, it accounts for about 60% of perinatal mortality and nearly 50% of all long-term neurological morbidity5. Short-term morbidities associated with early preterm delivery include respiratory distress syndrome, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, patent ductus arteriosus and retinopathy of prematurity. Long-term morbidities include cerebral palsy, cognitive defects and social and behavioral problems. This recital of the well-known complications of early PTB does not convey the devastating effects on the parents of a severely damaged child, the daily disruption to normal life, the anxieties and stress, the constant visits to hospital, or the sense of isolation and social exclusion from other parents with normal children6. Nor does it convey the long-term pain and suffering and frustrated lives of the children who are affected, usually with multiple disorders7. Unsurprisingly, many marriages do not survive the stresses imposed on them by a severely disabled child8 and, in those that do survive, few couples have the time and resources to attempt to have further children. In purely financial terms, the short- and long-term costs of caring for PTBs are staggering. Short-term hospital costs in the USA, over the first year of life of short gestation/low birth-weight infants, were estimated to be $ 5.6 billion9 and estimates for the annual societal economic burden in the USA was at a minimum of $ 26.2 billion in 200510. A UK study11 using a decision-analytic model estimated the costs to the public purse of children born prematurely up to 18 years of age to be £2.95 billion ($ 4.6 billion). The model calculated that a hypothetical intervention that delayed PTB by 1 week across all gestational-age categories would reduce these costs to £1.95 billion. Judgment on the success or otherwise of any preventative treatment should focus on deliveries occurring before 33 completed weeks of gestation, when the morbidity and mortality rates are high and the incremental cost of care to 18 years of age, compared to a term survivor, is almost $ 100 00011. The legendary Danish/American obstetrician Fritz Fuchs carried out the first randomized double-blind study of progesterone in the prevention of preterm delivery12. He was influenced by the work of Arpad Csapo which showed that the uterine myometrium was held in a state of quiescence by a ‘progesterone block’ and that normal labor was initiated by a fall in progesterone and withdrawal of this block13. Csapo's work was carried out on rabbits and laboratory rodents, where the source of progesterone depends on the corpus luteum and the fall in progesterone occurs following the involution of the corpus luteum. Progesterone withdrawal also occurs in larger placental sub-primates, such as sheep, as a consequence of a shift of steroidogenesis that favors estrogen production at the expense of progesterone. However, a fall in serum progesterone levels does not occur in primates and Fuchs's attempts to treat women who had experienced premature contractions with ‘high-dose’ daily oral progesterone was ineffective in delaying delivery. Nevertheless, it was widely recognized that progesterone plays a major role in maintaining uterine tranquillity in human pregnancy and several studies of low power and sometimes poor design, and with conflicting results, were subsequently carried out to assess the efficacy of a variety of mainly synthetic progestins in the prevention of recurrent miscarriage and preterm delivery. A meta-analysis published in 1989 by Goldstein et al.14 seemed to put the issue to rest; they found no benefit of progesterone in either the prevention of miscarriage or of preterm delivery in high-risk patients and recommended that progestogens should not be used outside of randomized trials. The following year, Keirse15 published a further meta-analysis, including only studies which used 17α-hydroxyprogesterone caproate (17OHP-C) administered by weekly intramuscular (IM) injection and found that, although ineffective in the prevention of miscarriage, this particular formulation, when given to women with a history of preterm delivery, was associated with a significant reduction in the incidence of PTB in the current pregnancy. However, it was too late; the damage to the reputation of progestins was apparently fatal and the world moved on to finding the perfect tocolytic, on the assumption that preterm labor was due to a primary activation of myometrial contractility, probably through an interaction between oxytocin and prostaglandin F2α16. Prevention gave way to the suppression of premature contractions and, over the next 20 years, there was a plethora of randomized trials studying a large number of tocolytics, including beta-2 receptor agonists, calcium channel blockers, prostaglandin synthetase inhibitors, oxytocin receptor blockers, magnesium sulphate and nitric oxide donors. The seemingly endless search for the perfect tocolytic ended in failure. A meta-analysis17 including all robust RCTs that compared tocolytics either with controls or with no treatment concluded that while most would delay delivery for up to 1 week, tocolytics were not associated with improved neonatal outcomes and many were associated with significant side effects. Indeed, tocolytics were shown not to be associated with a significant reduction in deliveries before 30, 32 or 37 weeks' gestation. By the end of the 20th century, researchers had turned again to the idea of prevention, a move stimulated by three developments: 1) a greater understanding of the etiological factors leading to spontaneous PTB; 2) improved prediction of spontaneous PTB by measurement of the of progesterone. 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of et that first attention to the that the transvaginal measurement of be used to a risk for preterm delivery for a significant of all this there have been of the of the on transvaginal including in the and of at the or without of of the in the of the and all of these are in spontaneous PTB, studies have that the is the and that all other to the of this However, it is usually recommended to the cervix for about 30 to occurring a which can be up by of and of the cervix is a for by no of the of preterm delivery. of early PTBs would be by a short cervix is many of the studies were on high-risk those studies carried out on normal give conflicting et in a study of women at and weeks' gestation, found that a 20 of PTBs occurring before et an UK between and weeks' gestation and found that a in of the and of occurring before 32 The also In the the at weeks for deliveries before weeks was while in the the for before 32 weeks was et from The developed a model risk factors with and found that the of age and history of PTB improved the The rate of screening for preterm delivery before 32 weeks at a rate of was for for and for This is when which patients to include in spontaneous PTB prevention programs. progestins had been shown to be in it was recognized from an early that in women with progesterone was to and pregnancy as with and the of can with corpus luteum and progesterone for progesterone which be daily by or were and oral treatment levels of several studies have shown progesterone in women who vaginal progesterone serum some of between the and a vaginal progesterone treatment is associated with serum levels of and side effects is oral and patients it to finding it and associated with progesterone can be in progesterone in and progesterone as a are The for can be as high as for the and daily for the A meta-analysis of randomized showed that there was no in for between the vaginal at accepted and that side effects were will be vaginal progesterone is now being used in the prevention of spontaneous The used for the for this are one those that are in although the used for the are In three RCTs on high-risk with a history of PTB were with conflicting et published a randomized study of weekly of and a reduction in the rate of PTB in the treatment group significant at < < and < 32 in neonatal morbidity was a study no long-term effects of the synthetic In a study from et randomized high-risk to a daily vaginal of 100 progesterone or and found a large reduction in deliveries before weeks in the treatment et in the of these women with a history of PTB who were randomized at weeks to a vaginal progesterone daily or was no reduction in the frequency of recurrent PTB 32 weeks or neonatal be that these conflicting were the result of the as the of the is to or possibly to that of the vaginal this is A is the of history as the for et this in of the The measurement of the cervix at the time of In the it was found that in women with a < the rate of PTB 32 weeks was in the progesterone with a significant reduction in respiratory distress in the This study the problem that had all intervention studies where is on a history of PTB, as this is to have a on the rate of spontaneous PTB of spontaneous early PTB occur in women with a The problem with the was that the of only patients were in the progesterone in the and that was on obstetric history and not on The from this study was that should be on The first study of progesterone on on was by et and The in a women to have a transvaginal between and weeks' women had a of or and of these patients were randomized to vaginal progesterone or was on the was a significant reduction in spontaneous deliveries before weeks' gestation in the progesterone group and a reduction in neonatal mortality and The study randomized on the of is from Hassan et al.1 and is in this issue of the This is an of women from a of 32 who had measurement at weeks' women had a between and 20 of were randomized to progesterone in or a by to treat a significant reduction in deliveries < 33 weeks a 50% reduction in < weeks and a reduction in very infants in the progesterone In the treatment group there was also a significant reduction in respiratory distress and a of neonatal morbidity in the the of the studies were The Hassan a significant in of neonatal morbidity which were not by the although in the study there was a This be by the that the study was not for this and, the Hassan which have not been shown to to progesterone the studies used of for in the Hassan et < on the that these patients were to to progesterone This the 50% incidence of PTBs in the group in the study as the incidence of early preterm delivery occurs with of and are an meta-analysis of the and studies which should the from these a of the and of these and the of et and Werner et al.2 is as A transvaginal in the trimester in singleton carried out between and weeks to is the with which to a group of women of the who would benefit from progesterone treatment to spontaneous Progesterone in women with a short using progesterone by the vaginal the incidence of PTB before 33 weeks by Progesterone will reduce the incidence of respiratory distress and of neonatal progesterone has no side effects to the and treatment is high Progesterone for women with a short cervix to be a with the to financial benefit to the healthcare compared with a no treatment is now that although progesterone has a uterine the of in preterm labor the synthetic and progesterone treatment have the of the and studies have that in the first trimester and at Progesterone can be as a and withdrawal of progesterone at the will result in the of with and of the cervix not uterine Progesterone treatment at the to the of and of the is also to progesterone the of the of the to be is whether the of progesterone being is for women with a very short The vaginal progesterone used for in with vaginal not the can be three those used in PTB and have side effects or long-term for the Spontaneous PTB has many a short is the for many of these In the study of et the was or in of and this group of all spontaneous PTBs occurring before weeks of gestation. A of progesterone prevention on this has been shown to be cost this is a on treatment on history which of the number of before weeks' gestation. The study found that the was in of and this group of spontaneous PTBs occurring before weeks of gestation. be for the screening to of up to as this would almost 50% of women who would give birth before weeks to progesterone therapy. In most countries, developed and a is carried out and is recommended by the in the UK it is recommended by the for and the of and of this to include a transvaginal to would not a significant in Furthermore, a significant reduction in PTBs before weeks was by the screening to include of or the that Hassan et showed a significant reduction between and 20 is the on the of spontaneous PTBs this A further question is Hassan et al.1 these from study as had a high incidence of in the of such when the is there is a high of an to delivery that is to be by progesterone. also a from that in the women with < were to progesterone would to at the group of patients with of as they over of women with < 20 and are associated with an incidence of delivery before 32 weeks' gestation. 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In singleton pregnancies, the rate of spontaneous premature birth before weeks is about while in it is et carried out a study of measurement at weeks' gestation in were of were The rate of delivery before 32 weeks' gestation was associated with of < < 20 and < the rates of spontaneous PTB before 32 weeks' gestation were and and had a similar incidence of early all randomized trials the prevention of spontaneous PTB in with progestins have The was carried out on women between and 33 weeks' gestation who were randomized to weekly of or was no reduction in the rate of PTB or perinatal morbidity in the treatment et carried out a similar study with larger and with the being between and 20 weeks and weeks' gestation or delivery. before weeks in of women in the group and in the In a double-blind women with were randomized to either vaginal progesterone or for weeks from weeks' gestation. 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In the of women with a early PTB, $ and in of life years The assumption was that 50% of women would for care before weeks' gestation, of these being with a prior PTB and with a prior early PTB 32 weeks' the calculated are the number of women for treatment would reduce the on the financial burden of et used a decision-analytic model to the cost of progesterone no treatment on an estimated annual delivery rate of annual birth rate in the The calculated annual on spontaneous PTBs < weeks and morbidity from $ billion to $ billion an annual of $ which was greater calculated from treatment on the of history ($ or screening in high-risk ($ billion). et estimated a 50% in PTBs in the which was the reduction estimated in the by Werner et on the cost of published in this issue of the The Werner study used a decision-analytic with estimates on the study of et and on neonatal mortality and morbidity on those found in the published the of was estimated to be for born before weeks and for born from to The cost estimates of the model are and include a of $ for the and $ for vaginal progesterone The model calculated a of over $ for 100 women with being in the progesterone This is when the model a reduction of only of before weeks gestation and a reduction in neurological The study is in the of the and the which, in some are screening and progesterone in and many countries of the where the is of care, the cost of the in the Werner model would be the costs of this the calculated in this model are it should be that they are as in the study of et a reduction in neonatal morbidity was not However, in an Werner et model using the of Hassan et which demonstrate a reduction in neonatal morbidity The model now improved of over $ women and a of compared with no In these studies to the healthcare from screening and vaginal progesterone which are to be in any healthcare or in any in the the past 40 years, in neonatal care by have to the reduction in neonatal morbidity and mortality, for low birth-weight has also major to the reduction of infant not only through the of and of pregnancy also through improved prediction and of the in the has been spontaneous PTB, for this is by the cause of neonatal morbidity and long-term and damage to the that a to the prevention of a which pre-eclampsia as a of However, following the that and of the cervix is the to many not most of spontaneous PTB, is now about to a major this problem by the of at high risk for early preterm delivery, following measurement of from to weeks' gestation and of progesterone to women with a short The study of Hassan et al.1 of the of this in of the incidence of early preterm delivery, and for the first time of an in neonatal of morbidity such as respiratory distress This with the study from The will cause an care is of a which should lives and a significant of and in children. The screening is and in most can be on to an The of Werner et al.2 demonstrate that such a is cost The treatment is vaginal which has been shown to be and to have no side at the larger given in early pregnancy for in programs. studies will the for in the treatment and whether should be However, this should not delay the of a on the paper of Hassan et patients and no