Assisted Reproduction and Preterm Birth

Preterm parturition is a syndrome (Romero, Gomez et al., 1997; Romero R, Espinoza J et al., 2004) that is one of the leading causes for perinatal morbidity and mortality. Moreover, prematurity is a leading cause for neonatal mortality, as well as short and long term morbidity. The incidence of preterm delivery is constantly increasing, crossing the 12% in the USA, and it's annual cost reached 26.2 billion US dollars in 2005, posing a huge burden on public health (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007). Prematurity can be either spontaneous due to preterm labor with intact membranes (PTL) or preterm prelabor rupture of the chorioamniotic membranes (preterm PROM); or indicated, meaning induced preterm delivery by the medical team due to maternal (i.e. preeclampsia) or fetal (growth restriction, non-reassuring fetal heart rate tracing) indication (Goldenberg, Culhane et al., 2008). The incidence of the latter group, especially after 34 weeks of gestation, is constantly rising (Ananth, Joseph et al., 2005; Ananth and Vintzileos, 2006a; Ananth, Getahun et al., 2006). Emerging contributors for the increasing rate of preterm birth are assisted reproduction technologies (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007). The use of infertility treatments has risen dramatically in the past 20 years; between 1996 and 2003, the number of cycles of Assisted reproductive technologies (ART) nearly doubled from 64,681 to 122,872. The number of live births resulting from conceptions achieved by the use of ARTs more than doubled from 14,507 to 35,785 (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 1980). This has been associated with the trend to delay childbearing, indeed, more than 50 percent of these women were 35 years of age or older. In recent years, an unintended consequence of the use of these technologies, multiple gestations and the increased risk for preterm delivery, has become a focus of attention, and the institute of Medicine in the USA has concluded that "Fertility treatments are a significant contributor to preterm birth among both multiple and singleton pregnancies." (Institute of


Introduction
Preterm parturition is a syndrome (Romero, Gomez et al., 1997;Romero R, Espinoza J et al., 2004) that is one of the leading causes for perinatal morbidity and mortality.Moreover, prematurity is a leading cause for neonatal mortality, as well as short and long term morbidity.The incidence of preterm delivery is constantly increasing, crossing the 12% in the USA, and it's annual cost reached 26.2 billion US dollars in 2005, posing a huge burden on public health (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007).Prematurity can be either spontaneous due to preterm labor with intact membranes (PTL) or preterm prelabor rupture of the chorioamniotic membranes (preterm PROM); or indicated, meaning induced preterm delivery by the medical team due to maternal (i.e.preeclampsia) or fetal (growth restriction, non-reassuring fetal heart rate tracing) indication (Goldenberg, Culhane et al., 2008).The incidence of the latter group, especially after 34 weeks of gestation, is constantly rising (Ananth, Joseph et al., 2005;Ananth and Vintzileos, 2006a;Ananth, Getahun et al., 2006).Emerging contributors for the increasing rate of preterm birth are assisted reproduction technologies (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007).The use of infertility treatments has risen dramatically in the past 20 years; between 1996 and 2003, the number of cycles of Assisted reproductive technologies (ART) nearly doubled from 64,681 to 122,872.The number of live births resulting from conceptions achieved by the use of ARTs more than doubled from 14,507 to 35,785 (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 1980).This has been associated with the trend to delay childbearing, indeed, more than 50 percent of these women were 35 years of age or older.In recent years, an unintended consequence of the use of these technologies, multiple gestations and the increased risk for preterm delivery, has become a focus of attention, and the institute of Medicine in the USA has concluded that "Fertility treatments are a significant contributor to preterm birth among both multiple and singleton pregnancies."(Institute of www.intechopen.comThe mechanisms in which assisted reproduction technologies increases the risk for preterm birth are still under investigation.Aside the contribution of ART to the increase number of multiple gestations (especially twins) that increases the risk for preterm delivery; The mechanisms leading to preterm delivery in singleton gestations conceived through ART have not been thoroughly investigated.Preliminary evidence suggests that some of the underlying maternal conditions that lead to infertility (i.e.inflammation and insulin resistance) may contribute to this observation.The current chapter will explore the epidemiology, underlying mechanisms, and possible tools for the prevention of preterm delivery in pregnancies conceived by assisted reproduction.

Infertility: Treatments, epidemiology and trends 2.1 Definitions
The most commonly used definition of infertility is a failure to conceive after 12 months of regular, unprotected intercourse.However, existing definitions of infertility lack uniformity, rendering comparisons of prevalence between countries or over time problematic.The absence of an agreed definition also compromises clinical management and undermines the impact of research findings.Gurunath at al suggested that the definition will be based on the duration of trying for pregnancy coupled with female age.(Gurunath, Pandian et al., 2011) According to the report of The Centers for Disease Control and Prevention (CDC), in 2002, 7% of married couples in which the woman was of reproductive age (2.1 million couples) reported that they had not used contraception for 12 months and the woman had not become pregnant.Many of these patients are treated by ARTs.These technologies are defined by the CDC as procedures in which the ovum and the sperm are handled in the laboratory.During the past few decades several options of ART have developed including: 1) in vitro fertilization (IVF); 2) intra-cytoplasmic sperm injection (ICSI); 3) gamete intrafallopian transfer (GIFT) and 4) zygote intra-fallopian transfer (ZIFT) (Centers for Disease Control and Prevention 2008).

What is the magnitude of ART utilization in developed countries?
The use of infertility treatments has risen dramatically in the past 10 years and has been associated with the trend to delay childbearing.Today, over 1% of all infants born in the United States every year are conceived using ART; and the number of ART cycles performed has nearly doubled, from 87,636 cycles in 1999 to 148,055 in 2008.Similarly, the number of live-birth in 2008 (46,326) was more than twice the number recorded 1999 (21,746).Because in many of the ART pregnancies more than one infant is born alive (e.g., twins, triplets), the total number of infants born is greater than the number of live-birth.The trend in the number of infants delivered after ART cycles was in accord to the trends observed in the number of pregnancies and live-births.Thus, the number of infants born in 2008, (61,426) was more than twice than the 30,629 that were delivered in 1999 (Figure 1).Outside the USA, The Canadian Assisted Reproductive Technologies Register (CARTR), in its 2007 annual publication, reported a 12% increase in the total number of ART cycles, and an increase in the rate of clinical pregnancies and live-birth, along with a decrease in highorder multiple births in comparison to these parameters in 2006 (Gunby, Bissonnette et al., ART often is categorized according to whether the procedure used a woman's own eggs (self) or eggs from another woman (donor) and according to whether the embryos used were newly fertilized (fresh) or previously fertilized, frozen, and then thawed (frozen).For approximately 71% of ART cycles performed in USA in 2008, self-fresh eggs or embryos were used.ART cycles that used self-frozen embryos were the next most common type, accounting for approximately 17% of the total.In about 12% of cycles, eggs or embryos were donated by another woman (Figure 2).The average age of women using ART services in the USA in 2008 was 36.However, the largest group of women using ART services were women younger than 35, representing approximately 39% of all ART cycles performed in 2008.Approximately 21% of ART cycles were performed in women aged 35-37, 20% in women aged 38-40, 10% in women aged 41-42, 6% in women aged 43-44, and 5% among women older than 44 ( Figure 4).In Europe, the age distribution of women treated with IVF varied across the continent.In some countries, more than 20% of women were aged 40 years or older (Greece, Ireland, Italy, Macedonia, Montenegro, Serbia and Switzerland), whereas in Bulgaria, Czech Republic, Lithuania, Norway, Poland, Portugal, and Ukraine <10% were 40 years or older.(ESHRE,2006) The success rate of ART decreases with age, indeed, pregnancy rates decreased from 28.2% in women aged ≤34, to 9.6% at the age ≥40 years.A similar trend was seen for the delivery rates (26.6%, and 8.6%).In egg donation cycles, the recipients were aged 40 years or more in 50.0% of cases, in almost all countries.Pregnancy and delivery rates in oocyte recipients were comparable across different age groups.(ESHRE,2006)

The effect of maternal age on reproduction and pregnancy outcome
The average fertility rate (live births per 1,000 women of childbearing age 15-44 years) in USA from 1991-2008 is about 66.5, with mild fluctuations over the years.When it is divided in subgroups by maternal age, the birth rate has declined for women under 30-s on the other hand among women in their 30's-40's the fertility rate had steadily increased from 1978 onward.In the last three decades a new group of women aged 50 and over has increased more than 10 percent annually since 1997 (Martin, Hamilton et al., 2010).The trend in the fertility rate among European women is somewhat different.From the 1960s up to the beginning of the 21st century, the number of live births in the Europe declined sharply.However, from 2002 onward there has been a modest rebound in the number of live births born in this continent.As with the American women, the late increase during the last years may be, in part, attributed to a catching-up process following a general pattern of postponing the child bearing age.When women give birth later in life, the total fertility rate first indicates a decrease in fertility, followed later by a recovery (Atkinson and Marlier, 2010).For example, in Finland the rate of women giving birth after the age of 35 increased from 16.7%in 1997 to 19.2% in 2007 (Lampinen, Vehvilainen-Julkunen et al., 2009).The corresponding mean maternal age in Japan between 1970 and 2000 increased from 25.6 to 28.0 years (Mathews and Hamilton, 2002).rate of trisomy 13 and by 25% in the rate of trisomy 18.These findings are consistent with those predicted to be associated with the increases in maternal age (Savva, Walker et al., 2010).The link between Down syndrome and advanced maternal age deserves special attention.This association was already reported by Penrose in the mid 1930's (Penrose, 1933;Penrose, 1934).Lately, Graves Allen et al (Allen, Freeman et al., 2009) examined the origin of the meiotic error leading to the association between maternal age and chromosome 21 nondisjunction.They emphasis that the a significant association between advanced maternal age and chromosome 21 non-disjunction was restricted to meiotic errors in the egg and was not observed in sperm or in post-zygotic mitotic errors.The authors reported that the advanced maternal age was significantly associated with a higher rate of non-disjunction in both meiosis I (MI) and meiosis II (MII).Indeed, compared to mothers of euploid neonates, mothers of infants with trisomy 21 due to MI non-disjunction were 8.5 times more likely to be ≥40 years old than 20-24 years old at the birth of the index case (95% CI = 5.6-12.9).Where non-disjunction occurred in MII, mothers were 15.1 times more likely to be ≥40 years (95% CI = 8.4-27.3)(Allen, Freeman et al., 2009).Women's age has a major impact on the rate of chronic maternal diseases and pregnancy outcome.Indeed, the rate of diabetes increases with maternal age.The 2010 National Vital Statistics Reports reported that in 2007 the rate of diabetes among USA mothers under the age of 20 was 14.0 per 1,000, and it increases almost 7 times higher to 100.5 per 1,000 in women over the age of 40 (Table 1).Similar trends were reported regarding the rate of chronic hypertension.The prevalence of this disease increases from 3.9 per 1000 in women younger than 20 years old to 32.2 per 1000 in women older than 40.In contrast to the linear association between diabetes, as well as chronic hypertension and maternal age, the incidence of gestational hypertension as a function of maternal age has a U shape curve with a prevalence of 41.8 per 1000 among patients under 20 years and 50.1 per 1000 for women over 40, and the lowest incidence is between 20-35 years old.Similarly to the National Vital Statistics Reports, a different population based cohort involving 1,160,000 women delivered during a 2-year period found increased rate of preeclampsia and gestational diabetes among women aged 40 years or older in comparison to those aged 20-29 (Gilbert, Nesbitt et al., 1999).Yogev et al (Yogev, Melamed et al., 2010) stratified the rate of pregnancy complication according to maternal age with a special attention to women aged ≥45 years (n = 177) with an additional subgroup analysis of women aged 45-49 years with those women aged ≥50 years.Similar to previous studies the authors reported that the rates of gestational diabetes mellitus and hypertensive complications of pregnancy were increased among women aged 45 years and older.Maternal age also influences perinatal outcome, small-for-gestational age births (SGA) are common and can have serious immediate consequences for the infant (Das and Sysyn, 2004;Salem, Levy et al., 2011).They have also been associated with the development of a range of chronic diseases in subsequent adult life (Nepomnyaschy and Reichman, 2006;Barker, 2004).There is an association between maternal age and the delivery of an SGA neonate.In the FASTER trial, patients aged 35-39 years were at increased risk to a deliver low birthweight neonate (adjusted OR 1.6) (Cleary-Goldman, Malone et al., 2005).In addition, Salem-Yaniv et al, in a retrospective population based study found a significant increase in low birth weight among older women (35-40 and  Women ≥ 35 years have a significantly higher rate of fetal death than their younger counterparts.Fretts and colleagues documented that the fetal death rate decreased by more than 70 percent over the past 30 years among white Canadian women.Although the absolute stillbirth rate declined significantly for women of all ages and parity groups, older women remained at higher risk for fetal death, even after controlling for diabetes, hypertension, and placental abruption (Fretts, Schmittdiel et al., 1995).This report was in accord with other publications regarding the increased rate of fetal demise among older women (Jacobsson, Ladfors et al., 2004

, 2010a
).There is a strong evidence to support the association between IVF treatments and preterm birth.Indeed, ART are independently associated with preterm birth in singleton as well as in twin gestation.

The association between preterm birth and assisted reproduction
Preterm delivery is the leading cause for perinatal morbidity and mortality worldwide (Goldenberg, Culhane et al., 2008) ).The number of live births resulting from conceptions achieved by the use of ARTs more than doubled from 14,507 to 35,785.This has been associated with the trend to delay childbearing, indeed, more than 50 percent of these women were 35 years of age or older.In recent years, an unintended consequence of the use of these technologies, multiple gestations and the increased risk for preterm delivery, has become a focus of attention.Indeed, the institute of Medicine in the USA has concluded that "Fertility  ART are associated with increased rate of pregnancy complication.Several questions are being raised in regard with this topic:1) what are the causes or mechanisms leading for such complications?Is it the treatment or the underlying maternal condition that leads to infertility?2) Are these complications due to multiple gestation or they affect also singleton gestations? 3) Is there an association with between the ART protocol and adverse pregnancy outcome?

The association between ART and multiple gestations
There is a direct relationship between the rise in the use of assisted reproduction and the increasing rate of multiple gestations.This trend is mostly due to the transfer of multiple embryos.In spite of the new regulation regarding the maximal embryos transferred during IVF cycle.In 2008, among the ART cycles that used fresh non-donor eggs or frozen-thawed embryos and progressed to the embryo transfer stage, approximately 38% involved the transfer of three or more embryos, about 13% of cycles involved the transfer of four or more embryos, and approximately 4% of cycles involved the transfer of five or more embryos.In addition, ART conceived pregnancies have a higher rate of zygotic splitting in cycles were a single embryo was transferred resulting in increased rate of monochorionic twins than spontaneously conceived pregnancies (Blickstein, Jones et al., 2003;Blickstein, Verhoeven et al., 1999).Among the 38,631 pregnancies that resulted from ART cycles using fresh nondonor eggs or embryos, approximately 61% were singleton, 29% were twins, and about 4% were triplets or more.Approximately 32% of the pregnancies ending in live births produced more than one infant (30% twins and approximately 2% triplets or more).This compares with a multiple-infant birth rate of slightly more than 3% in the general U.S. population Figure 5.The proportions of multiple birth in Europe is lower than in the USA, and is declining in the recent years.Indeed, the proportion of singleton, twin and triplet deliveries after IVF and ICSI combined was 79.2, 19.9 and 0.9%, respectively.This gives a total multiple delivery rates of 20.8% compared with 21.8% in 2005 and 22.7% in 2004 (ESHRE, 2006).In an effort to reduce the number of higher-order multiple pregnancies, the American society for reproductive medicine (ASRM) and the Society for Assisted Reproductive Technology Data (SART) have developed guidelines for the number of embryos to be transferred in IVF cycle.

5.1.1
What is the effect of the mode of conception on the risk for preterm birth in twin gestations?Twin and higher order of multiple gestation are at increased risk to deliver preterm.Nevertheless, the effect of mode of conception on the prematurity rate in twin pregnancies is under continues debate.

Are singleton ART pregnancies at increased risk for preterm birth?
One of the major questions regarding the association between ART and preterm birth was whether this effect is mainly due to the increase in the rate of multiple pregnancies or is it relevant also for singleton gestations ( ). 5) Singletons conceived through the use of IVF are twice as likely to be born preterm and die within 1 week of birth as those not conceived through IVF and 2.7 times more likely to have a low birth weight (Hampton, 2004).6) A meta-analysis that compiled information from 12,283 singleton births resulting from IVF pregnancies and 1.9 million spontaneously conceived singleton births noted a twofold increase in the risk of preterm delivery (Jackson et al., 2004).7) According to the CDC report among the infants conceived through the use of ART, singletons that resulted from fetal reduction (either spontaneous or medically) had a higher rate of preterm birth (19%) than those who started as a singleton gestation (12%) (Figure 7).

What are the possible mechanisms associated with the increased risk for preterm birth in ART pregnancies?
The mechanisms in which assisted reproduction technologies increases the risk for preterm birth are still under investigation.Aside the contribution of ART to the increase number of multiple gestations (especially twins) that increases the risk for preterm delivery; the mechanisms leading to preterm delivery in singleton gestation conceived by ART have not been thoroughly investigated yet.Preliminary evidence suggests that underlying maternal conditions that may lead to infertility including insulin resistance and inflammation may contribute to this observation.

Preterm parturition as a syndrome
The implicit paradigm that has governed much of the study of preterm parturition is that term and preterm labor are fundamentally the same process except for the gestational age at which they occur (

Utero-placenta ischemia
Abnormal placentation and vascular lesions in the fetal and maternal sides of the placenta are the second most prevalent lesions observed in patients who deliver preterm (Arias, Rodriquez et al., 1993).Several possible mechanisms can lead to such findings including vaginal and decidual bleeding, spontaneous or iatrogenic death of intrauterine sibling, and uterine vascular changes such as atherosclerosis that are more prevalent in older parturient.
First trimester bleeding among patients with singleton gestation who conceived by ART was associated with an increased risk for: Among the 59 premenopausal women, 55.9% had intimal thickening, 40.7% had simple plaques and 3.7% had complex lesions in the uterine artery samples.Among postmenopausal women, 40% had intimal fibrosis, 20% had simple plaques, and 40% had complex lesions.Postmenopausal status was correlated strongly with the presence of advanced atherosclerotic disease (P < 0.001).Postmenopausal women had significantly greater intimal area (P = 0.01), intimal area/medial area (P = 0.002), intimal area/vessel area (P =0.002), maximal intimal thickness/medial thickness (P = 0.01), and significantly less medial thickness (P <0.001).A significant linear correlation existed between age and the intimal/medial ratio among premenopausal women (P = 0.04) and postmenopausal women (P = 0.01).Patients with electrocardiogram (ECG) abnormalities had significantly greater intimal/medial area as well (P = 0.02).Hypertension was associated with complex lesions among the postmenopausal patients (P = 0.01).Preoperative cholesterol levels greater than 200 mg/dL were associated with greater intimal thickness (P = 0.05) and intimal thickness/medial thickness (P = 0.03) (Crawford, Davis et al., 1997).Moreover, Naeye et al (Naeye, 1983) reported that sclerotic lesions in the myometrial arteries are a possible cause of underperfusion because the proportion of arteries with these lesions increased from 11% at age 17 to 19 years to 83% after the age of 36.This finding is in accord with the report that uterine artery PI during pregnancy increases with maternal age (Pirhonen, Bergersen et al., 2005).These observations are supported also by the clinical findings including an increased rate of SGA neonates among patients with preterm labor and intact membranes as well as those with preterm PROM, and the higher prevalence of low birthweight in ART pregnancies.Decidual bleeding is thought to play a role in the pathogenesis of preterm labor and preterm PROM leading to preterm birth.Indeed, hemosiderin deposition, that are regarded as a marker for bleeding are found in the decidua and retro-chorionic hematoma formation is present in 37.5% of patients who deliver preterm after PROM between 22 and 32 weeks of gestation, and 36% of patients with preterm delivery and intact membranes (Salafia, Lopez-Zeno et al., 1995).In contrast these lesions are found only in 0.8% of placentas of those who deliver at term.
The effect of decidual bleeding on the activation of premature uterine contractions and/or rupture of membranes is thought to be mediated by thrombin (Lockwood, Krikun et , 2007).Evidence in support of the increase activation of the coagulation cascade among patients with preterm labor and intact membranes as well as women with preterm PROM include: 1) women with spontaneous preterm labor without intra-amniotic infection or inflammation and women with vaginal bleeding who delivered preterm, have a lower median maternal plasma protein Z (a co factor of protein Z dependent protease inhibitor that inhibits the activity of factor X) than that of normal pregnant women (Kusanovic, Espinoza et al., 2007); 2) regardless to the presence of intra-amniotic infection/inflammation, women with preterm labor and intact membranes have a higher median tissue factor activity and a lower median tissue factor pathway inhibitor than those with a normal pregnancy 3) patients with preterm PROM have a higher median maternal plasma tissue factor concentration and a lower median TFPI concentrations than normal pregnant women (Erez, Espinoza et al., 2008); 4) patients with PTL as well as those with preterm PROM have a higher median maternal plasma thrombin-antithrombin III concentration than that of women with a normal pregnancy (Chaiworapongsa, Espinoza et al., 2002;Elovitz, Baron et al., 2001;Rosen, Kuczynski et al., 2001); and 5) maternal plasma thrombin-antithrombin III complex concentration in the mid trimester were lower in patients about to deliver preterm than in those who subsequently delivered at term (Hackney, Catov et al., 2010).Moreover, increased thrombin generation was detected not only in the maternal circulation but also in the amniotic fluid (Erez,Romero,et al.,2009).Women with preterm labor who delivered preterm had a higher median thrombin anti-thrombin III concentration than those who delivered at term (Erez, Romer et al., 2009).This was particularly evident among those without intra-amniotic infection/inflammation, in which elevated amniotic fluid of thrombin anti-thrombin complex concentrations were associated with a shorter amniocentesis to delivery interval and a lower gestational age at delivery than those with normal or low concentrations of this complex (Erez,Romero,et al.,2009).A vanishing twin can be an additional possible source for increase intrauterine thrombin generation that may lead to preterm birth.Indeed, vanishing twins among women who conceived by IVF/ICSI was associated with a higher rate of preterm birth <37 and <32 weeks of gestation, especially in the vanishing of the twin occur in later stages of gestation (Pinborg, Lidegaard et al., 2005).A possible explanation for this observation is the report that intrauterine fetal demise is associated with an increased intra-amniotic thrombin generation (Erez, Gotsch et al., 2009).This may be the case also in patients with a vanishing twin, meaning, the increased thrombin generation associated with the dissolving of the dead twin increases the risk for preterm delivery of the surviving fetus.Thrombin can activate preterm parturition through several mechanisms: 1) it has a uterotonic activity, indeed, the administration of a whole blood into a non-pregnant uterus generated uterine contractions that were not evident when saline or heparinzed blood were introduced into the uterine cavity (Elovitz, Saunders et al., 2000;Elovitz, Baron et al., 2001); 2) thrombin and activated coagulation factor X can induce pro inflammatory cytokines production (IL-6 and IL-1) that may leads to prostaglandins generation and premature myometrial activation and contractions (Lockwood, Toti et al., 2005); and 3) thrombin activates matrix degrading enzymes such as matrix metalloproteneinases (MMPs) 1, 3 and 9 that can degrade the chorioamniotic membranes leading to rupture of membranes (Rosen, Schatz et al., 2002;Stephenson, Lockwood et al., 2005).

Uterine over-distention
Women with a multiple pregnancy are at increased risk for spontaneous preterm labor and preterm birth.Intra-amniotic pressure remains relatively constant throughout gestation despite the growth of the fetus and placenta.This has been attributed to progressive myometrial relaxation due to the effects of progesterone and endogenous myometrial relaxants such as nitric oxide (  (Kanayama and Fukamizu, 1989).Recent studies using an in vitro cell culture model for fetal membrane distension revealed upregulation of IL-8 and pre-B-cell colony-enhancing factor (Nemeth, Tashima et al., 2000).When fetal membrane explants were distended in an in vitro distension device to mimic the situation in vivo, and the gene expressions of distended explants were compared with that of nondistended explants, three genes, namely IL enhancer binding factor 2, huntingtininteracting protein 2, and interferon-stimulated gene encoding a 54 kDa protein, were found to be upregulated (Nemeth, Millar et al., 2000).Collectively, these observations suggest that mechanical forces associated with uterine overdistension may result in activation of mechanisms leading to membrane rupture.

Insulin resistance
The association between infertility and maternal insulin resistance is well documented and polycystic ovary disease is its classical feature (Lobo, 1995;Barbieri, 1992

Endocrine effect of ART
The controlled ovarian hyperstimulation during ART cycles has endocrine implication that may contribute to the increasing rate of preterm birth in these patients.Human Chorionic Gonadotropin (hCG) induces the secretion of relaxin by the corpus luteum (Kristiansson, Svardsudd et al., 1996;Weiss, Goldsmith et al., 1993).Due to the ovarian hyperstimulation during ART cycle the maternal luteal mass is more prominent than that observed during spontaneously conceived pregnancies resulting in the significant increase in relaxin secretion in response to hCG, and indeed, pregnancies following ART were associated with hyper relaxinemia (Kristiansson, Svardsudd et al., 1996;Weiss, Goldsmith et al., 1993).Higher maternal relaxin concentrations were found to be significantly associated with preterm birth (Iams, Goldsmith et al., 2001;Vogel, Salvig et al., 2001;Vogel, Glavind-Kristensen et al., 2002).Relaxin acts by promoting collagenolysis through inducing the activity of matrixmetaloproteinase (MMP) 1-3 and inhibiting tissue inhibitor of metalloprotease-1 (TIMP-1) (Palejwala, Stein et al., 2001); the net effect is remodeling and ripening of the uterine cervix and increased uterotonic activity.Progesterone can counter act relaxin activity by inducing an anti-inflammatory response and decrease the MMP concentrations and uterine contractility (Palejwala, Stein et al., 2001).

Prevention of preterm birth
The prevention of preterm birth is one of the major objectives of modern obstetrics.In the US there is an initiative to reduce the rate of preterm birth to 6.1% by 2010, and the March of Dimes has made this topic its main field of interest.In spite of all efforts, at present there is www.intechopen.comno specific treatment for spontaneous preterm birth and this is attributed to the syndromic nature of preterm delivery that cannot be resolved by a single medication or intervention.Currently there is wide agreement regarding the beneficial effect of two treatments: (1) the administration of corticosteroids for patients at risk for preterm birth to reduced acute neonatal morbidity; and (2) prophylactic antibiotic treatment for patients with preterm PROM that has occurred from 24 to 32 weeks of gestation (Mercer, Miodovnik et al., 1997;Kenyon, Taylor et al., 2001) but not for preterm labor with intact membranes (Kenyon, Brocklehurst et al., 2008).This treatment has been proven to prolong pregnancy and reduce the rate of acute neonatal morbidity in patients with preterm PROM (Kenyon, Brocklehurst et al., 2008).However, the results of the follow up of children after 7 years were as follows: (1) In children who were born after preterm PROM, neither antibiotic regime was associated with a significant effect on the overall level of behavioral, medical status and academics achievements (Kenyon, Pike et al., 2008).( 2) In contrast, prophylactic antibiotic treatment of patients with preterm labor had a negative effect on the children's outcome at the age of 7.
Treatment with erythromycin was associated with increased functional impairment of children of mother with preterm labor and intact membranes (Kenyon, Pike et al., 2008).The more worrisome outcome was the higher rate of cerebral palsy among children whose mothers were treated with erythromycin (OR 1.93, 95% CI 1.21-3.09)as well as in those treated with co-amoxicalve (OR 1.69, 95% CI 1.07-2.67)(Kenyon, Pike et al., 2008).Thus, prophylactic antibiotic treatment should not be administrated to patients and preterm labor with intact membranes.Yet, these treatments are targeted to reduce the rate of complications rather than to prevent the "disease".In the recent years, attempts to prevent spontaneous preterm birth are mainly by two approaches: (1) the administration of progesterone to patients with a history of preterm birth or with a short sonographic cervix; and (2) placement of a cerclage for cervical os insufficiency.

Progesterone for the prevention of preterm birth
Progestogens administration for the prevention of recurrent abortion or preterm birth has been a subject of The frequency of NICU admission was lower in women with a cervical length of ≤30 mm and <28 mm and who had received progesterone treatment than in those allocated to placebo.The same was the case for the duration of NICU length of stay (Defranco, O'Brien et al., 2007).However, these conclusions must be considered tentative because they derive from a secondary analysis which is intended to be hypothesis-generating.
In contrast to the results in singleton gestations, the administration of progesterone for the prevention of preterm birth in twin gestation had no beneficial effect.Hartikainen-Sorri et al (Hartikainen-Sorri, Kauppila et al., 1980) more than twenty-five years ago, and recently Rouse et al (Rouse, Caritis et al., 2007) reported the results of a multicenter, placebocontrolled, double-blind, randomized clinical trials of 17-OHPC for prevention of preterm birth in twin pregnancies.Both studies concluded that there was no beneficial effect of 17-OHPC administration for the prevention of preterm birth in twin gestation.

The role of cervical cerclage in the prevention of preterm birth
Keeping with the view that cervical insufficiency is a mechanical disorder of the cervix, placement of a cervical stitch (cerclage) has been proposed as a treatment for this disorder.The clinical value of cervical cerclage has been subject of many observational and randomized clinical trials (To, Palaniappan et al., 2002;1993 However, a recent randomize clinical trial conducted by the NICHD MFM network among patients with a prior preterm birth <34 weeks of gestation.Patients with a cervical length <25 mm randomly assigned to cerclage reported a beneficial effect of cerclage (Owen, Hankins et al., 2009).This benefit was highly concentrated in women with very short cervical length (<15 mm) (Owen, Hankins et al., 2009).(3) Among patients at risk for preterm delivery, serial sonographic examinations of the cervix followed by cerclage in those who shortened the cervix is a reasonable alternative to prophylactic placement of cerclage based upon uncontrolled studies (Guzman, Forster et al., 1998

The role of progesterone in primary prevention of preterm birth
A recent study by Hassan et al (Hassan, Romero et al., 2011)raised for the first time the possibility of primary prevention of preterm delivery.The study included patients with a short cervix (cervical length between 10-20 mm) who were randomized at 19-24 weeks to the administration of daily vaginal progesterone gel vs. placebo, regardless to their obstetrical history.32,091 were screened, of them 733 had a short cervix, and 465 were randomized.Women at the progesterone group had a significant reduction in the rate of preterm birth before 33 weeks of gestation and a significant lower rate of neonatal complications in comparison to those in the placebo group (Hassan, Romero et al., 2011).Thus, cervical length is an effective risk assessment tool for the identification of patients at risk for preterm birth and vaginal progesterone gel can prevent preterm delivery in a significant portion of patients with a short cervix.

Summary
Assisted reproduction aids a substantial proportion of women to conceive and deliver, however, these pregnancies are at increased risk for preterm birth.Some of the mechanisms leading to preterm parturition in these patients are inherited from the nature of conception like multiple gestations along with their complications.In addition, especially among singleton gestations, ART are an independent risk factor for preterm delivery and this may result from the underlying mechanisms leading to maternal infertility like infection/inflammation of the genital tract as well as other mechanisms.Thus, women who conceived following ART cycles should be followed and treated as a patient at risk for preterm birth. www.intechopen.com

Preterm Birth -Mother and Child 2
Medicine (US) Committee on Understanding Premature Birth and Assuring HealthyOutcomes, 2007).

Fig. 1 .
Fig. 1.Number of ART cycles performed, live-birth delivery, and infants born used ART, 1999-2008 From Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology.2006 Assisted Reproductive Technology Success Rates: National summary and fertilityNclinic reports.Atlanta: Centers for Disease Control and Prevention,2008.

Fig. 2 .
Fig. 2. Distribution of ART cycles according to the source of the ovum and whether the cycle was fresh or frozen.(CDC 2008, USA).
treatments are a significant contributor to preterm birth among both multiple and singleton pregnancies."(Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007).

Fig. 4 .
Fig. 4. Chances over time in the rate of preterm birth according to gestational age at delivery and the number of fetuses.

Fig. 5 .
Fig. 5. Risk of having multi-frtus pregnancies and multiple infant live birth from ART cycles using fresh non-donor eggs or embryos-US CDC 2008.

Fig. 7 .
Fig. 7. Proportion of preterm birth resulting from ART cycles using fresh non-donor eggs or embryos, by number of infants born-USA, CDC 2008.

age Diabetes per 1,000 live births in specified group Chronic Hypertension per 1,000 live births in specified group
above 40 years of age) in comparison to women younger than 35 years old (Salem, Levy et al., 2011).

4. Pregnancy outcome in patients conceived through assisted reproduction
(Martin, Hamilton et al., 2009)tin, Hamilton et al., 2009;Slattery and Morrison, 2002)cardiovascular disease later in life.(Nardi,Zureiketal., 2006;Smith, Pell et al., 2001)The premature newborn is at risk for acute (i.e.respiratory distress syndrome, necrotizing enterocolitis, and intraventricular hemorrhage) and chronic (i.e.retinopathy of prematurity, cerebral palsy, broncho pulmonary dysplasia) illness, as well as social and behavioral maladjustment later in life.(Moster,Lieetal., 2008)The prevalence of preterm birth varies from 6% to 15% of all deliveries depending on the geographical and demographical characteristics of the population tested.(Romero,Mazoretal., 1994;Martin, Hamilton et al., 2009;Slattery and Morrison, 2002).In Europe the rate of preterm deliveries varies from 5% to 9%(Slattery and Morrison, 2002), while the rate of preterm birth in the United States reached 12.8% by 2006(Martin, Hamilton et al., 2009), 20% higher than in 1990.Of interest, while the rate of early (<34 weeks) preterm birth remained relatively constant (2.9% among singleton and 3.3% to 3.6% among multiple gestations) the rate of late preterm birth (34-37 weeks) increased among singleton by 19.1% (Ananth and Vintzileos, 2006a;Ananth, Getahun et al., 2006)rm birth in the United States exceeded $26.2 billion in 2005 (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007).Preterm birth is associated with short and long term maternal and fetal sequel.The www.intechopen.com(from6.1% to 8.1%) and by 24.7% among all pluralities from 1990 to 2005 (Martin, Hamilton et al., 2007) (Figure 4).Preterm delivery can be either spontaneous or medically induced (indicated) regardless of the gestational age at delivery.Spontaneous preterm birth account for 75% of all preterm deliveries (Meis, Ernest et al., 1987; Meis, Goldenberg et al., 1998; Meis, Michielutte et al., 1995) and can be the end result of three main clinical presentations: 1) preterm labor with intact membranes; 2) preterm prelabor rupture of membranes (preterm PROM); and 3) cervical insufficiency.(McElrath,Hechtetal., 2008) Indicated preterm birth results from medical intervention due to maternal or fetal complications that necessitate medical intervention.(AnanthandVintzileos,2006b;Mazaki-Tovi,Romeroet al., 2007; Meis, Michielutte et al., 1995; Ananth and Vintzileos, 2006a; Ananth, Getahun et al., 2006) Although many studies have focused on the rate of preterm birth, (1999; Joseph, Kramer et al., 1998; Vintzileos,Ananth et al., 2002)an important consideration is whether these deliveries are the result of spontaneous labor or "indicated" preterm deliveries.The need for this distinction is based on the premise that the risk factors for recurrent preterm PROM, preterm labor with intact membranes, preeclampsia, and/or SGA are different.However, recent observations suggest that there may be overlap among these conditions,(Ananth and Vintzileos, 2006a;Ananth, Getahun et al., 2006) so that a patient with an "indicated" preterm birth may also be at risk for spontaneous preterm birth(Ananth and Vintzileos, 2006a;Ananth, Getahun et al., 2006).The converse may also be true (i.e. that a patient with a spontaneous preterm birth is at risk for an "indicated" preterm birth in a subsequent pregnancy).Assisted reproduction technologies are emerging contributors for the increasing rate of preterm birth.The use of infertility treatments has risen dramatically in the past 20 years; between 1996 and 2003, the number of cycles of ART nearly doubled from 64,681 to 122,872 (Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes, 2007 (McDonald, Han et al., 2010) population based cohort study reported that ARTs are an independent risk factor for preterm birth after adjustment to parity, rupture of membranes, severe preeclampsia(Erez, Mayer et al., 2008).In a systematic review and meta-analysis including eleven case-control studies that involved 2303 IVF twins and 2326 spontaneously conceived twins, as well as, three cohort studies that involved at least 1509 IVF twins IVF twins have an increase risk for PTB from 32 to 36 weeks of gestation compared with spontaneously conceived twins who were matched for maternal age (OR, 1.48; 95% CI, 1.05-2.10).The OR for PTB at< 37 weeks of gestation in studies that also matched for parity was similar and approached statistical significance at a 5% level of significance (OR, 1.47; 95% CI, 1.01-2.44).The origin of the increase in PTB has yet to be determined(McDonald, Han et al., 2010).Collectively these studies suggest that in comparison to spontaneously conceived twin gestations, twin pregnancies that result from ART are at increased for preterm birth especially between 32-36 weeks of gestation.
(McDonald, Brocklehurst et al., 2007), Morency et al., 2008)olph, Reinicke et al., 1993)et al., 1998;Hassan, Romero et al., 2000)on is defined as the anatomical, physiological, biochemical, endocrinological, immunological, and clinical events that occur in the mother and/or fetus in both term and preterm labor.The fundamental difference between term and preterm parturition is that the former results from physiological activation of the common pathway, while preterm labor arises from pathological processes that extemporaneously activate one or more of the components of the common pathway of parturition.Preterm labor (PTL) is the clinical presentation of different underlying mechanisms,(Romero, Espinoza et al., 2004c)including: intrauterine infection,(Romero, Sirtori et al., 1989;Romero, Mazor et al., 1988b;Minkoff, 1983; Goncalves, Chaiworapongsa et al., 2002)uteroplacental ischemia,(Romero, Sepulveda et al., 1993;Combs, Katz et al., 1993;Arias, 1990;Arias, Rodriquez et al., 1993)uterine over-distention,(Hill, Breckle et al., 1987;Phelan, Park et al., 1990;Besinger and Carlson, 1995)cervical disease,(Romero, Mazor et al., 1993;Romero, Espinoza et al., 2006a;Romero, 1996;Heath, Southall et al., 1998;Hassan, Romero et al., 2000)abnormal allograft reaction,(Romero, Sepulveda et al., 1993)allergic phenomena,(Holloway, Warner et al., 2000;Jones, Miles et al., 1996;Rudolph, Reinicke et al., 1993)and endocrine disorders.(Belt,Baldassareetal., 1999;Allport, Pieber et al., 2001)The current taxonomy of disease in obstetrics is based on the clinical presentation of the mother and not on the mechanism of disease responsible for the clinical manifestations.The term 'preterm labor' does not indicate whether the condition is caused by infection, a vascular insult, uterine overdistension, an abnormal allogeneic recognition, stress, or some other pathological process.The same applies to pre-eclampsia, intrauterine growth restriction, fetal death, recurrent abortions, as well as, nausea and vomiting during pregnancy, and failure to progress in labor, in which the diagnoses simply describe the clinical manifestations without consideration of the specific etiology.The lack of recognition that these conditions simply represent a collection of signs and symptoms with little reference to the underlying mechanisms of disease may be responsible for the expectation that one diagnostic test and treatment will detect and cure each of these conditions.This has implications for the fundamental understanding of the biology of preterm parturition and the clinical strategies to diagnose, treat, and prevent spontaneous preterm labour(Romero, Espinoza et al., 2004a; Romero, Espinoza et al., 2006b).McKay and Wong, 1963; Rieder and Thomas, 1960; Romero, Munoz et al., 1994; Skarnes and Harper, 1972; Takeda and Tsuchiya I., 1953; Zahl and Bjerknes, 1943; Gomez, Ghezzi et al., 1995; Romero, Sirtori et al., 1989; Goncalves, Chaiworapongsa et al., 2002) Microbiological and histo-pathological studies suggest that infection-related inflammation may account for 25 to 40% of cases of preterm deliveries.Goncalves et al(Goncalves, Chaiworapongsa et al., 2002)studied the rate of positive amniotic fluid cultures for microorganisms in women with preterm labor and intact membranes.The authors reviewed the results of amniotic fluid cultures from 33 studies and the prevalence of microbial invasion of amniotic fluid among patients with preterm labor was 12.8%(Goncalves, Chaiworapongsa et al., 2002; Romero, Espinoza et al., 2002), and about 50% of them were polymicrobial.The rate of microbial invasion of the amniotic cavity in patients with preterm labor and intact membrane is gestational age dependant.It is as high as 45% at 23-26 weeks and decreases to 11.5% at 31-34 weeks of gestation(Watts, Krohn et al., 1992).Thus, the earlier the gestational age at preterm birth, the more likely that microbial invasion of the amniotic cavity is present(Watts, Krohn et al., 1992).In preterm PROM, the prevalence of a positive amniotic fluid culture for microorganisms is approximately 32.4%.(Goncalves,Chaiworapongsaetal., 2002; Romero, Espinoza et al.,  2002)However, when amniocenteses were performed at the time of the onset of labor, 75% of patients had microbial invasion of the amniotic cavity(Romero, Quintero et al., 1988), suggesting that some patients are already infected prior to the clinical rupture of membranes, while others are infected after the membrane have ruptured.Therate of microbial invasion of amniotic cavity among women presenting with a cervical insufficiency in the mid-trimester is around 33% (range 13%-52%)(Romero, Gonzalez et al., 1992;Bujold, Morency et al., 2008)and 45% to 51% in the early third trimester(Bujold, Morency et al., 2008).In addition, a recent study has demonstrated that while only 8% of patients with cervical insufficiency had a positive amniotic fluid culture, 80% have intra-amniotic ET, either because of failure of implantation or the induction of sub clinical spontaneous abortion(Romero, Espinoza et al., 2004b).Endotoxin is a component of the cell wall of Gram negative bacteria and its detection in biological fluid is evidence of microbial invasion of a sterile compartment such as the amniotic cavity.An increased concentration in non-sterile body fluids such as cervical mucus or vaginal fluid is an indication of enlarged Grannegative microbial population and has been reported in women with bacterial vaginosis(Romero, Espinoza et al., 2004b).Adler et al., 2003)of 18 studies (20,232 patients) concluded that bacterial vaginosis was associated with an increased risk for preterm delivery < 37 weeks of gestation (OR 2.19, 95%CI 1.54-3.12),andthiseffect was significant among singleton gestations, as well as among low and high risk pregnancies for preterm delivery.before20weeks of gestation may reduce the risk for preterm delivery < 37 weeks (OR 0.72 95%CI 0.55-0.95)(McDonald,Brocklehurstet al., 2007).In conclusion, treatment of bacterial vaginosis before 20 weeks of gestation in patients with a history of previous preterm birth, may reduce the risk for preterm PROM and low birthweight.
al.,  2007;Lockwood, Paidas et al., 2009).The decidua is reach with tissue factor the most potent activator of the coagulation cascade.Thus, any minor decidual bleeding activates the coagulation cascade leading to the generation of thrombin thrombin(Stephenson,  Lockwood etal.,2005;Lockwood, Toti et al., 2005; Sarno, Schatz et al., 2006; Lockwood, Krikun et al. (Millar, Stollberg et al., 2000)ard-Sadler et al., 2002)al., 1997) induce increased myometrial contractility(Laudanski and Rocki, 1975), prostaglandin release(Kloeck and Jung, 1973), expression of gap junction protein or connexin-43(Ou, Orsino et al., 1997), and increased oxytocin receptor in pregnant and nonpregnant myometrium(Ou, Chen et al., 1998).The stretch-induced contraction-associated protein gene expression during pregnancy is inhibited by progesterone(Ou, Orsino et al., 1997).The effect of stretch increases in late gestation and is maximal during labor as a consequence of the relative reduction in uterine growth compared with fetal growth and of the declining circulating and/or local concentrations of progesterone(Ticconi and Lye, 2002;Chow and Lye, 1994;Ou, Orsino et al., 1997).The nature of force/pressure-sensing mechanisms of the myometrium has yet to be determined.A role for integrins and their ligands has been proposed for other organs(Shyy and Chien, 2002;Lee, Millward-Sadler et al., 2002).Stretch may not only induce increased myometrial contractility but may also modify the contractile response through 'mechanoelectrical feedback' similar to the one reported in the heart.The chorioamniotic membranes are distended by 40% at 25-29 weeks of gestation, 60% at 30-34 weeks of gestation, and 70% at term(Millar, Stollberg et al., 2000).Stretching of the membranes in vitro induces histological changes characterized by elongation of the amnion cells and increased production of collagenase activity and IL-8(Maradny, Kanayama et al.,  1996; Maehara, Kanayama et al., 1996), while stretching of amnion cells in culture results in increased production of prostaglandin E2 (Li and Xu, 2000;Hu, Bock et al., 1998) et al., 1999)ptors(Tzima, del Pozo et al., 2001), stretch-activated calcium channels(Holm, Rich et al., 2000;Farrugia, Holm et al., 1999), phosphorylation of platelet-derived growth factor receptor(Hu, Bock et al., 1998)and activation of G proteins(Li and Xu, 2000;Hu, Bock et al., 1998).Once mechanical force is sensed, it leads to activation of protein kinase C and mitogen-activated protein kinases, increased gene expression of c-fos and c-jun, and enhanced binding activity of transcription factor activator protein-1(Shynlova, Oldenhof etal., 2002; Oldenhof, Shynlova et al., 2002; Mitchell and Lye, 2002; Mitchell and Lye, 2001; Piersanti and Lye, 1995; Lefebvre, Piersanti et al., 1995).Other effects of physical forces relevant to myometrium include increased expression of prostaglandin H synthase 2 (Wu, Ma et al., 1999), superoxide dismutase, and nitric oxide synthase.
(Iams, Goldenberg et al., 1996;Iams, Goldenberg et al., 2001;Iams, Johnson et al., 1995)S, 1952;Check, Chase et al., 1987;Tognoni, Ferrario et al., 1980;Gerhard, Gwinner et al., 1987;Johnson, Austin et al., 1975;Hauth, Gilstrap, III et al., 1983;Yemini, Borenstein et al., 1985;Hartikainen-Sorri, Kauppila et al., 1980;Breart, Lanfranchi et al., 1979)et al., 1979)and meta-analyses(Daya, 1989;Goldstein, Berrier et al., 1989;Keirse, 1990)or several decades.However, progesterone gained a wide acceptance as a valid treatment for the prevention of preterm birth (2003) only after the publication of the studies by da Fonseca (daFonseca, Bittar et al., 2003)and the NICHD MFMU(Meis, Klebanoff et al., 2003)who investigated its efficacy in the prevention of preterm birth in women with a history of preterm delivery.The rate of preterm delivery <37 weeks and <34 weeks was lower in the progesterone group than in the placebo group (<37 weeks, progesterone: 13.8% vs. placebo: 28.5%, p=0.03; and < 34 weeks, progesterone: 2.8% vs. 18.6%, p=0.002) (daFonseca, Bittar et al., 2003).The authors concluded that prophylactic vaginal progesterone appeared to reduce the rate of preterm delivery in women at high risk for preterm birth (daFonseca, Bittar et al., 2003).The NICHD-MFMU network(Meis, Klebanoff et al., 2003)reported the results of a multicenter double-blind, placebo-controlled clinical trial testing whether 17-hydroxy progesterone caproate (OHPC) administration can reduce the rate of preterm delivery in patients with a history of spontaneous preterm birth.The patients were enrolled at 16 to 20 weeks of gestation and randomly assigned in a 2:1 ratio to receive either a weekly injection of 250 mg of 17-OHPC or a weekly injection of placebo until delivery or 36 weeks of gestation.Treatment with 17-OHPC significantly reduced the rate of preterm delivery at less than 37 weeks, less than 35 weeks, and less than 32 weeks of gestation (<37 weeks, RR 0.66; 95% CI 0.54-0.81;<35weeks,RR0.67;95%CI0.48-0.93;and<32weeks,RR0.58; 95% CI 0.37-0.91].Moreover, neonates born to women treated with 17-OHPC had significantly lower rates of NEC, IVH and need for supplemental oxygen(Meis, Klebanoff et al., 2003).Thus, among women at high risk for preterm delivery, a weekly injection of 17-OHPC resulted in a reduction in the rate of recurrent preterm birth and several neonatal complications(Meis, Klebanoff et al., 2003).The beneficial effect of 17-OHPC and vaginal progesterone in the reduction of preterm birth and of 17-OHPC in the reduction of the rate of neonates with low birth weight were further supported by systematic reviews meta-analyses and a Cochrane 2007) reported the results of a multinational, randomized, doubleblind, placebo-controlled trial of progesterone vaginal gel administration to patients with a history of spontaneous preterm birth between 20 to 35 weeks of gestation.Women were randomized, between 18 to 22 completed weeks of gestation, to receive daily treatment of progesterone vaginal polycarbophil-based gel (Crinone ® , 8%, 90 mg) or placebo (Replens ® ) that were self-administered either until delivery, 37 weeks of gestation, or the occurrence of PROM.Vaginal progesterone did not reduce the rate of preterm birth at ≤32, ≤35, or ≤37 weeks of gestation.Moreover, there were no differences in the neonatal and maternal outcomes (O'Brien,Adair et al., 2007).The beneficial effect of progesterone in patients with a sonographic short cervix has been recently reported(Facchinetti, Paganelli et al., 2007).A randomized prospective clinical trial(Facchinetti, Paganelli et al., 2007)in which women with preterm labor and intact membranes (25 to 33 6/7 weeks) were allocated to either observation or IM administration of 341 mg of 17-OHPC twice a week until 36 weeks of gestation or delivery was performed.Patients allocated to receive 17-OHPC had a longer sonographic cervical length than those in the observation group(Facchinetti, Paganelli et al., 2007); suggesting that progesterone may have major effects on the uterine cervix.Fonseca et al.(Fonseca, Celik et al., 2007)reported the results of a randomized clinical trial evaluating the efficacy of vaginal progesterone in reducing the rate of preterm birth in women with a sonographic short cervix (≤15 mm by transvaginal ultrasound between 20 to 25 weeks of gestation).Women were allocated to daily vaginal administration of 200 mg of micronized progesterone or placebo (safflower oil) from 24 to 34 weeks.The frequency of spontaneous preterm delivery <34 weeks was significantly lower in the progesterone group than that in patients allocated to placebo (19.2% vs. 34.4%;p=0.007)(Fonseca,Celiketal., 2007).A secondary analysis of this trial indicated that among women without a history of delivery <34 weeks, the incidence of preterm birth was significantly lower in women receiving progesterone than in those allocated to placebo (RR 0.57, 95% CI 0.35-0.93)suggestingthatprogesteronemaybebeneficial to patients with a sonographic short cervix even without a history of preterm birth(Fonseca, Celik et al., 2007).The secondary retrospective analysis(Defranco, O'Brien et al., 2007)of the study by O'Brien et al(O'Brien, Adair et al., 2007).supports the findings of Fonseca et al(Fonseca, Celik et al., 2007)that patients with a short cervix may benefit from vaginal progesterone administration.However, the authors(Defranco, O'Brien et al., 2007)reported that vaginal progesterone gel may have a beneficial effect in reducing preterm delivery <32 weeks of gestation at a sonographic cervical length of <28 mm(Defranco, O'Brien et al., 2007).These findings imply that the cutoff of 15 mm may be too stringent and progesterone may also work in women with a longer cervix.As the frequency of a cervix of ≤15 mm is 1.7% but that of <28 mm is about 10%(Iams, Goldenberg et al., 1996;Iams, Goldenberg et al., 2001;Iams, Johnson et al., 1995), this could expand the therapeutic range of progesterone.The study of De Franco et al(Defranco, O'Brien et al., 2007)provides the first hint that vaginal progesterone administration may improve infant outcome in properly selected patients.