Obstetrics

Levetiracetam monotherapy appears to be an effective strategy for controlling seizures in pregnancy, results from a large Australian study demonstrated.

In fact, levetiracetam provided seizure control comparable with that of older antiepileptic drugs (AEDs) carbamazepine and valproate but superior when compared with other newer AEDs, including lamotrigine and topiramate. The findings suggest that levetiracetam can be considered "among the agents of first choice in women contemplating pregnancy, and to be suitable for use in most circumstances in women who have the potential for pregnancy, unless the type of seizure disorder present, or other consideration, makes a different agent clinically preferable," wrote Dr. Frank J. E. Vajda of the department of medicine at the University of Melbourne and his associates (Epilepsia 2014 July 3 [doi:10.1111/epi.12711]).

Using a national registry, the researchers analyzed data regarding seizure control in 1,111 pregnancies that began between the middle of 1998 and November of 2013, during which the patients took only one AED for at least the first trimester. The seizure occurrence rates for patients on levetiracetam monotherapy were 31.7% for any seizure and 13.4% for convulsive seizures, which were similar to the rates of all older AEDs combined (34.8% and 18.9%, respectively). Compared with levetiracetam, however, the rate of seizure-affected pregnancy was about 50% and 30% higher among patients on lamotrigine and topiramate, respectively.

The authors acknowledged certain limitations of the study, including the fact that the allocation of particular AEDs "was not randomized, and there can be no guarantee that the drugs were always taken as prescribed or necessarily employed optimally, guided by plasma AED concentration monitoring when that was available."

The researchers stated that they had no relevant financial conflicts.

dbrunk@frontlinemedcom.com

Levetiracetam monotherapy appears to be an effective strategy for controlling seizures in pregnancy, results from a large Australian study demonstrated.

In fact, levetiracetam provided seizure control comparable with that of older antiepileptic drugs (AEDs) carbamazepine and valproate but superior when compared with other newer AEDs, including lamotrigine and topiramate. The findings suggest that levetiracetam can be considered "among the agents of first choice in women contemplating pregnancy, and to be suitable for use in most circumstances in women who have the potential for pregnancy, unless the type of seizure disorder present, or other consideration, makes a different agent clinically preferable," wrote Dr. Frank J. E. Vajda of the department of medicine at the University of Melbourne and his associates (Epilepsia 2014 July 3 [doi:10.1111/epi.12711]).

Using a national registry, the researchers analyzed data regarding seizure control in 1,111 pregnancies that began between the middle of 1998 and November of 2013, during which the patients took only one AED for at least the first trimester. The seizure occurrence rates for patients on levetiracetam monotherapy were 31.7% for any seizure and 13.4% for convulsive seizures, which were similar to the rates of all older AEDs combined (34.8% and 18.9%, respectively). Compared with levetiracetam, however, the rate of seizure-affected pregnancy was about 50% and 30% higher among patients on lamotrigine and topiramate, respectively.

The authors acknowledged certain limitations of the study, including the fact that the allocation of particular AEDs "was not randomized, and there can be no guarantee that the drugs were always taken as prescribed or necessarily employed optimally, guided by plasma AED concentration monitoring when that was available."

The researchers stated that they had no relevant financial conflicts.

dbrunk@frontlinemedcom.com

Levetiracetam monotherapy appears to be an effective strategy for controlling seizures in pregnancy, results from a large Australian study demonstrated.

In fact, levetiracetam provided seizure control comparable with that of older antiepileptic drugs (AEDs) carbamazepine and valproate but superior when compared with other newer AEDs, including lamotrigine and topiramate. The findings suggest that levetiracetam can be considered "among the agents of first choice in women contemplating pregnancy, and to be suitable for use in most circumstances in women who have the potential for pregnancy, unless the type of seizure disorder present, or other consideration, makes a different agent clinically preferable," wrote Dr. Frank J. E. Vajda of the department of medicine at the University of Melbourne and his associates (Epilepsia 2014 July 3 [doi:10.1111/epi.12711]).

Using a national registry, the researchers analyzed data regarding seizure control in 1,111 pregnancies that began between the middle of 1998 and November of 2013, during which the patients took only one AED for at least the first trimester. The seizure occurrence rates for patients on levetiracetam monotherapy were 31.7% for any seizure and 13.4% for convulsive seizures, which were similar to the rates of all older AEDs combined (34.8% and 18.9%, respectively). Compared with levetiracetam, however, the rate of seizure-affected pregnancy was about 50% and 30% higher among patients on lamotrigine and topiramate, respectively.

The authors acknowledged certain limitations of the study, including the fact that the allocation of particular AEDs "was not randomized, and there can be no guarantee that the drugs were always taken as prescribed or necessarily employed optimally, guided by plasma AED concentration monitoring when that was available."

The researchers stated that they had no relevant financial conflicts.

dbrunk@frontlinemedcom.com

MUNICH – Women pregnant with an embryo produced by in vitro fertilization of a donated egg developed gestational hypertension at nearly four times the rate of matched women who were pregnant following IVF with a self egg, in a multicenter, case-control study with 580 participants.

In addition, preeclampsia was more than four times higher in the women who had received a donor egg as part of an IVF procedure, compared with women who used a self egg for their IVF, Dr. Hélène Letur-Könirsch reported at the annual meeting of the European Society of Human Reproduction and Embryology.

Mitchel L. Zoler/Frontline Medical News

Although the mechanism underlying this association is not known, one possible explanation is that when a woman carries an embryo that is completely allogenic, it triggers modified immune tolerance that leads to impaired trophoblast implantation. Other candidate hypotheses are that defective genes in the mother trigger abnormal metabolic pathways that cause hypertension and preeclampsia, and that ovarian insufficiency features reduced ovarian steroid production, causing vascular and immunologic changes that lead to pregnancy-induced hypertension.

Results from several prior studies also had shown a link between use of a donor egg for IVF and an increased rate of gestational hypertension and preeclampsia, but most prior studies had been smaller and failed to adequately control for possible confounders, said Dr. Letur-Könirsch, an endocrinologist at the Fertility Center of the Institut Mutualiste Montsouris in Paris.

She and her associates from seven IVF centers in France pooled data from their entire series of IVF cases that involved donated eggs during the period from February 2005 to September 2012, a total of 217 pregnant women. The analysis matched these cases with 363 control women who had IVF pregnancies during the study period using self eggs by parameters such as age, parity, time of pregnancy, and whether the IVF procedure involved transfer of a fresh or frozen embryo.

Women in the study averaged 35 years of age, with 82% aged 39 years or younger. Average body mass index was virtually identical in both groups, about 24 kg/m², and the live-birth rate was 79% in both groups. All women in both groups were normotensive prior to their IVF procedure.

The incidence of pregnancy-induced hypertension, defined as blood pressure that reached at least 140/90 mm Hg when measured in office on both arms with two separate measurements, was about 29% in the women who received a donated egg and 14% in those who used a self egg. Development of preeclampsia, defined as persistent gestational hypertension plus proteinuria of at least 0.3 g/day, occurred in about 18% of women who received a donated egg and 7% in those who used a self egg.

In a multivariate analysis that controlled for age, pregnancy history, and use of a fresh or frozen embryo, women who used a donated egg had a 3.9-fold increased rate of pregnancy-induced hypertension and a 4.6-fold increased rate of preeclampsia, compared with women who used a self egg – both statistically significant differences.

The findings suggested that before a woman embarks on pregnancy using a donated egg, she should undergo thorough evaluation for preexisting risk factors for gestational hypertension, including hypertension, obesity, diabetes, renal disease, chronic infection, autoimmune diseases such as systemic lupus erythematosus, a family history of preeclampsia, and living at a high altitude. If these risk factors are present, they should be controlled if possible. Women who have one or more of these risk factors may also be candidates for prophylactic treatment with aspirin to prevent development of preeclampsia, especially if they develop pregnancy-induced hypertension.

During pregnancy, women who received a donor egg should undergo regular and frequent blood pressure measurement, as well as assessment for other possible abnormalities such as Doppler ultrasound examination of uterine arteries and measuring serum and urine markers.

"Physicians and patients must be aware of the risk [from donor eggs] to assure that these women get adequate monitoring and management during pregnancy," Dr. Letur-Könirsch said.

Dr. Letur-Könirsch had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MUNICH – Women pregnant with an embryo produced by in vitro fertilization of a donated egg developed gestational hypertension at nearly four times the rate of matched women who were pregnant following IVF with a self egg, in a multicenter, case-control study with 580 participants.

In addition, preeclampsia was more than four times higher in the women who had received a donor egg as part of an IVF procedure, compared with women who used a self egg for their IVF, Dr. Hélène Letur-Könirsch reported at the annual meeting of the European Society of Human Reproduction and Embryology.

Mitchel L. Zoler/Frontline Medical News

Although the mechanism underlying this association is not known, one possible explanation is that when a woman carries an embryo that is completely allogenic, it triggers modified immune tolerance that leads to impaired trophoblast implantation. Other candidate hypotheses are that defective genes in the mother trigger abnormal metabolic pathways that cause hypertension and preeclampsia, and that ovarian insufficiency features reduced ovarian steroid production, causing vascular and immunologic changes that lead to pregnancy-induced hypertension.

Results from several prior studies also had shown a link between use of a donor egg for IVF and an increased rate of gestational hypertension and preeclampsia, but most prior studies had been smaller and failed to adequately control for possible confounders, said Dr. Letur-Könirsch, an endocrinologist at the Fertility Center of the Institut Mutualiste Montsouris in Paris.

She and her associates from seven IVF centers in France pooled data from their entire series of IVF cases that involved donated eggs during the period from February 2005 to September 2012, a total of 217 pregnant women. The analysis matched these cases with 363 control women who had IVF pregnancies during the study period using self eggs by parameters such as age, parity, time of pregnancy, and whether the IVF procedure involved transfer of a fresh or frozen embryo.

Women in the study averaged 35 years of age, with 82% aged 39 years or younger. Average body mass index was virtually identical in both groups, about 24 kg/m², and the live-birth rate was 79% in both groups. All women in both groups were normotensive prior to their IVF procedure.

The incidence of pregnancy-induced hypertension, defined as blood pressure that reached at least 140/90 mm Hg when measured in office on both arms with two separate measurements, was about 29% in the women who received a donated egg and 14% in those who used a self egg. Development of preeclampsia, defined as persistent gestational hypertension plus proteinuria of at least 0.3 g/day, occurred in about 18% of women who received a donated egg and 7% in those who used a self egg.

In a multivariate analysis that controlled for age, pregnancy history, and use of a fresh or frozen embryo, women who used a donated egg had a 3.9-fold increased rate of pregnancy-induced hypertension and a 4.6-fold increased rate of preeclampsia, compared with women who used a self egg – both statistically significant differences.

The findings suggested that before a woman embarks on pregnancy using a donated egg, she should undergo thorough evaluation for preexisting risk factors for gestational hypertension, including hypertension, obesity, diabetes, renal disease, chronic infection, autoimmune diseases such as systemic lupus erythematosus, a family history of preeclampsia, and living at a high altitude. If these risk factors are present, they should be controlled if possible. Women who have one or more of these risk factors may also be candidates for prophylactic treatment with aspirin to prevent development of preeclampsia, especially if they develop pregnancy-induced hypertension.

During pregnancy, women who received a donor egg should undergo regular and frequent blood pressure measurement, as well as assessment for other possible abnormalities such as Doppler ultrasound examination of uterine arteries and measuring serum and urine markers.

"Physicians and patients must be aware of the risk [from donor eggs] to assure that these women get adequate monitoring and management during pregnancy," Dr. Letur-Könirsch said.

Dr. Letur-Könirsch had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MUNICH – Women pregnant with an embryo produced by in vitro fertilization of a donated egg developed gestational hypertension at nearly four times the rate of matched women who were pregnant following IVF with a self egg, in a multicenter, case-control study with 580 participants.

In addition, preeclampsia was more than four times higher in the women who had received a donor egg as part of an IVF procedure, compared with women who used a self egg for their IVF, Dr. Hélène Letur-Könirsch reported at the annual meeting of the European Society of Human Reproduction and Embryology.

Mitchel L. Zoler/Frontline Medical News

Although the mechanism underlying this association is not known, one possible explanation is that when a woman carries an embryo that is completely allogenic, it triggers modified immune tolerance that leads to impaired trophoblast implantation. Other candidate hypotheses are that defective genes in the mother trigger abnormal metabolic pathways that cause hypertension and preeclampsia, and that ovarian insufficiency features reduced ovarian steroid production, causing vascular and immunologic changes that lead to pregnancy-induced hypertension.

Results from several prior studies also had shown a link between use of a donor egg for IVF and an increased rate of gestational hypertension and preeclampsia, but most prior studies had been smaller and failed to adequately control for possible confounders, said Dr. Letur-Könirsch, an endocrinologist at the Fertility Center of the Institut Mutualiste Montsouris in Paris.

She and her associates from seven IVF centers in France pooled data from their entire series of IVF cases that involved donated eggs during the period from February 2005 to September 2012, a total of 217 pregnant women. The analysis matched these cases with 363 control women who had IVF pregnancies during the study period using self eggs by parameters such as age, parity, time of pregnancy, and whether the IVF procedure involved transfer of a fresh or frozen embryo.

Women in the study averaged 35 years of age, with 82% aged 39 years or younger. Average body mass index was virtually identical in both groups, about 24 kg/m², and the live-birth rate was 79% in both groups. All women in both groups were normotensive prior to their IVF procedure.

The incidence of pregnancy-induced hypertension, defined as blood pressure that reached at least 140/90 mm Hg when measured in office on both arms with two separate measurements, was about 29% in the women who received a donated egg and 14% in those who used a self egg. Development of preeclampsia, defined as persistent gestational hypertension plus proteinuria of at least 0.3 g/day, occurred in about 18% of women who received a donated egg and 7% in those who used a self egg.

In a multivariate analysis that controlled for age, pregnancy history, and use of a fresh or frozen embryo, women who used a donated egg had a 3.9-fold increased rate of pregnancy-induced hypertension and a 4.6-fold increased rate of preeclampsia, compared with women who used a self egg – both statistically significant differences.

The findings suggested that before a woman embarks on pregnancy using a donated egg, she should undergo thorough evaluation for preexisting risk factors for gestational hypertension, including hypertension, obesity, diabetes, renal disease, chronic infection, autoimmune diseases such as systemic lupus erythematosus, a family history of preeclampsia, and living at a high altitude. If these risk factors are present, they should be controlled if possible. Women who have one or more of these risk factors may also be candidates for prophylactic treatment with aspirin to prevent development of preeclampsia, especially if they develop pregnancy-induced hypertension.

During pregnancy, women who received a donor egg should undergo regular and frequent blood pressure measurement, as well as assessment for other possible abnormalities such as Doppler ultrasound examination of uterine arteries and measuring serum and urine markers.

"Physicians and patients must be aware of the risk [from donor eggs] to assure that these women get adequate monitoring and management during pregnancy," Dr. Letur-Könirsch said.

Dr. Letur-Könirsch had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

CHICAGO – A one-time measurement of plasma kisspeptin – a family of placental peptides also being studied for fertility treatment – better predicts miscarriage than does serial measurement of human chorionic gonadotropin (HCG), a widely used measure.

British researchers measured both in 993 asymptomatic women at approximately 11 weeks’ gestation, 50 of whom later miscarried. Plasma kisspeptin proved a more accurate predictor of miscarriage than HCG: the area under the receiver operating characteristic (ROC) curve for plasma kisspeptin was 0.899, compared with 0.775 for serum HCG. Plasma kisspeptin above 1,306 pmol/L was associated with a highly significant 87% reduced risk of miscarriage, even after adjusting for age, body mass index, gestational age, smoking, and blood pressure.

Lead investigator Dr. Ali Abbara of Imperial College London explained why that matters at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

aotto@frontlinemedcom.com

CHICAGO – A one-time measurement of plasma kisspeptin – a family of placental peptides also being studied for fertility treatment – better predicts miscarriage than does serial measurement of human chorionic gonadotropin (HCG), a widely used measure.

British researchers measured both in 993 asymptomatic women at approximately 11 weeks’ gestation, 50 of whom later miscarried. Plasma kisspeptin proved a more accurate predictor of miscarriage than HCG: the area under the receiver operating characteristic (ROC) curve for plasma kisspeptin was 0.899, compared with 0.775 for serum HCG. Plasma kisspeptin above 1,306 pmol/L was associated with a highly significant 87% reduced risk of miscarriage, even after adjusting for age, body mass index, gestational age, smoking, and blood pressure.

Lead investigator Dr. Ali Abbara of Imperial College London explained why that matters at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

aotto@frontlinemedcom.com

CHICAGO – A one-time measurement of plasma kisspeptin – a family of placental peptides also being studied for fertility treatment – better predicts miscarriage than does serial measurement of human chorionic gonadotropin (HCG), a widely used measure.

British researchers measured both in 993 asymptomatic women at approximately 11 weeks’ gestation, 50 of whom later miscarried. Plasma kisspeptin proved a more accurate predictor of miscarriage than HCG: the area under the receiver operating characteristic (ROC) curve for plasma kisspeptin was 0.899, compared with 0.775 for serum HCG. Plasma kisspeptin above 1,306 pmol/L was associated with a highly significant 87% reduced risk of miscarriage, even after adjusting for age, body mass index, gestational age, smoking, and blood pressure.

Lead investigator Dr. Ali Abbara of Imperial College London explained why that matters at the joint meeting of the International Congress of Endocrinology and the Endocrine Society.

aotto@frontlinemedcom.com

CASE: NULLIPAROUS WOMAN WITH A SHORT CERVIX
Your ultrasound technician telephones to report that your 32-year-old nulliparous patient, who is currently at 20 weeks’ gestation, was incidentally found to have a short cervix (18 mm) at the time of her routine fetal anatomy survey.

How do you proceed? And how do you counsel the patient? What interventions might reduce the risk of preterm birth (PTB)? Would your recommendations change if she had a history of PTB or was carrying twins?

Preterm birth, defined as delivery prior to 37 weeks’ gestation, is the leading cause of neonatal morbidity and mortality in the United States. The rate of PTB peaked at 12.8% in 2006 and has slowly declined since but remains unacceptably high at 11.5%.¹ Most PTBs are spontaneous, arising from the onset of labor or from preterm premature rupture of membranes. Regrettably, tocolytics remain largely ­ineffective once the process of preterm parturition has begun.

Ideally, women at highest risk for PTB could be identified so that additional screening and interventions could be initiated. Few prognostic tests are available to predict which women will deliver preterm. Generally, the greatest risk factor for spontaneous PTB is a history of spontaneous PTB.^2,3 However, women with such a history account for only 10% of all births before 34 weeks’ gestation.

The appearance and length of the cervix during the second trimester appears to be an even better predictor of spontaneous PTB than history alone (FIGURE 1).^4,5 For example, in one study of unselected pregnant women at 22 to 24 weeks’ gestation, only 1.7% had a cervical length less than 15 mm, but they accounted for 58% of births before 32 weeks.⁶ The shorter the cervix, the greater the risk of spontaneous PTB.⁷ The presence of a short cervix is even more ominous in a woman with a history of spontaneous PTB.⁸

Optimal pregnancy management after detection of a short cervix remains somewhat unclear and varies, based on the rest of the patient’s clinical picture and obstetric history.

In this article, I address 8 critical questions about diagnosis and management of the short cervix in the second trimester and offer evidence-based answers for clinical practice.

1. How is a short cervix defined?
A cervical length below the 10th centile for gestational age is considered “short.” At 18 to 24 weeks’ gestation, the 10th centile corresponds to a cervical length of less than 25 mm.⁹

The cervix undergoes physiologic shortening that begins at 28 to 30 weeks of gestation. At 32 weeks, the 50th centile for cervical length is 25 mm. Therefore, cervical-length measurements that appear moderately short between 28 and 32 weeks and beyond are of limited clinical utility, and the clinician should incorporate gestational age into prematurity risk assessment.⁷

2. Who should be screened?
The question of whether universal cervical-length assessment should be performed is controversial. Several decision analyses in recent years suggest that universal sonographic screening for a short cervix is cost-effective.^10,11 Overall, however, the effectiveness of universal cervical-length screening remains clinically understudied, and it is difficult to draw conclusions from decision analyses. Moreover, there is considerable concern about resources and feasibility of implementing universal vaginal cervical-length assessment, as well as significant disagreement about the accuracy of transabdominal cervical-length assessment in the detection of a short cervix.

Transabdominal ultrasound may overestimate cervical length by as much as 10 to 15 mm. One recent study demonstrated that, using a transabdominal cutoff of 30 mm, the sensitivity of detecting a transvaginal cervical length of less than 20 mm was 90%; if the cutoff was increased to 35 mm, sensitivity increased to 100%.¹²

A collaborative practice guideline on obstetric ultrasound from the American College of Radiology, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, and the Society of Radiologists in Ultrasound recommends that the maternal cervix be examined “as clinically appropriate when technically feasible” during a standard second- or third-trimester ultrasound examination (FIGURE 2).¹³ The guideline also states that transvaginal or transperineal ultrasound may be considered if the cervix appears shortened or cannot be adequately visualized during the transabdominal ultrasound. However, no specific protocols are suggested.

Given the uncertainty, it is recommended that each practice or ultrasound unit adopt a standard protocol for cervical-length assessment during pregnancy. This protocol can entail either routine abdominal or vaginal assessment of the cervix, or a combination of abdominal and vaginal assessment. Clinical risk factors can be used to help stratify low-risk women when abdominal cervical-length assessment is the initial approach to evaluation.

In my practice, all women undergo ­cervical-length assessment at the time of the routine anatomy survey (18–22 weeks). Those who are at low risk for PTB are screened initially with transabdominal ultrasound, and a transvaginal examination is performed if the cervix cannot be seen or appears to be less than 30 mm in length.

Women with a history of spontaneous PTB undergo screening by transvaginal cervical-length assessment. Typically, the first measurement is obtained at the time of the fetal anatomic survey (18–22 weeks), when the lower uterine segment is sufficiently developed to accurately measure the cervix. We perform serial cervical-length assessment every 1 or 2 weeks until 28 weeks’ gestation in women with a prior early spontaneous PTB (<34 weeks), those with a history of recurrent PTB, and those who have an initial short cervix. Serial monitoring has been shown to increase the prediction of spontaneous PTB in high-risk women.¹⁴

See the algorithm presented in (FIGURE 3) for the screening and treatment of women with singleton gestations.

3. How do I counsel patients about the risk of prematurity?
The risk of spontaneous PTB varies with the gestational age that the short cervix is detected and with the degree of cervical shortening. The earlier in the pregnancy the cervix is found to be short, the higher the risk for spontaneous PTB. For example, results of one large multicenter study of almost 3,000 unselected women pregnant with a singleton gestation across the United States showed that a cervical length of 25 mm was associated with a 15% to 20% incidence of PTB when detected at 28 weeks’ gestation; the incidence rose to 30% to 35% if the short cervix was detected at 20 weeks.⁹ In this cohort, 84% of women had no history of PTB.

A short cervix and a prior PTB (particularly a very early prior PTB) are two major risk factors for PTB. Together, they significantly increase the risk of an early delivery over individual or single factors alone. Among women who have had a prior PTB and who now have a cervical length of less than 25 mm, the risk of recurrent PTB is 35% to 40%. In contrast, women with a prior PTB and a normal cervical length have a significantly lower risk of recurrence—around 10%.¹⁵

If the physical examination is concerning for cervical dilation or prolapsing membranes, women should be counseled about the poor prognosis for the pregnancy, particularly when these findings are detected at a previable or periviable gestational age, regardless of their history of PTB. In these circumstances, in the absence of labor or intra-amniotic infection, a “rescue” cervical cerclage may be considered as a last resort (see page 34 for more on cerclage).

4. What evaluation or monitoring is needed once a short cervix is identified?
Women found to have a short cervix should be evaluated for the presence of preterm labor and intra-amniotic infection. This evaluation may include a sterile speculum examination or digital cervical examination, or both, as well as screening for genitourinary tract infection. Other testing may include a complete blood count with a white blood cell differential and external tocometry with or without fetal heart rate monitoring (based on the gestational age, as appropriate). 

For some women with a short cervix, intra-amniotic infection may be a contributing factor (or it may develop if there are exposed membranes in the vagina). The presence of intra-amniotic infection precludes further expectant management of the pregnancy because of the risk of maternal infectious morbidity, including sepsis.

Women who have intra-amniotic infection are not candidates for any intervention such as cerclage or progesterone supplementation.

If the patient is at or beyond the point of fetal viability at the time her short cervix is detected, consider external fetal heart rate monitoring.

Antenatal corticosteroids can be administered, as appropriate, depending on the perceived risk of delivery.

5. Should I place a cerclage?
Numerous studies have examined the efficacy of ultrasound-indicated cerclage, a surgical procedure to stitch the cervix closed once a short cervix has been detected.

In general, placement of a cervical cerclage is not offered past the point of fetal viability, which is generally in the range of 23 to 25 weeks’ gestation, depending on local institutional and neonatal intensive care unit policies. Confirmed or suspected chorioamnionitis is also a contraindication to cerclage placement.

Among women without a history of PTB who are found to have a short cervix, existing data do not suggest a benefit for cerclage, although vaginal progesterone appears to be a reasonable option (see page 36).^16,17

As for women with a history of PTB, Owen and colleagues studied 302 patients with a cervical length less than 25 mm and a history of spontaneous PTB before 34 weeks.¹⁸ The women were randomly assigned to ultrasound-indicated cerclage or “usual care,” which consisted of recommendations of pelvic rest, physical activity restriction, and education about the symptoms of preterm labor. Otherwise, management was directed by clinical practice at each center. All women treated with cerclage had a reduced risk of previable PTB (<24 weeks’ gestation), and those who had the shortest cervical length (<15 mm) also had a lower risk of delivery before 35 weeks.

The degree of cervical shortening that has “qualified” women for study enrollment has varied between studies, with upper limits ranging from 15 to 25 mm. Berghella and colleagues performed a patient-level meta-analysis to determine whether efficacy of the cerclage varied by cervical length at the time of placement.⁸ They examined 552 women with singleton gestations from four randomized controlled trials that included 208 women with a short cervix and a history of spontaneous PTB. They found a significant reduction in the rate of preterm delivery before 35 weeks’ gestation among women with singleton pregnancies, a short cervix, and a history of spontaneous PTB; the reduction did not vary by the degree of cervical shortening. However, there was no significant reduction in the rate of PTB among the subset of women without a history of spontaneous PTB.

Berghella and colleagues estimated that, if a cervical cerclage were offered to the 8% of women with a prior spontaneous PTB and a cervical length of less than 25 mm, more than 6,500 newborns would be saved each year from perinatal death associated with prematurity.⁸

The placement of a “rescue” cerclage in the setting of cervical dilation with or without prolapsing membranes is associated with high rates of maternal and neonatal morbidity, regardless of the patient’s obstetric history. However, cerclage placement in this setting may be associated with better outcomes than expectant management with bed rest alone.¹⁹ Patients should be carefully counseled about this procedure, including the risk of infection and the possibility that pregnancy may be prolonged only from a previable to a periviable gestational age. Decisions as to whether a patient is a candidate for rescue cerclage should be made in consultation with a maternal-fetal medicine specialist.²⁰

6. Is a cervical pessary beneficial?
The pessary is another “mechanical” treatment similar to cerclage, and it may be helpful in reducing the incidence of PTB among women with a short cervix. In the largest study of this approach, 16,000 primarily low-risk women with singleton gestations were screened for a short cervix. Of these, 385 women with a cervical length of less than 25 mm were randomly assigned to undergo Arabin pessary placement or expectant management.²¹

Among those who received the pessary, the odds ratio (OR) for PTB before 34 weeks was significantly reduced (OR, 0.18; 95% confidence interval [CI], 0.08–0.37), and the OR for adverse composite neonatal outcome also was significantly reduced (OR, 0.14; 95% CI, 0.04–0.39).²¹

The Arabin pessary is not currently approved by the US Food and Drug Administration for this indication in the United States, nor is it available for insertion outside of research studies. Other ring-shaped pessaries are available in the United States, but their use in the setting of a short cervix is considered experimental and off-label. Additional studies of this promising intervention are currently under way.

7. Who is a candidate for supplemental progesterone?
Progesterone is a naturally occurring hormone essential to the maintenance of pregnancy. It has an overall quiescent effect on the myometrium, is known to have anti-inflammatory properties, and inhibits cervical ripening.²² It has been studied in a number of different formulations and doses.

Vaginal progesterone supplementation has been shown to reduce the risk of PTB among women with a shortened cervix regardless of their pregnancy history.^16,17,23,24 In the largest trials of unselected general obstetrics populations (including women with and without a history of PTB), use of vaginal progesterone among women with a short cervix reduced the rates of very early spontaneous PTB (<28 and <32 weeks’ gestation) by 40% to 50%.^16,17 As expected, progesterone also was associated with a significant reduction in the rates of respiratory distress syndrome and composite neonatal morbidity.

Intramuscular (IM) progesterone supplementation has been shown to reduce the rate of recurrent PTB among women with a history of spontaneous PTB. When caring for a woman with a history of PTB who is found to have a short cervix, IM progesterone should be offered if the woman is not already taking it. IM progesterone has not been proven effective among nulliparous women who are incidentally found to have a short cervix; it should not be offered in this situation.²⁵

8. Should the care of women carrying twins or triplets be managed differently?
Yes. Although women with multiple gestations are at higher risk for PTB than women carrying a singleton fetus, no interventions have proven to be effective in this population. Many studies have been limited to twin gestations as a group, with an inability to perform subgroup analyses or enroll women who also have a short cervix, due to sample size and power issues.

Progesterone in multiple gestations
Although several formulations of progesterone—including IM 17-alpha hydroxyprogesterone caproate, micronized progesterone, and progesterone suppositories—have been studied, no randomized trial data have demonstrated a reduction in PTB or neonatal morbidity.^26–29 Individual patient-level data from a meta-analysis of vaginal progesterone in the setting of multiple gestations with a short cervical length suggest trends toward a reduced rate of PTB before 33 weeks’ gestation (relative risk [RR], 0.70; 95% CI, 0.34–1.44) and lower composite neonatal morbidity and mortality (RR, 0.56; 95% CI, 0.30–0.97).³⁰

Mechanical strategies in multiple gestations
No randomized data suggest that a pessary is effective in multiple gestations. In one study of 813 multiple gestations in the Netherlands, women were randomly assigned—regardless of cervical length—to receive a pessary at 16 to 20 weeks versus standard care; no difference in adverse perinatal outcomes was detected between groups.³¹

As for cerclage, although data are limited, some studies suggest that placement of a cerclage in twin gestations with cervical shortening may increase the rate of PTB.³²

Bottom line for multiples
Although women carrying multiple gestations are at higher risk for PTB, data are extremely limited. At present, data do not support routine use of cerclage for a short cervix—and some suggest possible harm. Vaginal progesterone or placement of a pessary may be of benefit but should be used with caution and with the understanding that data are sparse.

CASE RESOLVED
You counsel your nulliparous patient that she has an elevated risk of PTB, based on her cervical length of 18 mm at 20 weeks’ gestation, and evaluate her clinically for evidence of preterm labor. Apart from the short cervix, her examination is unremarkable. You offer her nightly vaginal progesterone suppositories and schedule a visit to reevaluate her cervix in 1 week. If cervical dilation or prolapsing membranes are noted before the age of fetal viability, you will consider placing a “rescue” cervical cerclage.

Had this patient experienced a prior PTB, you would first ensure that she is taking IM 17-alpha hydroxyprogesterone caproate. It also would be reasonable to place an ultrasound-indicated cerclage or begin vaginal progesterone suppositories. Although data are limited on concomitant use of IM and vaginal progesterone, some experts may consider it, on an experimental basis, for patients with a short cervix and a prior PTB.

If this patient were carrying a twin gestation, vaginal progesterone would still be a consideration, provided she is counseled about the limited evidence of its efficacy in this setting. Cerclage would not be appropriate, given the possible risk of harm.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: obg@frontlinemedcom.com Please include your name, city and state. Stay in touch! Your feedback is important to us!

CASE: NULLIPAROUS WOMAN WITH A SHORT CERVIX
Your ultrasound technician telephones to report that your 32-year-old nulliparous patient, who is currently at 20 weeks’ gestation, was incidentally found to have a short cervix (18 mm) at the time of her routine fetal anatomy survey.

How do you proceed? And how do you counsel the patient? What interventions might reduce the risk of preterm birth (PTB)? Would your recommendations change if she had a history of PTB or was carrying twins?

Preterm birth, defined as delivery prior to 37 weeks’ gestation, is the leading cause of neonatal morbidity and mortality in the United States. The rate of PTB peaked at 12.8% in 2006 and has slowly declined since but remains unacceptably high at 11.5%.¹ Most PTBs are spontaneous, arising from the onset of labor or from preterm premature rupture of membranes. Regrettably, tocolytics remain largely ­ineffective once the process of preterm parturition has begun.

Ideally, women at highest risk for PTB could be identified so that additional screening and interventions could be initiated. Few prognostic tests are available to predict which women will deliver preterm. Generally, the greatest risk factor for spontaneous PTB is a history of spontaneous PTB.^2,3 However, women with such a history account for only 10% of all births before 34 weeks’ gestation.

The appearance and length of the cervix during the second trimester appears to be an even better predictor of spontaneous PTB than history alone (FIGURE 1).^4,5 For example, in one study of unselected pregnant women at 22 to 24 weeks’ gestation, only 1.7% had a cervical length less than 15 mm, but they accounted for 58% of births before 32 weeks.⁶ The shorter the cervix, the greater the risk of spontaneous PTB.⁷ The presence of a short cervix is even more ominous in a woman with a history of spontaneous PTB.⁸

Optimal pregnancy management after detection of a short cervix remains somewhat unclear and varies, based on the rest of the patient’s clinical picture and obstetric history.

In this article, I address 8 critical questions about diagnosis and management of the short cervix in the second trimester and offer evidence-based answers for clinical practice.

1. How is a short cervix defined?
A cervical length below the 10th centile for gestational age is considered “short.” At 18 to 24 weeks’ gestation, the 10th centile corresponds to a cervical length of less than 25 mm.⁹

The cervix undergoes physiologic shortening that begins at 28 to 30 weeks of gestation. At 32 weeks, the 50th centile for cervical length is 25 mm. Therefore, cervical-length measurements that appear moderately short between 28 and 32 weeks and beyond are of limited clinical utility, and the clinician should incorporate gestational age into prematurity risk assessment.⁷

2. Who should be screened?
The question of whether universal cervical-length assessment should be performed is controversial. Several decision analyses in recent years suggest that universal sonographic screening for a short cervix is cost-effective.^10,11 Overall, however, the effectiveness of universal cervical-length screening remains clinically understudied, and it is difficult to draw conclusions from decision analyses. Moreover, there is considerable concern about resources and feasibility of implementing universal vaginal cervical-length assessment, as well as significant disagreement about the accuracy of transabdominal cervical-length assessment in the detection of a short cervix.

Transabdominal ultrasound may overestimate cervical length by as much as 10 to 15 mm. One recent study demonstrated that, using a transabdominal cutoff of 30 mm, the sensitivity of detecting a transvaginal cervical length of less than 20 mm was 90%; if the cutoff was increased to 35 mm, sensitivity increased to 100%.¹²

A collaborative practice guideline on obstetric ultrasound from the American College of Radiology, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, and the Society of Radiologists in Ultrasound recommends that the maternal cervix be examined “as clinically appropriate when technically feasible” during a standard second- or third-trimester ultrasound examination (FIGURE 2).¹³ The guideline also states that transvaginal or transperineal ultrasound may be considered if the cervix appears shortened or cannot be adequately visualized during the transabdominal ultrasound. However, no specific protocols are suggested.

Given the uncertainty, it is recommended that each practice or ultrasound unit adopt a standard protocol for cervical-length assessment during pregnancy. This protocol can entail either routine abdominal or vaginal assessment of the cervix, or a combination of abdominal and vaginal assessment. Clinical risk factors can be used to help stratify low-risk women when abdominal cervical-length assessment is the initial approach to evaluation.

In my practice, all women undergo ­cervical-length assessment at the time of the routine anatomy survey (18–22 weeks). Those who are at low risk for PTB are screened initially with transabdominal ultrasound, and a transvaginal examination is performed if the cervix cannot be seen or appears to be less than 30 mm in length.

Women with a history of spontaneous PTB undergo screening by transvaginal cervical-length assessment. Typically, the first measurement is obtained at the time of the fetal anatomic survey (18–22 weeks), when the lower uterine segment is sufficiently developed to accurately measure the cervix. We perform serial cervical-length assessment every 1 or 2 weeks until 28 weeks’ gestation in women with a prior early spontaneous PTB (<34 weeks), those with a history of recurrent PTB, and those who have an initial short cervix. Serial monitoring has been shown to increase the prediction of spontaneous PTB in high-risk women.¹⁴

See the algorithm presented in (FIGURE 3) for the screening and treatment of women with singleton gestations.

3. How do I counsel patients about the risk of prematurity?
The risk of spontaneous PTB varies with the gestational age that the short cervix is detected and with the degree of cervical shortening. The earlier in the pregnancy the cervix is found to be short, the higher the risk for spontaneous PTB. For example, results of one large multicenter study of almost 3,000 unselected women pregnant with a singleton gestation across the United States showed that a cervical length of 25 mm was associated with a 15% to 20% incidence of PTB when detected at 28 weeks’ gestation; the incidence rose to 30% to 35% if the short cervix was detected at 20 weeks.⁹ In this cohort, 84% of women had no history of PTB.

A short cervix and a prior PTB (particularly a very early prior PTB) are two major risk factors for PTB. Together, they significantly increase the risk of an early delivery over individual or single factors alone. Among women who have had a prior PTB and who now have a cervical length of less than 25 mm, the risk of recurrent PTB is 35% to 40%. In contrast, women with a prior PTB and a normal cervical length have a significantly lower risk of recurrence—around 10%.¹⁵

If the physical examination is concerning for cervical dilation or prolapsing membranes, women should be counseled about the poor prognosis for the pregnancy, particularly when these findings are detected at a previable or periviable gestational age, regardless of their history of PTB. In these circumstances, in the absence of labor or intra-amniotic infection, a “rescue” cervical cerclage may be considered as a last resort (see page 34 for more on cerclage).

4. What evaluation or monitoring is needed once a short cervix is identified?
Women found to have a short cervix should be evaluated for the presence of preterm labor and intra-amniotic infection. This evaluation may include a sterile speculum examination or digital cervical examination, or both, as well as screening for genitourinary tract infection. Other testing may include a complete blood count with a white blood cell differential and external tocometry with or without fetal heart rate monitoring (based on the gestational age, as appropriate). 

For some women with a short cervix, intra-amniotic infection may be a contributing factor (or it may develop if there are exposed membranes in the vagina). The presence of intra-amniotic infection precludes further expectant management of the pregnancy because of the risk of maternal infectious morbidity, including sepsis.

Women who have intra-amniotic infection are not candidates for any intervention such as cerclage or progesterone supplementation.

If the patient is at or beyond the point of fetal viability at the time her short cervix is detected, consider external fetal heart rate monitoring.

Antenatal corticosteroids can be administered, as appropriate, depending on the perceived risk of delivery.

5. Should I place a cerclage?
Numerous studies have examined the efficacy of ultrasound-indicated cerclage, a surgical procedure to stitch the cervix closed once a short cervix has been detected.

In general, placement of a cervical cerclage is not offered past the point of fetal viability, which is generally in the range of 23 to 25 weeks’ gestation, depending on local institutional and neonatal intensive care unit policies. Confirmed or suspected chorioamnionitis is also a contraindication to cerclage placement.

Among women without a history of PTB who are found to have a short cervix, existing data do not suggest a benefit for cerclage, although vaginal progesterone appears to be a reasonable option (see page 36).^16,17

As for women with a history of PTB, Owen and colleagues studied 302 patients with a cervical length less than 25 mm and a history of spontaneous PTB before 34 weeks.¹⁸ The women were randomly assigned to ultrasound-indicated cerclage or “usual care,” which consisted of recommendations of pelvic rest, physical activity restriction, and education about the symptoms of preterm labor. Otherwise, management was directed by clinical practice at each center. All women treated with cerclage had a reduced risk of previable PTB (<24 weeks’ gestation), and those who had the shortest cervical length (<15 mm) also had a lower risk of delivery before 35 weeks.

The degree of cervical shortening that has “qualified” women for study enrollment has varied between studies, with upper limits ranging from 15 to 25 mm. Berghella and colleagues performed a patient-level meta-analysis to determine whether efficacy of the cerclage varied by cervical length at the time of placement.⁸ They examined 552 women with singleton gestations from four randomized controlled trials that included 208 women with a short cervix and a history of spontaneous PTB. They found a significant reduction in the rate of preterm delivery before 35 weeks’ gestation among women with singleton pregnancies, a short cervix, and a history of spontaneous PTB; the reduction did not vary by the degree of cervical shortening. However, there was no significant reduction in the rate of PTB among the subset of women without a history of spontaneous PTB.

Berghella and colleagues estimated that, if a cervical cerclage were offered to the 8% of women with a prior spontaneous PTB and a cervical length of less than 25 mm, more than 6,500 newborns would be saved each year from perinatal death associated with prematurity.⁸

The placement of a “rescue” cerclage in the setting of cervical dilation with or without prolapsing membranes is associated with high rates of maternal and neonatal morbidity, regardless of the patient’s obstetric history. However, cerclage placement in this setting may be associated with better outcomes than expectant management with bed rest alone.¹⁹ Patients should be carefully counseled about this procedure, including the risk of infection and the possibility that pregnancy may be prolonged only from a previable to a periviable gestational age. Decisions as to whether a patient is a candidate for rescue cerclage should be made in consultation with a maternal-fetal medicine specialist.²⁰

6. Is a cervical pessary beneficial?
The pessary is another “mechanical” treatment similar to cerclage, and it may be helpful in reducing the incidence of PTB among women with a short cervix. In the largest study of this approach, 16,000 primarily low-risk women with singleton gestations were screened for a short cervix. Of these, 385 women with a cervical length of less than 25 mm were randomly assigned to undergo Arabin pessary placement or expectant management.²¹

Among those who received the pessary, the odds ratio (OR) for PTB before 34 weeks was significantly reduced (OR, 0.18; 95% confidence interval [CI], 0.08–0.37), and the OR for adverse composite neonatal outcome also was significantly reduced (OR, 0.14; 95% CI, 0.04–0.39).²¹

The Arabin pessary is not currently approved by the US Food and Drug Administration for this indication in the United States, nor is it available for insertion outside of research studies. Other ring-shaped pessaries are available in the United States, but their use in the setting of a short cervix is considered experimental and off-label. Additional studies of this promising intervention are currently under way.

7. Who is a candidate for supplemental progesterone?
Progesterone is a naturally occurring hormone essential to the maintenance of pregnancy. It has an overall quiescent effect on the myometrium, is known to have anti-inflammatory properties, and inhibits cervical ripening.²² It has been studied in a number of different formulations and doses.

Vaginal progesterone supplementation has been shown to reduce the risk of PTB among women with a shortened cervix regardless of their pregnancy history.^16,17,23,24 In the largest trials of unselected general obstetrics populations (including women with and without a history of PTB), use of vaginal progesterone among women with a short cervix reduced the rates of very early spontaneous PTB (<28 and <32 weeks’ gestation) by 40% to 50%.^16,17 As expected, progesterone also was associated with a significant reduction in the rates of respiratory distress syndrome and composite neonatal morbidity.

Intramuscular (IM) progesterone supplementation has been shown to reduce the rate of recurrent PTB among women with a history of spontaneous PTB. When caring for a woman with a history of PTB who is found to have a short cervix, IM progesterone should be offered if the woman is not already taking it. IM progesterone has not been proven effective among nulliparous women who are incidentally found to have a short cervix; it should not be offered in this situation.²⁵

8. Should the care of women carrying twins or triplets be managed differently?
Yes. Although women with multiple gestations are at higher risk for PTB than women carrying a singleton fetus, no interventions have proven to be effective in this population. Many studies have been limited to twin gestations as a group, with an inability to perform subgroup analyses or enroll women who also have a short cervix, due to sample size and power issues.

Progesterone in multiple gestations
Although several formulations of progesterone—including IM 17-alpha hydroxyprogesterone caproate, micronized progesterone, and progesterone suppositories—have been studied, no randomized trial data have demonstrated a reduction in PTB or neonatal morbidity.^26–29 Individual patient-level data from a meta-analysis of vaginal progesterone in the setting of multiple gestations with a short cervical length suggest trends toward a reduced rate of PTB before 33 weeks’ gestation (relative risk [RR], 0.70; 95% CI, 0.34–1.44) and lower composite neonatal morbidity and mortality (RR, 0.56; 95% CI, 0.30–0.97).³⁰

Mechanical strategies in multiple gestations
No randomized data suggest that a pessary is effective in multiple gestations. In one study of 813 multiple gestations in the Netherlands, women were randomly assigned—regardless of cervical length—to receive a pessary at 16 to 20 weeks versus standard care; no difference in adverse perinatal outcomes was detected between groups.³¹

As for cerclage, although data are limited, some studies suggest that placement of a cerclage in twin gestations with cervical shortening may increase the rate of PTB.³²

Bottom line for multiples
Although women carrying multiple gestations are at higher risk for PTB, data are extremely limited. At present, data do not support routine use of cerclage for a short cervix—and some suggest possible harm. Vaginal progesterone or placement of a pessary may be of benefit but should be used with caution and with the understanding that data are sparse.

CASE RESOLVED
You counsel your nulliparous patient that she has an elevated risk of PTB, based on her cervical length of 18 mm at 20 weeks’ gestation, and evaluate her clinically for evidence of preterm labor. Apart from the short cervix, her examination is unremarkable. You offer her nightly vaginal progesterone suppositories and schedule a visit to reevaluate her cervix in 1 week. If cervical dilation or prolapsing membranes are noted before the age of fetal viability, you will consider placing a “rescue” cervical cerclage.

Had this patient experienced a prior PTB, you would first ensure that she is taking IM 17-alpha hydroxyprogesterone caproate. It also would be reasonable to place an ultrasound-indicated cerclage or begin vaginal progesterone suppositories. Although data are limited on concomitant use of IM and vaginal progesterone, some experts may consider it, on an experimental basis, for patients with a short cervix and a prior PTB.

If this patient were carrying a twin gestation, vaginal progesterone would still be a consideration, provided she is counseled about the limited evidence of its efficacy in this setting. Cerclage would not be appropriate, given the possible risk of harm.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: obg@frontlinemedcom.com Please include your name, city and state. Stay in touch! Your feedback is important to us!

CASE: NULLIPAROUS WOMAN WITH A SHORT CERVIX
Your ultrasound technician telephones to report that your 32-year-old nulliparous patient, who is currently at 20 weeks’ gestation, was incidentally found to have a short cervix (18 mm) at the time of her routine fetal anatomy survey.

How do you proceed? And how do you counsel the patient? What interventions might reduce the risk of preterm birth (PTB)? Would your recommendations change if she had a history of PTB or was carrying twins?

Preterm birth, defined as delivery prior to 37 weeks’ gestation, is the leading cause of neonatal morbidity and mortality in the United States. The rate of PTB peaked at 12.8% in 2006 and has slowly declined since but remains unacceptably high at 11.5%.¹ Most PTBs are spontaneous, arising from the onset of labor or from preterm premature rupture of membranes. Regrettably, tocolytics remain largely ­ineffective once the process of preterm parturition has begun.

Ideally, women at highest risk for PTB could be identified so that additional screening and interventions could be initiated. Few prognostic tests are available to predict which women will deliver preterm. Generally, the greatest risk factor for spontaneous PTB is a history of spontaneous PTB.^2,3 However, women with such a history account for only 10% of all births before 34 weeks’ gestation.

The appearance and length of the cervix during the second trimester appears to be an even better predictor of spontaneous PTB than history alone (FIGURE 1).^4,5 For example, in one study of unselected pregnant women at 22 to 24 weeks’ gestation, only 1.7% had a cervical length less than 15 mm, but they accounted for 58% of births before 32 weeks.⁶ The shorter the cervix, the greater the risk of spontaneous PTB.⁷ The presence of a short cervix is even more ominous in a woman with a history of spontaneous PTB.⁸

Optimal pregnancy management after detection of a short cervix remains somewhat unclear and varies, based on the rest of the patient’s clinical picture and obstetric history.

In this article, I address 8 critical questions about diagnosis and management of the short cervix in the second trimester and offer evidence-based answers for clinical practice.

1. How is a short cervix defined?
A cervical length below the 10th centile for gestational age is considered “short.” At 18 to 24 weeks’ gestation, the 10th centile corresponds to a cervical length of less than 25 mm.⁹

The cervix undergoes physiologic shortening that begins at 28 to 30 weeks of gestation. At 32 weeks, the 50th centile for cervical length is 25 mm. Therefore, cervical-length measurements that appear moderately short between 28 and 32 weeks and beyond are of limited clinical utility, and the clinician should incorporate gestational age into prematurity risk assessment.⁷

2. Who should be screened?
The question of whether universal cervical-length assessment should be performed is controversial. Several decision analyses in recent years suggest that universal sonographic screening for a short cervix is cost-effective.^10,11 Overall, however, the effectiveness of universal cervical-length screening remains clinically understudied, and it is difficult to draw conclusions from decision analyses. Moreover, there is considerable concern about resources and feasibility of implementing universal vaginal cervical-length assessment, as well as significant disagreement about the accuracy of transabdominal cervical-length assessment in the detection of a short cervix.

Transabdominal ultrasound may overestimate cervical length by as much as 10 to 15 mm. One recent study demonstrated that, using a transabdominal cutoff of 30 mm, the sensitivity of detecting a transvaginal cervical length of less than 20 mm was 90%; if the cutoff was increased to 35 mm, sensitivity increased to 100%.¹²

A collaborative practice guideline on obstetric ultrasound from the American College of Radiology, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, and the Society of Radiologists in Ultrasound recommends that the maternal cervix be examined “as clinically appropriate when technically feasible” during a standard second- or third-trimester ultrasound examination (FIGURE 2).¹³ The guideline also states that transvaginal or transperineal ultrasound may be considered if the cervix appears shortened or cannot be adequately visualized during the transabdominal ultrasound. However, no specific protocols are suggested.

Given the uncertainty, it is recommended that each practice or ultrasound unit adopt a standard protocol for cervical-length assessment during pregnancy. This protocol can entail either routine abdominal or vaginal assessment of the cervix, or a combination of abdominal and vaginal assessment. Clinical risk factors can be used to help stratify low-risk women when abdominal cervical-length assessment is the initial approach to evaluation.

In my practice, all women undergo ­cervical-length assessment at the time of the routine anatomy survey (18–22 weeks). Those who are at low risk for PTB are screened initially with transabdominal ultrasound, and a transvaginal examination is performed if the cervix cannot be seen or appears to be less than 30 mm in length.

Women with a history of spontaneous PTB undergo screening by transvaginal cervical-length assessment. Typically, the first measurement is obtained at the time of the fetal anatomic survey (18–22 weeks), when the lower uterine segment is sufficiently developed to accurately measure the cervix. We perform serial cervical-length assessment every 1 or 2 weeks until 28 weeks’ gestation in women with a prior early spontaneous PTB (<34 weeks), those with a history of recurrent PTB, and those who have an initial short cervix. Serial monitoring has been shown to increase the prediction of spontaneous PTB in high-risk women.¹⁴

See the algorithm presented in (FIGURE 3) for the screening and treatment of women with singleton gestations.

3. How do I counsel patients about the risk of prematurity?
The risk of spontaneous PTB varies with the gestational age that the short cervix is detected and with the degree of cervical shortening. The earlier in the pregnancy the cervix is found to be short, the higher the risk for spontaneous PTB. For example, results of one large multicenter study of almost 3,000 unselected women pregnant with a singleton gestation across the United States showed that a cervical length of 25 mm was associated with a 15% to 20% incidence of PTB when detected at 28 weeks’ gestation; the incidence rose to 30% to 35% if the short cervix was detected at 20 weeks.⁹ In this cohort, 84% of women had no history of PTB.

A short cervix and a prior PTB (particularly a very early prior PTB) are two major risk factors for PTB. Together, they significantly increase the risk of an early delivery over individual or single factors alone. Among women who have had a prior PTB and who now have a cervical length of less than 25 mm, the risk of recurrent PTB is 35% to 40%. In contrast, women with a prior PTB and a normal cervical length have a significantly lower risk of recurrence—around 10%.¹⁵

If the physical examination is concerning for cervical dilation or prolapsing membranes, women should be counseled about the poor prognosis for the pregnancy, particularly when these findings are detected at a previable or periviable gestational age, regardless of their history of PTB. In these circumstances, in the absence of labor or intra-amniotic infection, a “rescue” cervical cerclage may be considered as a last resort (see page 34 for more on cerclage).

4. What evaluation or monitoring is needed once a short cervix is identified?
Women found to have a short cervix should be evaluated for the presence of preterm labor and intra-amniotic infection. This evaluation may include a sterile speculum examination or digital cervical examination, or both, as well as screening for genitourinary tract infection. Other testing may include a complete blood count with a white blood cell differential and external tocometry with or without fetal heart rate monitoring (based on the gestational age, as appropriate). 

For some women with a short cervix, intra-amniotic infection may be a contributing factor (or it may develop if there are exposed membranes in the vagina). The presence of intra-amniotic infection precludes further expectant management of the pregnancy because of the risk of maternal infectious morbidity, including sepsis.

Women who have intra-amniotic infection are not candidates for any intervention such as cerclage or progesterone supplementation.

If the patient is at or beyond the point of fetal viability at the time her short cervix is detected, consider external fetal heart rate monitoring.

Antenatal corticosteroids can be administered, as appropriate, depending on the perceived risk of delivery.

5. Should I place a cerclage?
Numerous studies have examined the efficacy of ultrasound-indicated cerclage, a surgical procedure to stitch the cervix closed once a short cervix has been detected.

In general, placement of a cervical cerclage is not offered past the point of fetal viability, which is generally in the range of 23 to 25 weeks’ gestation, depending on local institutional and neonatal intensive care unit policies. Confirmed or suspected chorioamnionitis is also a contraindication to cerclage placement.

Among women without a history of PTB who are found to have a short cervix, existing data do not suggest a benefit for cerclage, although vaginal progesterone appears to be a reasonable option (see page 36).^16,17

As for women with a history of PTB, Owen and colleagues studied 302 patients with a cervical length less than 25 mm and a history of spontaneous PTB before 34 weeks.¹⁸ The women were randomly assigned to ultrasound-indicated cerclage or “usual care,” which consisted of recommendations of pelvic rest, physical activity restriction, and education about the symptoms of preterm labor. Otherwise, management was directed by clinical practice at each center. All women treated with cerclage had a reduced risk of previable PTB (<24 weeks’ gestation), and those who had the shortest cervical length (<15 mm) also had a lower risk of delivery before 35 weeks.

The degree of cervical shortening that has “qualified” women for study enrollment has varied between studies, with upper limits ranging from 15 to 25 mm. Berghella and colleagues performed a patient-level meta-analysis to determine whether efficacy of the cerclage varied by cervical length at the time of placement.⁸ They examined 552 women with singleton gestations from four randomized controlled trials that included 208 women with a short cervix and a history of spontaneous PTB. They found a significant reduction in the rate of preterm delivery before 35 weeks’ gestation among women with singleton pregnancies, a short cervix, and a history of spontaneous PTB; the reduction did not vary by the degree of cervical shortening. However, there was no significant reduction in the rate of PTB among the subset of women without a history of spontaneous PTB.

Berghella and colleagues estimated that, if a cervical cerclage were offered to the 8% of women with a prior spontaneous PTB and a cervical length of less than 25 mm, more than 6,500 newborns would be saved each year from perinatal death associated with prematurity.⁸

The placement of a “rescue” cerclage in the setting of cervical dilation with or without prolapsing membranes is associated with high rates of maternal and neonatal morbidity, regardless of the patient’s obstetric history. However, cerclage placement in this setting may be associated with better outcomes than expectant management with bed rest alone.¹⁹ Patients should be carefully counseled about this procedure, including the risk of infection and the possibility that pregnancy may be prolonged only from a previable to a periviable gestational age. Decisions as to whether a patient is a candidate for rescue cerclage should be made in consultation with a maternal-fetal medicine specialist.²⁰

6. Is a cervical pessary beneficial?
The pessary is another “mechanical” treatment similar to cerclage, and it may be helpful in reducing the incidence of PTB among women with a short cervix. In the largest study of this approach, 16,000 primarily low-risk women with singleton gestations were screened for a short cervix. Of these, 385 women with a cervical length of less than 25 mm were randomly assigned to undergo Arabin pessary placement or expectant management.²¹

Among those who received the pessary, the odds ratio (OR) for PTB before 34 weeks was significantly reduced (OR, 0.18; 95% confidence interval [CI], 0.08–0.37), and the OR for adverse composite neonatal outcome also was significantly reduced (OR, 0.14; 95% CI, 0.04–0.39).²¹

The Arabin pessary is not currently approved by the US Food and Drug Administration for this indication in the United States, nor is it available for insertion outside of research studies. Other ring-shaped pessaries are available in the United States, but their use in the setting of a short cervix is considered experimental and off-label. Additional studies of this promising intervention are currently under way.

7. Who is a candidate for supplemental progesterone?
Progesterone is a naturally occurring hormone essential to the maintenance of pregnancy. It has an overall quiescent effect on the myometrium, is known to have anti-inflammatory properties, and inhibits cervical ripening.²² It has been studied in a number of different formulations and doses.

Vaginal progesterone supplementation has been shown to reduce the risk of PTB among women with a shortened cervix regardless of their pregnancy history.^16,17,23,24 In the largest trials of unselected general obstetrics populations (including women with and without a history of PTB), use of vaginal progesterone among women with a short cervix reduced the rates of very early spontaneous PTB (<28 and <32 weeks’ gestation) by 40% to 50%.^16,17 As expected, progesterone also was associated with a significant reduction in the rates of respiratory distress syndrome and composite neonatal morbidity.

Intramuscular (IM) progesterone supplementation has been shown to reduce the rate of recurrent PTB among women with a history of spontaneous PTB. When caring for a woman with a history of PTB who is found to have a short cervix, IM progesterone should be offered if the woman is not already taking it. IM progesterone has not been proven effective among nulliparous women who are incidentally found to have a short cervix; it should not be offered in this situation.²⁵

8. Should the care of women carrying twins or triplets be managed differently?
Yes. Although women with multiple gestations are at higher risk for PTB than women carrying a singleton fetus, no interventions have proven to be effective in this population. Many studies have been limited to twin gestations as a group, with an inability to perform subgroup analyses or enroll women who also have a short cervix, due to sample size and power issues.

Progesterone in multiple gestations
Although several formulations of progesterone—including IM 17-alpha hydroxyprogesterone caproate, micronized progesterone, and progesterone suppositories—have been studied, no randomized trial data have demonstrated a reduction in PTB or neonatal morbidity.^26–29 Individual patient-level data from a meta-analysis of vaginal progesterone in the setting of multiple gestations with a short cervical length suggest trends toward a reduced rate of PTB before 33 weeks’ gestation (relative risk [RR], 0.70; 95% CI, 0.34–1.44) and lower composite neonatal morbidity and mortality (RR, 0.56; 95% CI, 0.30–0.97).³⁰

Mechanical strategies in multiple gestations
No randomized data suggest that a pessary is effective in multiple gestations. In one study of 813 multiple gestations in the Netherlands, women were randomly assigned—regardless of cervical length—to receive a pessary at 16 to 20 weeks versus standard care; no difference in adverse perinatal outcomes was detected between groups.³¹

As for cerclage, although data are limited, some studies suggest that placement of a cerclage in twin gestations with cervical shortening may increase the rate of PTB.³²

Bottom line for multiples
Although women carrying multiple gestations are at higher risk for PTB, data are extremely limited. At present, data do not support routine use of cerclage for a short cervix—and some suggest possible harm. Vaginal progesterone or placement of a pessary may be of benefit but should be used with caution and with the understanding that data are sparse.

CASE RESOLVED
You counsel your nulliparous patient that she has an elevated risk of PTB, based on her cervical length of 18 mm at 20 weeks’ gestation, and evaluate her clinically for evidence of preterm labor. Apart from the short cervix, her examination is unremarkable. You offer her nightly vaginal progesterone suppositories and schedule a visit to reevaluate her cervix in 1 week. If cervical dilation or prolapsing membranes are noted before the age of fetal viability, you will consider placing a “rescue” cervical cerclage.

Had this patient experienced a prior PTB, you would first ensure that she is taking IM 17-alpha hydroxyprogesterone caproate. It also would be reasonable to place an ultrasound-indicated cerclage or begin vaginal progesterone suppositories. Although data are limited on concomitant use of IM and vaginal progesterone, some experts may consider it, on an experimental basis, for patients with a short cervix and a prior PTB.

If this patient were carrying a twin gestation, vaginal progesterone would still be a consideration, provided she is counseled about the limited evidence of its efficacy in this setting. Cerclage would not be appropriate, given the possible risk of harm.

WE WANT TO HEAR FROM YOU!
Drop us a line and let us know what you think about this or other current articles, which topics you'd like to see covered in future issues, and what challenges you face in daily practice. Tell us what you think by emailing us at: obg@frontlinemedcom.com Please include your name, city and state. Stay in touch! Your feedback is important to us!

Both elective and emergency cesarean sections in first births appear to slightly increase the risk of stillbirth and ectopic pregnancy in subsequent pregnancies, according to a new study.

Compared with women whose first birth was a spontaneous vaginal delivery, primiparous women with a primary C-section were 14% more likely to have a subsequent stillbirth and 9% more likely to have a later ectopic pregnancy, but were no more likely to have a subsequent miscarriage, reported Sinéad O’Neill of Cork University Maternity Hospital, Ireland, and her associates (PLoS Med. 2014 July 1 [doi:10.1371/journal.pmed.1001670]).

The analysis was limited by incomplete data, and the increased rate of stillbirths and/or ectopic pregnancies could be driven by underlying factors that contributed to the need for a C-section, the researchers noted.

They analyzed Danish national registry data on 832,996 primiparous women with a live birth between Jan. 1, 1982, and Dec. 31, 2010, followed until the next stillbirth, miscarriage, ectopic pregnancy, live birth, death or emigration. Miscarriage was defined as loss before 28 weeks’ gestation until April 2004, and before 22 weeks’ gestation from 2004 onward.

The fully-adjusted analysis controlled for the following:

• Maternal age, origin, and marital status.

• Previous stillbirth, miscarriage, or ectopic pregnancy.

• Birth year.

• Socioeconomic status (mother’s education and both parents’ gross income).

• Medical complications in the first live birth, including multiples, diabetes, gestational diabetes, placental abruption, placenta previa, and hypertensive disorders.

• Gestational age at birth and birth weight.

The researchers lacked data on maternal body mass index, smoking status, and fertility treatment, as well as causes of stillbirth, maternally requested C-sections, and the gestational ages of the stillbirths and miscarriages.

The increased rate of stillbirth (hazard ratio 1.14) among women with a primary C-section, compared with women with an initial spontaneous vaginal birth, translated to an absolute risk increase of 0.03% and a number needed to harm of 3,333. Emergency C-sections showed a barely higher risk (HR 1.15), but the risk with elective C-sections (HR 1.11) did not reach statistical significance (95% CI 0.91, 1.35).

"Almost 50% of the explained stillbirths in this cohort were due to antenatal complications (including placental abruption/infarction, intrauterine growth restriction, preeclampsia, prematurity, and poor placental growth)," the researchers wrote. "The clinical importance is that although many of these complications are largely not preventable, an increased awareness that the fetus is at risk may facilitate increased surveillance and optimally timed delivery and may lead to improved perinatal outcomes."

The increased risk of ectopic pregnancy (HR 1.09) with overall primary C-sections translated to an absolute risk increase of 0.1% and number needed to harm of 1,000 women. The increased risk was similar for emergency (HR 1.09) and elective (HR 1.12) C-sections, both statistically significant. Overall, primary C-sections were not associated with miscarriage, and miscarriage risk was decreased (HR 0.72) for maternally requested C-sections.

The authors reported that C-section rates among first-time Danish mothers increased during the study period from 12.8% in 1982 to 23% in 2010. "This increase, coupled with better surveillance and detection of adverse or underlying complications earlier in pregnancy, could explain the increased hazard of subsequent stillbirth found in this study among women with a prior cesarean section," they wrote.

Although the findings may be particularly relevant for expectant mothers requesting a non–medically indicated C-section, "it must be acknowledged that a cesarean section can be a vital intervention, and the likelihood of adverse outcome may be decreased, for example, by choosing an elective cesarean section to avoid fetal death due to a failed vaginal birth after cesarean or to prevent sudden stillbirth post-term," the researchers wrote.

The research was supported by the National Perinatal Epidemiology Centre in Cork, Ireland, and as part of the Health Research Board PhD Scholars program in Health Services Research. A coauthor, Dr. Louise C. Kenny, is a Science Foundation Ireland Principal Investigator and director of Centre, INFANT, funded by Science Foundation Ireland.

Both elective and emergency cesarean sections in first births appear to slightly increase the risk of stillbirth and ectopic pregnancy in subsequent pregnancies, according to a new study.

Compared with women whose first birth was a spontaneous vaginal delivery, primiparous women with a primary C-section were 14% more likely to have a subsequent stillbirth and 9% more likely to have a later ectopic pregnancy, but were no more likely to have a subsequent miscarriage, reported Sinéad O’Neill of Cork University Maternity Hospital, Ireland, and her associates (PLoS Med. 2014 July 1 [doi:10.1371/journal.pmed.1001670]).

The analysis was limited by incomplete data, and the increased rate of stillbirths and/or ectopic pregnancies could be driven by underlying factors that contributed to the need for a C-section, the researchers noted.

They analyzed Danish national registry data on 832,996 primiparous women with a live birth between Jan. 1, 1982, and Dec. 31, 2010, followed until the next stillbirth, miscarriage, ectopic pregnancy, live birth, death or emigration. Miscarriage was defined as loss before 28 weeks’ gestation until April 2004, and before 22 weeks’ gestation from 2004 onward.

The fully-adjusted analysis controlled for the following:

• Maternal age, origin, and marital status.

• Previous stillbirth, miscarriage, or ectopic pregnancy.

• Birth year.

• Socioeconomic status (mother’s education and both parents’ gross income).

• Medical complications in the first live birth, including multiples, diabetes, gestational diabetes, placental abruption, placenta previa, and hypertensive disorders.

• Gestational age at birth and birth weight.

The researchers lacked data on maternal body mass index, smoking status, and fertility treatment, as well as causes of stillbirth, maternally requested C-sections, and the gestational ages of the stillbirths and miscarriages.

The increased rate of stillbirth (hazard ratio 1.14) among women with a primary C-section, compared with women with an initial spontaneous vaginal birth, translated to an absolute risk increase of 0.03% and a number needed to harm of 3,333. Emergency C-sections showed a barely higher risk (HR 1.15), but the risk with elective C-sections (HR 1.11) did not reach statistical significance (95% CI 0.91, 1.35).

"Almost 50% of the explained stillbirths in this cohort were due to antenatal complications (including placental abruption/infarction, intrauterine growth restriction, preeclampsia, prematurity, and poor placental growth)," the researchers wrote. "The clinical importance is that although many of these complications are largely not preventable, an increased awareness that the fetus is at risk may facilitate increased surveillance and optimally timed delivery and may lead to improved perinatal outcomes."

The increased risk of ectopic pregnancy (HR 1.09) with overall primary C-sections translated to an absolute risk increase of 0.1% and number needed to harm of 1,000 women. The increased risk was similar for emergency (HR 1.09) and elective (HR 1.12) C-sections, both statistically significant. Overall, primary C-sections were not associated with miscarriage, and miscarriage risk was decreased (HR 0.72) for maternally requested C-sections.

The authors reported that C-section rates among first-time Danish mothers increased during the study period from 12.8% in 1982 to 23% in 2010. "This increase, coupled with better surveillance and detection of adverse or underlying complications earlier in pregnancy, could explain the increased hazard of subsequent stillbirth found in this study among women with a prior cesarean section," they wrote.

Although the findings may be particularly relevant for expectant mothers requesting a non–medically indicated C-section, "it must be acknowledged that a cesarean section can be a vital intervention, and the likelihood of adverse outcome may be decreased, for example, by choosing an elective cesarean section to avoid fetal death due to a failed vaginal birth after cesarean or to prevent sudden stillbirth post-term," the researchers wrote.

The research was supported by the National Perinatal Epidemiology Centre in Cork, Ireland, and as part of the Health Research Board PhD Scholars program in Health Services Research. A coauthor, Dr. Louise C. Kenny, is a Science Foundation Ireland Principal Investigator and director of Centre, INFANT, funded by Science Foundation Ireland.

Both elective and emergency cesarean sections in first births appear to slightly increase the risk of stillbirth and ectopic pregnancy in subsequent pregnancies, according to a new study.

Compared with women whose first birth was a spontaneous vaginal delivery, primiparous women with a primary C-section were 14% more likely to have a subsequent stillbirth and 9% more likely to have a later ectopic pregnancy, but were no more likely to have a subsequent miscarriage, reported Sinéad O’Neill of Cork University Maternity Hospital, Ireland, and her associates (PLoS Med. 2014 July 1 [doi:10.1371/journal.pmed.1001670]).

The analysis was limited by incomplete data, and the increased rate of stillbirths and/or ectopic pregnancies could be driven by underlying factors that contributed to the need for a C-section, the researchers noted.

They analyzed Danish national registry data on 832,996 primiparous women with a live birth between Jan. 1, 1982, and Dec. 31, 2010, followed until the next stillbirth, miscarriage, ectopic pregnancy, live birth, death or emigration. Miscarriage was defined as loss before 28 weeks’ gestation until April 2004, and before 22 weeks’ gestation from 2004 onward.

The fully-adjusted analysis controlled for the following:

• Maternal age, origin, and marital status.

• Previous stillbirth, miscarriage, or ectopic pregnancy.

• Birth year.

• Socioeconomic status (mother’s education and both parents’ gross income).

• Medical complications in the first live birth, including multiples, diabetes, gestational diabetes, placental abruption, placenta previa, and hypertensive disorders.

• Gestational age at birth and birth weight.

The researchers lacked data on maternal body mass index, smoking status, and fertility treatment, as well as causes of stillbirth, maternally requested C-sections, and the gestational ages of the stillbirths and miscarriages.

The increased rate of stillbirth (hazard ratio 1.14) among women with a primary C-section, compared with women with an initial spontaneous vaginal birth, translated to an absolute risk increase of 0.03% and a number needed to harm of 3,333. Emergency C-sections showed a barely higher risk (HR 1.15), but the risk with elective C-sections (HR 1.11) did not reach statistical significance (95% CI 0.91, 1.35).

"Almost 50% of the explained stillbirths in this cohort were due to antenatal complications (including placental abruption/infarction, intrauterine growth restriction, preeclampsia, prematurity, and poor placental growth)," the researchers wrote. "The clinical importance is that although many of these complications are largely not preventable, an increased awareness that the fetus is at risk may facilitate increased surveillance and optimally timed delivery and may lead to improved perinatal outcomes."

The increased risk of ectopic pregnancy (HR 1.09) with overall primary C-sections translated to an absolute risk increase of 0.1% and number needed to harm of 1,000 women. The increased risk was similar for emergency (HR 1.09) and elective (HR 1.12) C-sections, both statistically significant. Overall, primary C-sections were not associated with miscarriage, and miscarriage risk was decreased (HR 0.72) for maternally requested C-sections.

The authors reported that C-section rates among first-time Danish mothers increased during the study period from 12.8% in 1982 to 23% in 2010. "This increase, coupled with better surveillance and detection of adverse or underlying complications earlier in pregnancy, could explain the increased hazard of subsequent stillbirth found in this study among women with a prior cesarean section," they wrote.

Although the findings may be particularly relevant for expectant mothers requesting a non–medically indicated C-section, "it must be acknowledged that a cesarean section can be a vital intervention, and the likelihood of adverse outcome may be decreased, for example, by choosing an elective cesarean section to avoid fetal death due to a failed vaginal birth after cesarean or to prevent sudden stillbirth post-term," the researchers wrote.

The research was supported by the National Perinatal Epidemiology Centre in Cork, Ireland, and as part of the Health Research Board PhD Scholars program in Health Services Research. A coauthor, Dr. Louise C. Kenny, is a Science Foundation Ireland Principal Investigator and director of Centre, INFANT, funded by Science Foundation Ireland.

Pregnant mothers with celiac disease have little to fear when it comes to birth defects, despite previous underpowered reports to the contrary, wrote Daniela Zugna, Ph.D., and her colleagues in the July issue of Clinical Gastroenterology and Hepatology (doi.org/10.1016/j.cgh.2013.10.012).

Dr. Zugna of University of Turin, in Italy, looked at a total of 5,774 mothers with celiac disease (CD) and 3,039 fathers with CD, cross-referenced with the Swedish Medical Birth Register, the Patient Register, the Register of Congenital Malformations and the Multigeneration Register.

From 1973 through 2009, the mothers gave birth to 11,382 children, and 6,002 children were born to fathers with CD.

These were compared with nearly 41,000 and 20,000 children of healthy mothers and fathers born over the same time period, respectively.

The authors found that 672 babies of mothers with CD (5.9%) and 2,098 control offspring (5.1%) were born with congenital malformations; these included heart defects, neural tube defects, limb deficiencies, and orofacial clefts, among others.

That amounted to an adjusted prevalence odds ratio of having a child with birth defects of 1.15 for mothers with CD (95% confidence interval, 1.05-1.26).

For fathers, the figures were 352 children with birth defects born to CD patients (5.9%) and 1,009 to healthy controls (5.1%), for a similar odds ratio of 1.14 (95% CI, 1.00-1.29).

However, when the data were restricted to births between 2000 and 2009, the significance of these differences vanished: in this most modern era, mothers with CD carried a nonsignificant OR of 1.11 (95% CI, 0.79-1.56).

By the same token, fathers of babies born between 2000 and 2009 had an OR of 1.01 for having a child with birth defects (95% CI, 0.81-1.26).

In postulating reasons for the slightly increased number of birth defects seen over the span of the study, the authors wrote: "While folic acid deficiency is common in newly diagnosed CD, it is sometimes seen after diagnosis, perhaps because of a lack of folic acid in the gluten-free diet."

And regarding the possible connection between fathers with CD and their children, "If spouses to men with CD are also primarily on a gluten-free diet, this may actually explain the excess risk for congenital malformation in paternal offspring."

Alternatively, "Low sperm quality in men with CD could potentially influence the risk of malformations."

The authors conceded several important weaknesses in this study. For one, they did not have data on diet adherence in CD, nor on the periconceptional or perinatal use of folic acid supplementation.

Moreover, a substantial proportion of pregnancies with neural tube defects discovered during prenatal screening were likely to have been terminated, potentially resulting in artificially low rates of this malformation: indeed, the authors pointed to data showing that between 1999 and 2009, between 51% and 93% of all NTD pregnancies were terminated, depending on the specific defect.

Finally, "Over time, symptoms have changed in CD," they wrote.

"It is possible that, with increased use of celiac serology, milder cases of CD are now diagnosed in which there is no association with congenital malformation."

The authors disclosed no conflicts of interest; individual authors disclosed several grants from nonprofit and research agencies in Europe, including the Italian Association for Cancer Research, the Stockholm County Council, the Danish Medical Research Council, and the Karolinska Institutet, among others.

Pregnant mothers with celiac disease have little to fear when it comes to birth defects, despite previous underpowered reports to the contrary, wrote Daniela Zugna, Ph.D., and her colleagues in the July issue of Clinical Gastroenterology and Hepatology (doi.org/10.1016/j.cgh.2013.10.012).

Dr. Zugna of University of Turin, in Italy, looked at a total of 5,774 mothers with celiac disease (CD) and 3,039 fathers with CD, cross-referenced with the Swedish Medical Birth Register, the Patient Register, the Register of Congenital Malformations and the Multigeneration Register.

From 1973 through 2009, the mothers gave birth to 11,382 children, and 6,002 children were born to fathers with CD.

These were compared with nearly 41,000 and 20,000 children of healthy mothers and fathers born over the same time period, respectively.

The authors found that 672 babies of mothers with CD (5.9%) and 2,098 control offspring (5.1%) were born with congenital malformations; these included heart defects, neural tube defects, limb deficiencies, and orofacial clefts, among others.

That amounted to an adjusted prevalence odds ratio of having a child with birth defects of 1.15 for mothers with CD (95% confidence interval, 1.05-1.26).

For fathers, the figures were 352 children with birth defects born to CD patients (5.9%) and 1,009 to healthy controls (5.1%), for a similar odds ratio of 1.14 (95% CI, 1.00-1.29).

However, when the data were restricted to births between 2000 and 2009, the significance of these differences vanished: in this most modern era, mothers with CD carried a nonsignificant OR of 1.11 (95% CI, 0.79-1.56).

By the same token, fathers of babies born between 2000 and 2009 had an OR of 1.01 for having a child with birth defects (95% CI, 0.81-1.26).

In postulating reasons for the slightly increased number of birth defects seen over the span of the study, the authors wrote: "While folic acid deficiency is common in newly diagnosed CD, it is sometimes seen after diagnosis, perhaps because of a lack of folic acid in the gluten-free diet."

And regarding the possible connection between fathers with CD and their children, "If spouses to men with CD are also primarily on a gluten-free diet, this may actually explain the excess risk for congenital malformation in paternal offspring."

Alternatively, "Low sperm quality in men with CD could potentially influence the risk of malformations."

The authors conceded several important weaknesses in this study. For one, they did not have data on diet adherence in CD, nor on the periconceptional or perinatal use of folic acid supplementation.

Moreover, a substantial proportion of pregnancies with neural tube defects discovered during prenatal screening were likely to have been terminated, potentially resulting in artificially low rates of this malformation: indeed, the authors pointed to data showing that between 1999 and 2009, between 51% and 93% of all NTD pregnancies were terminated, depending on the specific defect.

Finally, "Over time, symptoms have changed in CD," they wrote.

"It is possible that, with increased use of celiac serology, milder cases of CD are now diagnosed in which there is no association with congenital malformation."

The authors disclosed no conflicts of interest; individual authors disclosed several grants from nonprofit and research agencies in Europe, including the Italian Association for Cancer Research, the Stockholm County Council, the Danish Medical Research Council, and the Karolinska Institutet, among others.

Pregnant mothers with celiac disease have little to fear when it comes to birth defects, despite previous underpowered reports to the contrary, wrote Daniela Zugna, Ph.D., and her colleagues in the July issue of Clinical Gastroenterology and Hepatology (doi.org/10.1016/j.cgh.2013.10.012).

Dr. Zugna of University of Turin, in Italy, looked at a total of 5,774 mothers with celiac disease (CD) and 3,039 fathers with CD, cross-referenced with the Swedish Medical Birth Register, the Patient Register, the Register of Congenital Malformations and the Multigeneration Register.

From 1973 through 2009, the mothers gave birth to 11,382 children, and 6,002 children were born to fathers with CD.

These were compared with nearly 41,000 and 20,000 children of healthy mothers and fathers born over the same time period, respectively.

The authors found that 672 babies of mothers with CD (5.9%) and 2,098 control offspring (5.1%) were born with congenital malformations; these included heart defects, neural tube defects, limb deficiencies, and orofacial clefts, among others.

That amounted to an adjusted prevalence odds ratio of having a child with birth defects of 1.15 for mothers with CD (95% confidence interval, 1.05-1.26).

For fathers, the figures were 352 children with birth defects born to CD patients (5.9%) and 1,009 to healthy controls (5.1%), for a similar odds ratio of 1.14 (95% CI, 1.00-1.29).

However, when the data were restricted to births between 2000 and 2009, the significance of these differences vanished: in this most modern era, mothers with CD carried a nonsignificant OR of 1.11 (95% CI, 0.79-1.56).

By the same token, fathers of babies born between 2000 and 2009 had an OR of 1.01 for having a child with birth defects (95% CI, 0.81-1.26).

In postulating reasons for the slightly increased number of birth defects seen over the span of the study, the authors wrote: "While folic acid deficiency is common in newly diagnosed CD, it is sometimes seen after diagnosis, perhaps because of a lack of folic acid in the gluten-free diet."

And regarding the possible connection between fathers with CD and their children, "If spouses to men with CD are also primarily on a gluten-free diet, this may actually explain the excess risk for congenital malformation in paternal offspring."

Alternatively, "Low sperm quality in men with CD could potentially influence the risk of malformations."

The authors conceded several important weaknesses in this study. For one, they did not have data on diet adherence in CD, nor on the periconceptional or perinatal use of folic acid supplementation.

Moreover, a substantial proportion of pregnancies with neural tube defects discovered during prenatal screening were likely to have been terminated, potentially resulting in artificially low rates of this malformation: indeed, the authors pointed to data showing that between 1999 and 2009, between 51% and 93% of all NTD pregnancies were terminated, depending on the specific defect.

Finally, "Over time, symptoms have changed in CD," they wrote.

"It is possible that, with increased use of celiac serology, milder cases of CD are now diagnosed in which there is no association with congenital malformation."

The authors disclosed no conflicts of interest; individual authors disclosed several grants from nonprofit and research agencies in Europe, including the Italian Association for Cancer Research, the Stockholm County Council, the Danish Medical Research Council, and the Karolinska Institutet, among others.

WASHINGTON – For-profit companies cannot be compelled to provide insurance coverage for contraception if doing so violates the religious beliefs of the company’s owners, the Supreme Court ruled June 30.

Dissenting justices said that it had the potential to allow employers to use their religious beliefs as a way to object to providing coverage for vaccinations, blood transfusions, and other procedures, and that it could open the door to deny employment to certain individuals or groups.

The Court ruled 5-4 in the cases of Burwell v. Hobby Lobby Stores Inc. and Conestoga Wood Specialties Corp. v. Burwell.

Alicia Ault/Frontline Medical News

Justice Samuel Alito, reading the opinion for the majority, said that the Religious Freedom Restoration Act (RFRA) of 1993 protected the rights of not just individuals, but also of individuals who run closely held for-profit corporations.

The terms of that law "make it perfectly clear that Congress did not discriminate in this way against men and women who wish to run their businesses as for-profit corporations in the manner required by their religious beliefs," according to the opinion signed by Justice Alito, Justice Anthony P. Kennedy, Justice Antonin Scalia, and Justice Clarence Thomas, and Chief Justice John P. Roberts.

The plaintiffs in the cases said that being required by the Affordable Care Act to provide insurance coverage for contraception violated their religious beliefs. In particular, Hobby Lobby and Conestoga Wood both objected to four specific types of contraception that they said interfere with conception and thus constitute abortion: the Ella morning-after pill, the Plan B morning-after pill, and hormonal and copper intrauterine devices (IUDs).

The majority opinion said that by requiring companies that did not comply to pay fines, the government was placing an undue burden on these employers. Justice Alito noted that Hobby Lobby would have to either give up its religious tenets or pay up to $1.3 million a day in fines*.

"If these consequences don’t amount to a heavy burden, I’m not sure what would," he said.

The majority also said that since the government already makes exceptions to the contraception requirement for religious organizations and nonprofit religiously affiliated groups, that it could have made the same allowances for for-profit companies. The government also could have offered to pay for the contraceptives that companies refuse to cover, they said.

Justice Ruth Bader Ginsburg, who read the dissenting opinion, called the majority’s opinion "a decision of startling breadth." If allowed to stand, it could raise what she called "a host of ‘me, too’ questions," such as whether an employer could opt out of coverage for antidepressants, vaccinations, or medications derived from pigs, "based on the employer’s sincerely held religious beliefs opposing those medical practices."

Joined by Justice Stephen G. Breyer, Justice Elena Kagan, and Justice Sonia Sotomayor, she also said that while the ruling might seem to be limited to access to the four contraceptives in the cases, it was likely that companies would seek to deny coverage for all available contraceptive technologies.

The dissenters also said that they doubted that Congress intended for the RFRA to be used to allow a company to stand in between a woman and her physician. Any decision to use a contraceptive "will be the woman’s autonomous choice, informed by the physician she consults," they wrote.

Many physicians’ and women’s health organizations called it a dangerous precedent.

The American College of Obstetricians and Gynecologists President John C. Jennings said in a statement that the group was “profoundly disappointed” in the decision, as it “inappropriately allows employers to interfere in women’s health care decisions.” Dr. Jennings also said that contraceptives should not be treated differently than other health care services for women. “The value of family planning – including contraception – has been clearly demonstrated,” he said. “The ability of a woman to time and space her children reduces infant, child, and maternal morbidity and mortality, and can lead to more optimal health outcomes for mother and for baby.”

Contraception also helps prevent unintended pregnancy, he said, adding, “This is absolutely essential in America, where nearly one half of all pregnancies are unintended.”

In a statement, Dr.Reid Blackwelder, president of the American Academy of Family Physicians, said, "With this decision, the court has moved health care decisions out of the exam room, where patients can consult with their physicians — and where such decisions should be made — and put them into the hands of business owners who base decisions on personal beliefs rather than [on] medical science." Dr. Blackwelder added, "Personal or institutional beliefs should not put Americans’ health and lives at risk, simply because employers control the insurance available to their workers. Unfortunately, the Supreme Court decision opens the gate for just such consequences."

Dr. James M. Perrin, president of the American Academy of Pediatrics, said, "For pediatricians, the science is clear: contraception is a safe, effective tool to prevent unintended pregnancy in young women of any reproductive age. Today, we are disappointed that justice did not side with science."

Some physician groups expressed their support for the decision.

The American Association of Pro-Life Obstetricians and Gynecologists called the ruling a "tremendous victory for all Americans and their freedom of conscience." The group added that it was "hopeful that this recognition of conscientious objection will help to strengthen the rights of physicians to continue to refuse to participate in any medical procedure or to prescribe any drug that is designed and purposed to kill a living human being."

The Christian Medical Association also applauded the decision. In a statement, Dr. David Stevens, CEO, said, "We are very thankful that the Supreme Court acted to protect family businesses from government coercion and fines for simply honoring the tenets of their faith," and called it a "much-needed victory for faith freedoms."

In a joint press briefing, representatives from Planned Parenthood, NARAL, the American Civil Liberties Union, and the National Women’s Law Center said that they would work with Congress to try to reverse the Supreme Court ruling through legislation. The AAP will do the same, said Dr. Perrin.

Some Senate Democrats have said they will prepare legislation to address the case immediately. Sen. Patty Murray (D-Wash.), who filed a friend of the court brief on behalf of 18 Senators that sided with the government’s case, said in a statement that, "Since the Supreme Court decided it will not protect women’s access to health care, I will. In the coming days I will work with my colleagues and the Administration to protect this access, regardless of who signs your paycheck."

Senate Republican leader Mitch McConnell (R-Ky.), however, said that the decision was a validation of religious freedom. "Obamacare is the single worst piece of legislation to pass in the last 50 years, and I was glad to see the Supreme Court agree that this particular Obamacare mandate violates the Religious Freedom Restoration Act," Sen. McConnell said, in a statement.

aault@frontlinemedcom.com

On Twitter @aliciaault

*Clarification, 7/2/2014: An earlier version of this article did not include the intact quote from the majority opinion.

*This story was updated 7/2/2014.

WASHINGTON – For-profit companies cannot be compelled to provide insurance coverage for contraception if doing so violates the religious beliefs of the company’s owners, the Supreme Court ruled June 30.

Dissenting justices said that it had the potential to allow employers to use their religious beliefs as a way to object to providing coverage for vaccinations, blood transfusions, and other procedures, and that it could open the door to deny employment to certain individuals or groups.

The Court ruled 5-4 in the cases of Burwell v. Hobby Lobby Stores Inc. and Conestoga Wood Specialties Corp. v. Burwell.

Alicia Ault/Frontline Medical News

Justice Samuel Alito, reading the opinion for the majority, said that the Religious Freedom Restoration Act (RFRA) of 1993 protected the rights of not just individuals, but also of individuals who run closely held for-profit corporations.

The terms of that law "make it perfectly clear that Congress did not discriminate in this way against men and women who wish to run their businesses as for-profit corporations in the manner required by their religious beliefs," according to the opinion signed by Justice Alito, Justice Anthony P. Kennedy, Justice Antonin Scalia, and Justice Clarence Thomas, and Chief Justice John P. Roberts.

The plaintiffs in the cases said that being required by the Affordable Care Act to provide insurance coverage for contraception violated their religious beliefs. In particular, Hobby Lobby and Conestoga Wood both objected to four specific types of contraception that they said interfere with conception and thus constitute abortion: the Ella morning-after pill, the Plan B morning-after pill, and hormonal and copper intrauterine devices (IUDs).

The majority opinion said that by requiring companies that did not comply to pay fines, the government was placing an undue burden on these employers. Justice Alito noted that Hobby Lobby would have to either give up its religious tenets or pay up to $1.3 million a day in fines*.

"If these consequences don’t amount to a heavy burden, I’m not sure what would," he said.

The majority also said that since the government already makes exceptions to the contraception requirement for religious organizations and nonprofit religiously affiliated groups, that it could have made the same allowances for for-profit companies. The government also could have offered to pay for the contraceptives that companies refuse to cover, they said.

Justice Ruth Bader Ginsburg, who read the dissenting opinion, called the majority’s opinion "a decision of startling breadth." If allowed to stand, it could raise what she called "a host of ‘me, too’ questions," such as whether an employer could opt out of coverage for antidepressants, vaccinations, or medications derived from pigs, "based on the employer’s sincerely held religious beliefs opposing those medical practices."

Joined by Justice Stephen G. Breyer, Justice Elena Kagan, and Justice Sonia Sotomayor, she also said that while the ruling might seem to be limited to access to the four contraceptives in the cases, it was likely that companies would seek to deny coverage for all available contraceptive technologies.

The dissenters also said that they doubted that Congress intended for the RFRA to be used to allow a company to stand in between a woman and her physician. Any decision to use a contraceptive "will be the woman’s autonomous choice, informed by the physician she consults," they wrote.

Many physicians’ and women’s health organizations called it a dangerous precedent.

The American College of Obstetricians and Gynecologists President John C. Jennings said in a statement that the group was “profoundly disappointed” in the decision, as it “inappropriately allows employers to interfere in women’s health care decisions.” Dr. Jennings also said that contraceptives should not be treated differently than other health care services for women. “The value of family planning – including contraception – has been clearly demonstrated,” he said. “The ability of a woman to time and space her children reduces infant, child, and maternal morbidity and mortality, and can lead to more optimal health outcomes for mother and for baby.”

Contraception also helps prevent unintended pregnancy, he said, adding, “This is absolutely essential in America, where nearly one half of all pregnancies are unintended.”

In a statement, Dr.Reid Blackwelder, president of the American Academy of Family Physicians, said, "With this decision, the court has moved health care decisions out of the exam room, where patients can consult with their physicians — and where such decisions should be made — and put them into the hands of business owners who base decisions on personal beliefs rather than [on] medical science." Dr. Blackwelder added, "Personal or institutional beliefs should not put Americans’ health and lives at risk, simply because employers control the insurance available to their workers. Unfortunately, the Supreme Court decision opens the gate for just such consequences."

Dr. James M. Perrin, president of the American Academy of Pediatrics, said, "For pediatricians, the science is clear: contraception is a safe, effective tool to prevent unintended pregnancy in young women of any reproductive age. Today, we are disappointed that justice did not side with science."

Some physician groups expressed their support for the decision.

The American Association of Pro-Life Obstetricians and Gynecologists called the ruling a "tremendous victory for all Americans and their freedom of conscience." The group added that it was "hopeful that this recognition of conscientious objection will help to strengthen the rights of physicians to continue to refuse to participate in any medical procedure or to prescribe any drug that is designed and purposed to kill a living human being."

The Christian Medical Association also applauded the decision. In a statement, Dr. David Stevens, CEO, said, "We are very thankful that the Supreme Court acted to protect family businesses from government coercion and fines for simply honoring the tenets of their faith," and called it a "much-needed victory for faith freedoms."

In a joint press briefing, representatives from Planned Parenthood, NARAL, the American Civil Liberties Union, and the National Women’s Law Center said that they would work with Congress to try to reverse the Supreme Court ruling through legislation. The AAP will do the same, said Dr. Perrin.

Some Senate Democrats have said they will prepare legislation to address the case immediately. Sen. Patty Murray (D-Wash.), who filed a friend of the court brief on behalf of 18 Senators that sided with the government’s case, said in a statement that, "Since the Supreme Court decided it will not protect women’s access to health care, I will. In the coming days I will work with my colleagues and the Administration to protect this access, regardless of who signs your paycheck."

Senate Republican leader Mitch McConnell (R-Ky.), however, said that the decision was a validation of religious freedom. "Obamacare is the single worst piece of legislation to pass in the last 50 years, and I was glad to see the Supreme Court agree that this particular Obamacare mandate violates the Religious Freedom Restoration Act," Sen. McConnell said, in a statement.

aault@frontlinemedcom.com

On Twitter @aliciaault

*Clarification, 7/2/2014: An earlier version of this article did not include the intact quote from the majority opinion.

*This story was updated 7/2/2014.

WASHINGTON – For-profit companies cannot be compelled to provide insurance coverage for contraception if doing so violates the religious beliefs of the company’s owners, the Supreme Court ruled June 30.

Dissenting justices said that it had the potential to allow employers to use their religious beliefs as a way to object to providing coverage for vaccinations, blood transfusions, and other procedures, and that it could open the door to deny employment to certain individuals or groups.

The Court ruled 5-4 in the cases of Burwell v. Hobby Lobby Stores Inc. and Conestoga Wood Specialties Corp. v. Burwell.

Alicia Ault/Frontline Medical News

Justice Samuel Alito, reading the opinion for the majority, said that the Religious Freedom Restoration Act (RFRA) of 1993 protected the rights of not just individuals, but also of individuals who run closely held for-profit corporations.

The terms of that law "make it perfectly clear that Congress did not discriminate in this way against men and women who wish to run their businesses as for-profit corporations in the manner required by their religious beliefs," according to the opinion signed by Justice Alito, Justice Anthony P. Kennedy, Justice Antonin Scalia, and Justice Clarence Thomas, and Chief Justice John P. Roberts.

The plaintiffs in the cases said that being required by the Affordable Care Act to provide insurance coverage for contraception violated their religious beliefs. In particular, Hobby Lobby and Conestoga Wood both objected to four specific types of contraception that they said interfere with conception and thus constitute abortion: the Ella morning-after pill, the Plan B morning-after pill, and hormonal and copper intrauterine devices (IUDs).

The majority opinion said that by requiring companies that did not comply to pay fines, the government was placing an undue burden on these employers. Justice Alito noted that Hobby Lobby would have to either give up its religious tenets or pay up to $1.3 million a day in fines*.

"If these consequences don’t amount to a heavy burden, I’m not sure what would," he said.

The majority also said that since the government already makes exceptions to the contraception requirement for religious organizations and nonprofit religiously affiliated groups, that it could have made the same allowances for for-profit companies. The government also could have offered to pay for the contraceptives that companies refuse to cover, they said.

Justice Ruth Bader Ginsburg, who read the dissenting opinion, called the majority’s opinion "a decision of startling breadth." If allowed to stand, it could raise what she called "a host of ‘me, too’ questions," such as whether an employer could opt out of coverage for antidepressants, vaccinations, or medications derived from pigs, "based on the employer’s sincerely held religious beliefs opposing those medical practices."

Joined by Justice Stephen G. Breyer, Justice Elena Kagan, and Justice Sonia Sotomayor, she also said that while the ruling might seem to be limited to access to the four contraceptives in the cases, it was likely that companies would seek to deny coverage for all available contraceptive technologies.

The dissenters also said that they doubted that Congress intended for the RFRA to be used to allow a company to stand in between a woman and her physician. Any decision to use a contraceptive "will be the woman’s autonomous choice, informed by the physician she consults," they wrote.

Many physicians’ and women’s health organizations called it a dangerous precedent.

The American College of Obstetricians and Gynecologists President John C. Jennings said in a statement that the group was “profoundly disappointed” in the decision, as it “inappropriately allows employers to interfere in women’s health care decisions.” Dr. Jennings also said that contraceptives should not be treated differently than other health care services for women. “The value of family planning – including contraception – has been clearly demonstrated,” he said. “The ability of a woman to time and space her children reduces infant, child, and maternal morbidity and mortality, and can lead to more optimal health outcomes for mother and for baby.”

Contraception also helps prevent unintended pregnancy, he said, adding, “This is absolutely essential in America, where nearly one half of all pregnancies are unintended.”

In a statement, Dr.Reid Blackwelder, president of the American Academy of Family Physicians, said, "With this decision, the court has moved health care decisions out of the exam room, where patients can consult with their physicians — and where such decisions should be made — and put them into the hands of business owners who base decisions on personal beliefs rather than [on] medical science." Dr. Blackwelder added, "Personal or institutional beliefs should not put Americans’ health and lives at risk, simply because employers control the insurance available to their workers. Unfortunately, the Supreme Court decision opens the gate for just such consequences."

Dr. James M. Perrin, president of the American Academy of Pediatrics, said, "For pediatricians, the science is clear: contraception is a safe, effective tool to prevent unintended pregnancy in young women of any reproductive age. Today, we are disappointed that justice did not side with science."

Some physician groups expressed their support for the decision.

The American Association of Pro-Life Obstetricians and Gynecologists called the ruling a "tremendous victory for all Americans and their freedom of conscience." The group added that it was "hopeful that this recognition of conscientious objection will help to strengthen the rights of physicians to continue to refuse to participate in any medical procedure or to prescribe any drug that is designed and purposed to kill a living human being."

The Christian Medical Association also applauded the decision. In a statement, Dr. David Stevens, CEO, said, "We are very thankful that the Supreme Court acted to protect family businesses from government coercion and fines for simply honoring the tenets of their faith," and called it a "much-needed victory for faith freedoms."

In a joint press briefing, representatives from Planned Parenthood, NARAL, the American Civil Liberties Union, and the National Women’s Law Center said that they would work with Congress to try to reverse the Supreme Court ruling through legislation. The AAP will do the same, said Dr. Perrin.

Some Senate Democrats have said they will prepare legislation to address the case immediately. Sen. Patty Murray (D-Wash.), who filed a friend of the court brief on behalf of 18 Senators that sided with the government’s case, said in a statement that, "Since the Supreme Court decided it will not protect women’s access to health care, I will. In the coming days I will work with my colleagues and the Administration to protect this access, regardless of who signs your paycheck."

Senate Republican leader Mitch McConnell (R-Ky.), however, said that the decision was a validation of religious freedom. "Obamacare is the single worst piece of legislation to pass in the last 50 years, and I was glad to see the Supreme Court agree that this particular Obamacare mandate violates the Religious Freedom Restoration Act," Sen. McConnell said, in a statement.

aault@frontlinemedcom.com

On Twitter @aliciaault

*Clarification, 7/2/2014: An earlier version of this article did not include the intact quote from the majority opinion.

*This story was updated 7/2/2014.

PARIS – The live birth rate among women taking belimumab for systemic lupus erythematosus is similar to the background rate for women with the disorder, a study showed.

An analysis of clinical trials found that women who were taking the drug when they became pregnant had a live birth rate of 48% – in line with studies that place the rate at 55%-88%, Dr. Marcy Powell said at the annual European Congress of Rheumatology.

Although the number of pregnancies examined in the studies was small – with 80 exposed to belimumab (Benlysta) and 6 to placebo – the results were echoed by the initial findings in a recently established belimumab pregnancy registry, said Dr. Powell, director of safety evaluation and risk management at GlaxoSmithKline, which manufactures the drug.

More than 3,000 adult patients have been treated with belimumab – many for more than 10 years, but there are scant data on pregnancy outcomes. It’s a category C drug; women are advised to avoid pregnancy while taking it and for at least 4 months after stopping it. Thus, the only available pregnancy data are from inadvertent exposures in which the drug was stopped as soon as the pregnancy was discovered.

The data were drawn from the BLISS 52 and 78 studies, which enrolled more than 1,600 patients, 94% of whom were women. At baseline, the patients’ mean age was 38 years. Other medications were common in the cohort: 86% of patients were using corticosteroids, with 58% of those taking a prednisone equivalent of more than 5.7 mg/day. More than half (65%) were using antimalarials, and 49% were taking another immunosuppressant, including azathioprine, methotrexate, or mycophenolate mofetil.

Of the six pregnancies among patients assigned to placebo, there were three elective terminations, two spontaneous miscarriages, and one stillbirth, for a total fetal loss rate of 50%. The three pregnancies with fetal loss included two women who tested positive for anticardiolipin antibodies.

Among the 80 drug-exposed pregnancies, there were 21 elective terminations as well as 20 miscarriages and 1 stillbirth, yielding a total fetal loss rate of 26%. The background miscarriage rate was 12%-22%, and the background stillbirth rate was 2%-5%, both of which are similar to rates observed in the exposed pregnancies. Overall, women tested positive for anticardiolipin antibodies in 20 pregnancies exposed to belimumab, including 21% of the live births and 38% of the fetal losses.

There were 38 live births (48%). Four neonates had a congenital anomaly:

• One with Dandy-Walker syndrome.

• One with an unbalanced translocation (11 and 13) of maternal origin, a strictly genetic anomaly.

• One born at 27 weeks’ gestation with patent ductus arteriosus.

• One with bilateral enlarged kidneys with abnormal function whose mother was receiving ambrisentan, a known teratogen, for portal hypertension. (The infant was placed on dialysis and had the right kidney removed.)

The stillbirths in the placebo and belimumab patients occurred in conjunction with severe, very early third-trimester preeclampsia, Dr. Powell said. She noted that the sample size is so small that it’s unclear whether the results can be extrapolated to larger populations.

However, the Belimumab Pregnancy Registry, established by GlaxoSmithKline, could provide more reliable data, she said. So far, the registry has enrolled nine pregnancies, seven of which have been completed. Among those, there have been six live births and one miscarriage. Three of the infants were preterm, born at 32, 35, and 36 weeks’ gestation. There was one birth defect (mild Epstein’s anomaly of the tricuspid valve).

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PARIS – The live birth rate among women taking belimumab for systemic lupus erythematosus is similar to the background rate for women with the disorder, a study showed.

An analysis of clinical trials found that women who were taking the drug when they became pregnant had a live birth rate of 48% – in line with studies that place the rate at 55%-88%, Dr. Marcy Powell said at the annual European Congress of Rheumatology.

Although the number of pregnancies examined in the studies was small – with 80 exposed to belimumab (Benlysta) and 6 to placebo – the results were echoed by the initial findings in a recently established belimumab pregnancy registry, said Dr. Powell, director of safety evaluation and risk management at GlaxoSmithKline, which manufactures the drug.

More than 3,000 adult patients have been treated with belimumab – many for more than 10 years, but there are scant data on pregnancy outcomes. It’s a category C drug; women are advised to avoid pregnancy while taking it and for at least 4 months after stopping it. Thus, the only available pregnancy data are from inadvertent exposures in which the drug was stopped as soon as the pregnancy was discovered.

The data were drawn from the BLISS 52 and 78 studies, which enrolled more than 1,600 patients, 94% of whom were women. At baseline, the patients’ mean age was 38 years. Other medications were common in the cohort: 86% of patients were using corticosteroids, with 58% of those taking a prednisone equivalent of more than 5.7 mg/day. More than half (65%) were using antimalarials, and 49% were taking another immunosuppressant, including azathioprine, methotrexate, or mycophenolate mofetil.

Of the six pregnancies among patients assigned to placebo, there were three elective terminations, two spontaneous miscarriages, and one stillbirth, for a total fetal loss rate of 50%. The three pregnancies with fetal loss included two women who tested positive for anticardiolipin antibodies.

Among the 80 drug-exposed pregnancies, there were 21 elective terminations as well as 20 miscarriages and 1 stillbirth, yielding a total fetal loss rate of 26%. The background miscarriage rate was 12%-22%, and the background stillbirth rate was 2%-5%, both of which are similar to rates observed in the exposed pregnancies. Overall, women tested positive for anticardiolipin antibodies in 20 pregnancies exposed to belimumab, including 21% of the live births and 38% of the fetal losses.

There were 38 live births (48%). Four neonates had a congenital anomaly:

• One with Dandy-Walker syndrome.

• One with an unbalanced translocation (11 and 13) of maternal origin, a strictly genetic anomaly.

• One born at 27 weeks’ gestation with patent ductus arteriosus.

• One with bilateral enlarged kidneys with abnormal function whose mother was receiving ambrisentan, a known teratogen, for portal hypertension. (The infant was placed on dialysis and had the right kidney removed.)

The stillbirths in the placebo and belimumab patients occurred in conjunction with severe, very early third-trimester preeclampsia, Dr. Powell said. She noted that the sample size is so small that it’s unclear whether the results can be extrapolated to larger populations.

However, the Belimumab Pregnancy Registry, established by GlaxoSmithKline, could provide more reliable data, she said. So far, the registry has enrolled nine pregnancies, seven of which have been completed. Among those, there have been six live births and one miscarriage. Three of the infants were preterm, born at 32, 35, and 36 weeks’ gestation. There was one birth defect (mild Epstein’s anomaly of the tricuspid valve).

msullivan@frontlinemedcom.com

On Twitter @alz_gal

PARIS – The live birth rate among women taking belimumab for systemic lupus erythematosus is similar to the background rate for women with the disorder, a study showed.

An analysis of clinical trials found that women who were taking the drug when they became pregnant had a live birth rate of 48% – in line with studies that place the rate at 55%-88%, Dr. Marcy Powell said at the annual European Congress of Rheumatology.

Although the number of pregnancies examined in the studies was small – with 80 exposed to belimumab (Benlysta) and 6 to placebo – the results were echoed by the initial findings in a recently established belimumab pregnancy registry, said Dr. Powell, director of safety evaluation and risk management at GlaxoSmithKline, which manufactures the drug.

More than 3,000 adult patients have been treated with belimumab – many for more than 10 years, but there are scant data on pregnancy outcomes. It’s a category C drug; women are advised to avoid pregnancy while taking it and for at least 4 months after stopping it. Thus, the only available pregnancy data are from inadvertent exposures in which the drug was stopped as soon as the pregnancy was discovered.

The data were drawn from the BLISS 52 and 78 studies, which enrolled more than 1,600 patients, 94% of whom were women. At baseline, the patients’ mean age was 38 years. Other medications were common in the cohort: 86% of patients were using corticosteroids, with 58% of those taking a prednisone equivalent of more than 5.7 mg/day. More than half (65%) were using antimalarials, and 49% were taking another immunosuppressant, including azathioprine, methotrexate, or mycophenolate mofetil.

Of the six pregnancies among patients assigned to placebo, there were three elective terminations, two spontaneous miscarriages, and one stillbirth, for a total fetal loss rate of 50%. The three pregnancies with fetal loss included two women who tested positive for anticardiolipin antibodies.

Among the 80 drug-exposed pregnancies, there were 21 elective terminations as well as 20 miscarriages and 1 stillbirth, yielding a total fetal loss rate of 26%. The background miscarriage rate was 12%-22%, and the background stillbirth rate was 2%-5%, both of which are similar to rates observed in the exposed pregnancies. Overall, women tested positive for anticardiolipin antibodies in 20 pregnancies exposed to belimumab, including 21% of the live births and 38% of the fetal losses.

There were 38 live births (48%). Four neonates had a congenital anomaly:

• One with Dandy-Walker syndrome.

• One with an unbalanced translocation (11 and 13) of maternal origin, a strictly genetic anomaly.

• One born at 27 weeks’ gestation with patent ductus arteriosus.

• One with bilateral enlarged kidneys with abnormal function whose mother was receiving ambrisentan, a known teratogen, for portal hypertension. (The infant was placed on dialysis and had the right kidney removed.)

The stillbirths in the placebo and belimumab patients occurred in conjunction with severe, very early third-trimester preeclampsia, Dr. Powell said. She noted that the sample size is so small that it’s unclear whether the results can be extrapolated to larger populations.

However, the Belimumab Pregnancy Registry, established by GlaxoSmithKline, could provide more reliable data, she said. So far, the registry has enrolled nine pregnancies, seven of which have been completed. Among those, there have been six live births and one miscarriage. Three of the infants were preterm, born at 32, 35, and 36 weeks’ gestation. There was one birth defect (mild Epstein’s anomaly of the tricuspid valve).

msullivan@frontlinemedcom.com

On Twitter @alz_gal