Obstetrics

A large pooled analysis of almost 24,000 women showed women who breastfed had a 24% lower risk of invasive ovarian cancer.

Bonnie Becker/MDedge News

Multiple studies have reported a link between breastfeeding and a reduced risk of ovarian cancer, but other studies have found no such link, and the evidence that the protective effects differ by histologic types has been inconclusive.

“This large study with extensive information on breastfeeding provides epidemiological evidence that breastfeeding, a potentially modifiable factor, may confer significant reduction in ovarian cancer risk, including high-grade serous, the deadliest subtype,” Ana Babic, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues reported in JAMA Oncology.

Dr. Babic led the study of a pooled analysis of women from 13 case-control studies participating in the Ovarian Cancer Association Consortium. The study evaluated 9,973 women who had ovarian cancer and 13,843 controls, with a mean age of 57 and 56 years, respectively. The data were collected over 20 years through December 2009. Dr. Babic and colleagues claimed that this is the largest study of breastfeeding and ovarian cancer risk to date.

Besides calculating a lower risk of invasive cancer, the analysis also determined that any breastfeeding was associated with a 28% lower risk of borderline cancers, compared with women who never breastfed. “Among invasive tumors, the association was statistically significant for high-grade serous, endometrioid and clear-cell tumors,” Dr. Babic and colleagues wrote, with 25%, 27% and 22% reduced risk, respectively. The researchers also noted a similar, although not statistically significant, reduced risk for low-grade serous tumors, but no such association for mucinous tumors. For borderline tumors, breastfeeding correlated with a 32% lower risk for mucinous tumors and 23% reduction in risk for serous tumors.

The analysis included five studies with data on exclusive breastfeeding. Women who breastfed exclusively for at least 3 months had a 19% reduced risk of ovarian cancer, compared with women who never breastfed, while women who breastfed albeit not exclusively for 3 months had a 30% reduced risk. The analysis also found an association between longer duration of breastfeeding and reduced risk of invasive ovarian cancer: less than 3 months duration per child was associated with an 18% lower risk, while more than 12 months was associated with a 34% lower risk (P < .001). Other factors that seemed to mitigate risk were older age when breastfeeding and breastfeeding within the previous 10 years.

One of the strengths of the studies is that it separated low-grade and the more common and deadly high-grade serous tumors. While the analysis found similar trends with endometrioid ovarian cancers, it didn’t reach a conclusion about other invasive histotypes because there were fewer cases to evaluate. Because the study population was predominantly white, the researchers acknowledged they could not sufficiently evaluate patterns among blacks, Asian, and other ethnic groups. “The association between breastfeeding and ovarian cancer needs to be investigated in large populations of other races and ethnicities,” Dr. Babic and colleagues added.

Nonetheless, they noted that their results support the World Health Organization recommendations of at least 6 months of exclusive breastfeeding and continued breastfeeding with complementary foods for 2 years or more, even though breastfeeding for less than 3 months is associated with a significant reduction in ovarian cancer risk.

The study is significant because of its “thoughtful approach to addressing potential confounders (parity, age, etc.),” said David Barrington, MD, gynecologic oncology fellow at Ohio State University James Cancer Center in Columbus.

“For general obstetricians and gynecologists, this study provides an additional reason to advocate for breastfeeding,” Dr. Barrington added. “This data should be included in a thorough discussion of the multitudes of benefits breastfeeding provides to both the infant and the mother.”

He added that future studies should evaluate breastfeeding and ovarian cancer risks in a more ethnically diverse population. “Understanding the potential impact of modifiable risk factors for ovarian cancer is paramount to overcoming racial disparities in outcomes,” Dr. Barrington said.

The study was supported by the U.S. National Cancer Institute. Dr. Babic reported grants from the U.S. National Institutes of Health. Some coauthors reported grants from the NIH, the National Health and Medical Research Council of Australia, the Federal Ministry of Education and Research of Germany, the Danish Cancer Society, or the Mermaid I Project. Some coauthors had no disclosures to report. Dr. Barrington has no relevant relationships to disclose.

SOURCE: Babic A et al. JAMA Oncology. 2020. doi: 10.1001/jamaoncol.2020.0421.

A large pooled analysis of almost 24,000 women showed women who breastfed had a 24% lower risk of invasive ovarian cancer.

Bonnie Becker/MDedge News

Multiple studies have reported a link between breastfeeding and a reduced risk of ovarian cancer, but other studies have found no such link, and the evidence that the protective effects differ by histologic types has been inconclusive.

“This large study with extensive information on breastfeeding provides epidemiological evidence that breastfeeding, a potentially modifiable factor, may confer significant reduction in ovarian cancer risk, including high-grade serous, the deadliest subtype,” Ana Babic, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues reported in JAMA Oncology.

Dr. Babic led the study of a pooled analysis of women from 13 case-control studies participating in the Ovarian Cancer Association Consortium. The study evaluated 9,973 women who had ovarian cancer and 13,843 controls, with a mean age of 57 and 56 years, respectively. The data were collected over 20 years through December 2009. Dr. Babic and colleagues claimed that this is the largest study of breastfeeding and ovarian cancer risk to date.

Besides calculating a lower risk of invasive cancer, the analysis also determined that any breastfeeding was associated with a 28% lower risk of borderline cancers, compared with women who never breastfed. “Among invasive tumors, the association was statistically significant for high-grade serous, endometrioid and clear-cell tumors,” Dr. Babic and colleagues wrote, with 25%, 27% and 22% reduced risk, respectively. The researchers also noted a similar, although not statistically significant, reduced risk for low-grade serous tumors, but no such association for mucinous tumors. For borderline tumors, breastfeeding correlated with a 32% lower risk for mucinous tumors and 23% reduction in risk for serous tumors.

The analysis included five studies with data on exclusive breastfeeding. Women who breastfed exclusively for at least 3 months had a 19% reduced risk of ovarian cancer, compared with women who never breastfed, while women who breastfed albeit not exclusively for 3 months had a 30% reduced risk. The analysis also found an association between longer duration of breastfeeding and reduced risk of invasive ovarian cancer: less than 3 months duration per child was associated with an 18% lower risk, while more than 12 months was associated with a 34% lower risk (P < .001). Other factors that seemed to mitigate risk were older age when breastfeeding and breastfeeding within the previous 10 years.

One of the strengths of the studies is that it separated low-grade and the more common and deadly high-grade serous tumors. While the analysis found similar trends with endometrioid ovarian cancers, it didn’t reach a conclusion about other invasive histotypes because there were fewer cases to evaluate. Because the study population was predominantly white, the researchers acknowledged they could not sufficiently evaluate patterns among blacks, Asian, and other ethnic groups. “The association between breastfeeding and ovarian cancer needs to be investigated in large populations of other races and ethnicities,” Dr. Babic and colleagues added.

Nonetheless, they noted that their results support the World Health Organization recommendations of at least 6 months of exclusive breastfeeding and continued breastfeeding with complementary foods for 2 years or more, even though breastfeeding for less than 3 months is associated with a significant reduction in ovarian cancer risk.

The study is significant because of its “thoughtful approach to addressing potential confounders (parity, age, etc.),” said David Barrington, MD, gynecologic oncology fellow at Ohio State University James Cancer Center in Columbus.

“For general obstetricians and gynecologists, this study provides an additional reason to advocate for breastfeeding,” Dr. Barrington added. “This data should be included in a thorough discussion of the multitudes of benefits breastfeeding provides to both the infant and the mother.”

He added that future studies should evaluate breastfeeding and ovarian cancer risks in a more ethnically diverse population. “Understanding the potential impact of modifiable risk factors for ovarian cancer is paramount to overcoming racial disparities in outcomes,” Dr. Barrington said.

The study was supported by the U.S. National Cancer Institute. Dr. Babic reported grants from the U.S. National Institutes of Health. Some coauthors reported grants from the NIH, the National Health and Medical Research Council of Australia, the Federal Ministry of Education and Research of Germany, the Danish Cancer Society, or the Mermaid I Project. Some coauthors had no disclosures to report. Dr. Barrington has no relevant relationships to disclose.

SOURCE: Babic A et al. JAMA Oncology. 2020. doi: 10.1001/jamaoncol.2020.0421.

A large pooled analysis of almost 24,000 women showed women who breastfed had a 24% lower risk of invasive ovarian cancer.

Bonnie Becker/MDedge News

Multiple studies have reported a link between breastfeeding and a reduced risk of ovarian cancer, but other studies have found no such link, and the evidence that the protective effects differ by histologic types has been inconclusive.

“This large study with extensive information on breastfeeding provides epidemiological evidence that breastfeeding, a potentially modifiable factor, may confer significant reduction in ovarian cancer risk, including high-grade serous, the deadliest subtype,” Ana Babic, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues reported in JAMA Oncology.

Dr. Babic led the study of a pooled analysis of women from 13 case-control studies participating in the Ovarian Cancer Association Consortium. The study evaluated 9,973 women who had ovarian cancer and 13,843 controls, with a mean age of 57 and 56 years, respectively. The data were collected over 20 years through December 2009. Dr. Babic and colleagues claimed that this is the largest study of breastfeeding and ovarian cancer risk to date.

Besides calculating a lower risk of invasive cancer, the analysis also determined that any breastfeeding was associated with a 28% lower risk of borderline cancers, compared with women who never breastfed. “Among invasive tumors, the association was statistically significant for high-grade serous, endometrioid and clear-cell tumors,” Dr. Babic and colleagues wrote, with 25%, 27% and 22% reduced risk, respectively. The researchers also noted a similar, although not statistically significant, reduced risk for low-grade serous tumors, but no such association for mucinous tumors. For borderline tumors, breastfeeding correlated with a 32% lower risk for mucinous tumors and 23% reduction in risk for serous tumors.

The analysis included five studies with data on exclusive breastfeeding. Women who breastfed exclusively for at least 3 months had a 19% reduced risk of ovarian cancer, compared with women who never breastfed, while women who breastfed albeit not exclusively for 3 months had a 30% reduced risk. The analysis also found an association between longer duration of breastfeeding and reduced risk of invasive ovarian cancer: less than 3 months duration per child was associated with an 18% lower risk, while more than 12 months was associated with a 34% lower risk (P < .001). Other factors that seemed to mitigate risk were older age when breastfeeding and breastfeeding within the previous 10 years.

One of the strengths of the studies is that it separated low-grade and the more common and deadly high-grade serous tumors. While the analysis found similar trends with endometrioid ovarian cancers, it didn’t reach a conclusion about other invasive histotypes because there were fewer cases to evaluate. Because the study population was predominantly white, the researchers acknowledged they could not sufficiently evaluate patterns among blacks, Asian, and other ethnic groups. “The association between breastfeeding and ovarian cancer needs to be investigated in large populations of other races and ethnicities,” Dr. Babic and colleagues added.

Nonetheless, they noted that their results support the World Health Organization recommendations of at least 6 months of exclusive breastfeeding and continued breastfeeding with complementary foods for 2 years or more, even though breastfeeding for less than 3 months is associated with a significant reduction in ovarian cancer risk.

The study is significant because of its “thoughtful approach to addressing potential confounders (parity, age, etc.),” said David Barrington, MD, gynecologic oncology fellow at Ohio State University James Cancer Center in Columbus.

“For general obstetricians and gynecologists, this study provides an additional reason to advocate for breastfeeding,” Dr. Barrington added. “This data should be included in a thorough discussion of the multitudes of benefits breastfeeding provides to both the infant and the mother.”

He added that future studies should evaluate breastfeeding and ovarian cancer risks in a more ethnically diverse population. “Understanding the potential impact of modifiable risk factors for ovarian cancer is paramount to overcoming racial disparities in outcomes,” Dr. Barrington said.

The study was supported by the U.S. National Cancer Institute. Dr. Babic reported grants from the U.S. National Institutes of Health. Some coauthors reported grants from the NIH, the National Health and Medical Research Council of Australia, the Federal Ministry of Education and Research of Germany, the Danish Cancer Society, or the Mermaid I Project. Some coauthors had no disclosures to report. Dr. Barrington has no relevant relationships to disclose.

SOURCE: Babic A et al. JAMA Oncology. 2020. doi: 10.1001/jamaoncol.2020.0421.

In my New Mexico reproductive health clinic one week in early April, I saw more than twice the number of patients usually scheduled, all seeking abortion care. Two-thirds of those patients were from Texas – some came from towns as close as 6 hours away, and at least two drove for more than 11 hours to receive care at our clinic. In addition to the many reasons women pursue abortion care, all of my patients had an overriding concern about the COVID-19 pandemic. Many worried for the safety of their parents and children; some worried about the safety of continuing a pregnancy during the pandemic; and many were worried for themselves because of the risk involved in their employment or their status as the sole breadwinner for their families. One patient chose an abortion for severe fetal anomalies diagnosed in the early second trimester; she had an appointment with a provider in Texas, which was canceled the day the Texas abortion ban was reinstated. New Mexico, more than 10 hours away, was the closest location to receive the care she needed; she traveled by car with her children.

I am fortunate to live in New Mexico. On March 24, New Mexico Secretary of Health Kathyleen “Kathy” Kunkel affirmed reproductive health care as an essential service. The American College of Obstetricians and Gynecologists, the U.S. professional organization for reproductive health care, agrees. In a joint statement with seven other professional organizations, they emphasize the importance of abortion access: “Abortion is an essential component of comprehensive health care. It is also a time-sensitive service. The consequences of being unable to obtain an abortion profoundly impact a person’s life, health, and well-being.”

Anti-abortion politicians are using the crisis as an opportunity to restrict health care access as they have done for my patients who have driven hundreds of miles for essential care they should receive in their home communities. My heart goes out to our patients and the burden they have been forced to take on at a time when our politicians should be protecting and ensuring their safety. Particularly during this national emergency, we should come together to support women and families, and to ensure all of our health care needs are met.

Dr. Espey is an obstetrician and gynecologist in New Mexico. She has no relevant financial disclosures. Dr. Espey is a member of the Ob.Gyn. News Editorial Advisory Board. Email her at [email protected].

In my New Mexico reproductive health clinic one week in early April, I saw more than twice the number of patients usually scheduled, all seeking abortion care. Two-thirds of those patients were from Texas – some came from towns as close as 6 hours away, and at least two drove for more than 11 hours to receive care at our clinic. In addition to the many reasons women pursue abortion care, all of my patients had an overriding concern about the COVID-19 pandemic. Many worried for the safety of their parents and children; some worried about the safety of continuing a pregnancy during the pandemic; and many were worried for themselves because of the risk involved in their employment or their status as the sole breadwinner for their families. One patient chose an abortion for severe fetal anomalies diagnosed in the early second trimester; she had an appointment with a provider in Texas, which was canceled the day the Texas abortion ban was reinstated. New Mexico, more than 10 hours away, was the closest location to receive the care she needed; she traveled by car with her children.

I am fortunate to live in New Mexico. On March 24, New Mexico Secretary of Health Kathyleen “Kathy” Kunkel affirmed reproductive health care as an essential service. The American College of Obstetricians and Gynecologists, the U.S. professional organization for reproductive health care, agrees. In a joint statement with seven other professional organizations, they emphasize the importance of abortion access: “Abortion is an essential component of comprehensive health care. It is also a time-sensitive service. The consequences of being unable to obtain an abortion profoundly impact a person’s life, health, and well-being.”

Anti-abortion politicians are using the crisis as an opportunity to restrict health care access as they have done for my patients who have driven hundreds of miles for essential care they should receive in their home communities. My heart goes out to our patients and the burden they have been forced to take on at a time when our politicians should be protecting and ensuring their safety. Particularly during this national emergency, we should come together to support women and families, and to ensure all of our health care needs are met.

Dr. Espey is an obstetrician and gynecologist in New Mexico. She has no relevant financial disclosures. Dr. Espey is a member of the Ob.Gyn. News Editorial Advisory Board. Email her at [email protected].

In my New Mexico reproductive health clinic one week in early April, I saw more than twice the number of patients usually scheduled, all seeking abortion care. Two-thirds of those patients were from Texas – some came from towns as close as 6 hours away, and at least two drove for more than 11 hours to receive care at our clinic. In addition to the many reasons women pursue abortion care, all of my patients had an overriding concern about the COVID-19 pandemic. Many worried for the safety of their parents and children; some worried about the safety of continuing a pregnancy during the pandemic; and many were worried for themselves because of the risk involved in their employment or their status as the sole breadwinner for their families. One patient chose an abortion for severe fetal anomalies diagnosed in the early second trimester; she had an appointment with a provider in Texas, which was canceled the day the Texas abortion ban was reinstated. New Mexico, more than 10 hours away, was the closest location to receive the care she needed; she traveled by car with her children.

I am fortunate to live in New Mexico. On March 24, New Mexico Secretary of Health Kathyleen “Kathy” Kunkel affirmed reproductive health care as an essential service. The American College of Obstetricians and Gynecologists, the U.S. professional organization for reproductive health care, agrees. In a joint statement with seven other professional organizations, they emphasize the importance of abortion access: “Abortion is an essential component of comprehensive health care. It is also a time-sensitive service. The consequences of being unable to obtain an abortion profoundly impact a person’s life, health, and well-being.”

Anti-abortion politicians are using the crisis as an opportunity to restrict health care access as they have done for my patients who have driven hundreds of miles for essential care they should receive in their home communities. My heart goes out to our patients and the burden they have been forced to take on at a time when our politicians should be protecting and ensuring their safety. Particularly during this national emergency, we should come together to support women and families, and to ensure all of our health care needs are met.

Dr. Espey is an obstetrician and gynecologist in New Mexico. She has no relevant financial disclosures. Dr. Espey is a member of the Ob.Gyn. News Editorial Advisory Board. Email her at [email protected].

Maternal preconception exposure to phthalates was associated with increased risk of preterm birth, according to a study of 420 births to subfertile couples over a 13-year period.

Previous studies have shown increased risk of preterm birth associated with prenatal exposure to phthalates, which are commonly found in a range of household and commercial products as well as medical equipment and some pharmaceuticals.

“Our results suggest that female exposure to [4 di(2-ethylhexyl) phthalate] DEHP before conception might be an unrecognized risk factor for adverse pregnancy outcomes, often overlooked in clinical practice,” wrote Yu Zhang of the department of environmental health at Harvard T.H. Chan School of Public Health, Boston, and colleagues.

The prospective cohort study evaluated preconception urinary levels of phthalates and phthalate substitutes in 419 women and 229 men participating in the Environment and Reproductive Health (EARTH) study, a cohort of couples seeking fertility care at the Massachusetts General Hospital Fertility Center. The study cohort gave birth during 2005-2018. The average gestational age of the 420 singleton children born to this cohort was 39 weeks, with 8% (n = 34) born preterm.

Adjusted models showed that maternal preconception urinary concentrations of phthalates and of cyclohexane-1, 2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH), a metabolite of a nonphthalate plasticizer substitute, were associated with a 50% and 70% increased risk of preterm birth, respectively (P = .01, .11), according to results published in JAMA Network Open .

Sensitivity analysis showed that maternal preconception MHiNCH concentrations above the median were associated with a fourfold increased risk of preterm birth (risk ratio, 4.02; P = .08), Maternal preconception MHiNCH concentrations were associated with an average 2-day reduction in gestational age (P = .02).

Covariate-adjusted models found that paternal urinary phthalate metabolite concentrations were associated with an increased risk of preterm birth (RR, 1.41; P = .09), but this association was attenuated toward zero (RR, 1.06) in models that accounted for maternal preconception phthalate concentrations. Sensitivity analysis of 228 couples found the associations of maternal preconception phthalate metabolite concentrations and preterm birth remained robust in three different models: a twofold increased risk in covariate-adjusted models (P < .001); an almost fivefold increased risk in adjusting for prenatal levels (RR, 4.98; P < .001); and a twofold risk (P = .001) in adjusting for paternal levels. “Couple-based analyses confirmed the results for an association between maternal preconception DEHP concentrations and increased risk of preterm birth,” the investigators said.

“To our knowledge, this is the first study evaluating couples’ exposure to phthalate metabolites during the preconception window and its association with preterm birth,” the researchers wrote. “Our findings support a novel hypothesis: Maternal phthalate exposure during the critical period before conception may be associated with shorter gestation.”

“This study is consistent with several, but not all, prior studies supporting maternal prenatal exposure to phthalates increase preterm birth,” said Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida, Orlando. “The uniqueness of the current study was the assessment of couples’ exposures and the outcome, though paternal exposure to phthalates did not demonstrate a significant association.”

Dr. Trolice noted that about 25% of women in the study were smokers, but the study didn’t adjust for tobacco use and phthalate exposure, and 85% of the women were white. He urged caution in applying the study results in practice, adding that the study didn’t adjust for method of conception. “Assisted reproductive technology, multiple gestation, and advanced age are all known risk factors for preterm birth,”

The National Institute of Environmental Health Science funded the study. Two study coauthors received grants from the NIEHS, one coauthor received grants from the National Institutes of Health, and one received a grant from the Canadian Institutes of Health Research. No other disclosures were reported. Dr. Trolice has no financial relationships to disclose.

SOURCE: Zhang Y et al. JAMA Network Open. 2020; doi: 10.1001/jamanetworkopen.2020.2159.

Maternal preconception exposure to phthalates was associated with increased risk of preterm birth, according to a study of 420 births to subfertile couples over a 13-year period.

Previous studies have shown increased risk of preterm birth associated with prenatal exposure to phthalates, which are commonly found in a range of household and commercial products as well as medical equipment and some pharmaceuticals.

“Our results suggest that female exposure to [4 di(2-ethylhexyl) phthalate] DEHP before conception might be an unrecognized risk factor for adverse pregnancy outcomes, often overlooked in clinical practice,” wrote Yu Zhang of the department of environmental health at Harvard T.H. Chan School of Public Health, Boston, and colleagues.

The prospective cohort study evaluated preconception urinary levels of phthalates and phthalate substitutes in 419 women and 229 men participating in the Environment and Reproductive Health (EARTH) study, a cohort of couples seeking fertility care at the Massachusetts General Hospital Fertility Center. The study cohort gave birth during 2005-2018. The average gestational age of the 420 singleton children born to this cohort was 39 weeks, with 8% (n = 34) born preterm.

Adjusted models showed that maternal preconception urinary concentrations of phthalates and of cyclohexane-1, 2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH), a metabolite of a nonphthalate plasticizer substitute, were associated with a 50% and 70% increased risk of preterm birth, respectively (P = .01, .11), according to results published in JAMA Network Open .

Sensitivity analysis showed that maternal preconception MHiNCH concentrations above the median were associated with a fourfold increased risk of preterm birth (risk ratio, 4.02; P = .08), Maternal preconception MHiNCH concentrations were associated with an average 2-day reduction in gestational age (P = .02).

Covariate-adjusted models found that paternal urinary phthalate metabolite concentrations were associated with an increased risk of preterm birth (RR, 1.41; P = .09), but this association was attenuated toward zero (RR, 1.06) in models that accounted for maternal preconception phthalate concentrations. Sensitivity analysis of 228 couples found the associations of maternal preconception phthalate metabolite concentrations and preterm birth remained robust in three different models: a twofold increased risk in covariate-adjusted models (P < .001); an almost fivefold increased risk in adjusting for prenatal levels (RR, 4.98; P < .001); and a twofold risk (P = .001) in adjusting for paternal levels. “Couple-based analyses confirmed the results for an association between maternal preconception DEHP concentrations and increased risk of preterm birth,” the investigators said.

“To our knowledge, this is the first study evaluating couples’ exposure to phthalate metabolites during the preconception window and its association with preterm birth,” the researchers wrote. “Our findings support a novel hypothesis: Maternal phthalate exposure during the critical period before conception may be associated with shorter gestation.”

“This study is consistent with several, but not all, prior studies supporting maternal prenatal exposure to phthalates increase preterm birth,” said Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida, Orlando. “The uniqueness of the current study was the assessment of couples’ exposures and the outcome, though paternal exposure to phthalates did not demonstrate a significant association.”

Dr. Trolice noted that about 25% of women in the study were smokers, but the study didn’t adjust for tobacco use and phthalate exposure, and 85% of the women were white. He urged caution in applying the study results in practice, adding that the study didn’t adjust for method of conception. “Assisted reproductive technology, multiple gestation, and advanced age are all known risk factors for preterm birth,”

The National Institute of Environmental Health Science funded the study. Two study coauthors received grants from the NIEHS, one coauthor received grants from the National Institutes of Health, and one received a grant from the Canadian Institutes of Health Research. No other disclosures were reported. Dr. Trolice has no financial relationships to disclose.

SOURCE: Zhang Y et al. JAMA Network Open. 2020; doi: 10.1001/jamanetworkopen.2020.2159.

Maternal preconception exposure to phthalates was associated with increased risk of preterm birth, according to a study of 420 births to subfertile couples over a 13-year period.

Previous studies have shown increased risk of preterm birth associated with prenatal exposure to phthalates, which are commonly found in a range of household and commercial products as well as medical equipment and some pharmaceuticals.

“Our results suggest that female exposure to [4 di(2-ethylhexyl) phthalate] DEHP before conception might be an unrecognized risk factor for adverse pregnancy outcomes, often overlooked in clinical practice,” wrote Yu Zhang of the department of environmental health at Harvard T.H. Chan School of Public Health, Boston, and colleagues.

The prospective cohort study evaluated preconception urinary levels of phthalates and phthalate substitutes in 419 women and 229 men participating in the Environment and Reproductive Health (EARTH) study, a cohort of couples seeking fertility care at the Massachusetts General Hospital Fertility Center. The study cohort gave birth during 2005-2018. The average gestational age of the 420 singleton children born to this cohort was 39 weeks, with 8% (n = 34) born preterm.

Adjusted models showed that maternal preconception urinary concentrations of phthalates and of cyclohexane-1, 2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH), a metabolite of a nonphthalate plasticizer substitute, were associated with a 50% and 70% increased risk of preterm birth, respectively (P = .01, .11), according to results published in JAMA Network Open .

Sensitivity analysis showed that maternal preconception MHiNCH concentrations above the median were associated with a fourfold increased risk of preterm birth (risk ratio, 4.02; P = .08), Maternal preconception MHiNCH concentrations were associated with an average 2-day reduction in gestational age (P = .02).

Covariate-adjusted models found that paternal urinary phthalate metabolite concentrations were associated with an increased risk of preterm birth (RR, 1.41; P = .09), but this association was attenuated toward zero (RR, 1.06) in models that accounted for maternal preconception phthalate concentrations. Sensitivity analysis of 228 couples found the associations of maternal preconception phthalate metabolite concentrations and preterm birth remained robust in three different models: a twofold increased risk in covariate-adjusted models (P < .001); an almost fivefold increased risk in adjusting for prenatal levels (RR, 4.98; P < .001); and a twofold risk (P = .001) in adjusting for paternal levels. “Couple-based analyses confirmed the results for an association between maternal preconception DEHP concentrations and increased risk of preterm birth,” the investigators said.

“To our knowledge, this is the first study evaluating couples’ exposure to phthalate metabolites during the preconception window and its association with preterm birth,” the researchers wrote. “Our findings support a novel hypothesis: Maternal phthalate exposure during the critical period before conception may be associated with shorter gestation.”

“This study is consistent with several, but not all, prior studies supporting maternal prenatal exposure to phthalates increase preterm birth,” said Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida, Orlando. “The uniqueness of the current study was the assessment of couples’ exposures and the outcome, though paternal exposure to phthalates did not demonstrate a significant association.”

Dr. Trolice noted that about 25% of women in the study were smokers, but the study didn’t adjust for tobacco use and phthalate exposure, and 85% of the women were white. He urged caution in applying the study results in practice, adding that the study didn’t adjust for method of conception. “Assisted reproductive technology, multiple gestation, and advanced age are all known risk factors for preterm birth,”

The National Institute of Environmental Health Science funded the study. Two study coauthors received grants from the NIEHS, one coauthor received grants from the National Institutes of Health, and one received a grant from the Canadian Institutes of Health Research. No other disclosures were reported. Dr. Trolice has no financial relationships to disclose.

SOURCE: Zhang Y et al. JAMA Network Open. 2020; doi: 10.1001/jamanetworkopen.2020.2159.

Authors of a recent Cochrane review concluded that low-dose aspirin treatment of 1,000 pregnant women at risk of developing preeclampsia resulted in 16 fewer cases of preeclampsia, 16 fewer preterm births, 7 fewer cases of small-for-gestational age newborns, and 5 fewer fetal or neonatal deaths.¹

The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend treatment with 81 mg of aspirin daily, initiated before 16 weeks of pregnancy to prevent preeclampsia in women with one major risk factor (personal history of preeclampsia, multifetal gestation, chronic hypertension, type 1 or 2 diabetes, renal or autoimmune disease) or at least two moderate risk factors (nulliparity; obesity; mother or sister with preeclampsia; a sociodemographic characteristic such as African American race or low socioeconomic status; age ≥35 years; personal history factors such as prior low birth weight infant, previous adverse pregnancy outcome, or >10-year interpregnancy interval).^2,3 Healthy pregnant women with a previous uncomplicated full-term delivery do not need treatment with low-dose aspirin.^2,3

However, evolving data and expert opinion suggest that expanding the indications for aspirin treatment and increasing the recommended dose of aspirin may be warranted. 

Nulliparity

Nulliparity is the single clinical characteristic that is associated with the greatest number of cases of preeclampsia.⁴ Hence, from a public health perspective, reducing the rate of preeclampsia among nulliparous women is a top priority.

ACOG and USPSTF do not recommend aspirin treatment for all nulliparous women because risk factors help to identify those nulliparous women who benefit from aspirin treatment.

However, a recent cost-effectiveness analysis compared the health care costs and rates of preeclampsia for 4 prevention strategies among all pregnant women in the United States (nulliparous and parous)⁵:

1. no aspirin use
2. use of aspirin based on biomarker and ultrasound measurements
3. use of aspirin based on USPSTF guidelines for identifying women at risk
4. prescription of aspirin to all pregnant women.

Health care costs and rates of preeclampsia were lowest with the universal prescription of aspirin to all pregnant women in the United States. Compared with universal prescription of aspirin, the USPSTF approach, the biomarker-ultrasound approach, and the no aspirin approach were associated with 346, 308, and 762 additional cases of preeclampsia per 100,000 women. In sensitivity analyses, universal aspirin was the optimal strategy under most assumptions.

Another cost effectiveness analysis concluded that among nulliparous pregnant women, universal aspirin treatment was superior to aspirin treatment based on biomarker-ultrasound identification of women at high risk.⁶ 

In a recent clinical trial performed in India, Guatemala, Pakistan, Democratic Republic of Congo, Kenya, and Zambia, 14,361 nulliparous women were randomly assigned to placebo or 81 mg of aspirin daily between 6 and 14 weeks of gestation.⁷ Preterm birth (<37 weeks’ gestation) occurred in 13.1% and 11.6% of women treated with placebo or aspirin (relative risk [RR], 0.89; 95% confidence interval [CI], 0.81 to 0.98, P = .012). Most of the decrease in preterm birth appeared to be due to a decrease in the rate of preeclampsia in the aspirin-treated nulliparous women. The investigators also noted that aspirin treatment of nulliparous women resulted in a statistically significant decrease in perinatal mortality (RR, 0.86) and early preterm delivery, <34 weeks’ gestation (RR, 0.75). 

Universal prescription of low-dose aspirin to nulliparous women in order to prevent preeclampsia and preterm birth may become recognized as an optimal public health strategy. As a step toward universal prescription of aspirin to nulliparous women, an opt-out rather than a screen-in strategy might be considered.⁸

Continue to: Booking systolic blood pressure, 120 to 134 mm Hg...

Booking systolic blood pressure, 120 to 134 mm Hg

All obstetricians recognize that women with chronic hypertension should be treated with low-dose aspirin because they are at high risk for preeclampsia. However, there is evidence that nulliparous women with a booking systolic pressure ≥120 mm Hg might also benefit from low-dose aspirin treatment. In one US trial, 3,135 nulliparous normotensive women (booking blood pressure [BP] <135/85 mm Hg) were randomly assigned to treatment with aspirin (60 mg daily) or placebo initiated between 13 and 26 weeks’ gestation. Preeclampsia occurred in 6.3% and 4.6% of the women treated with placebo or aspirin, respectively (RR, 0.7; 95% CI, 0.6–1.0; P = .05).⁹ A secondary analysis showed that, among 519 nulliparous women with a booking systolic BP from 120 to 134 mm Hg, compared with placebo, low-dose aspirin treatment reduced the rate of preeclampsia from 11.9% to 5.6%.⁹ Aspirin did not reduce the rate of preeclampsia among nulliparous women with a booking systolic BP <120 mm Hg.⁹ A systematic review of risk factors for developing preeclampsia reported that a booking diastolic BP of ≥80 mm Hg was associated with an increased risk of developing preeclampsia (RR, 1.38).¹⁰ 

The American Heart Association (AHA) and the American College of Cardiology (ACC) recently updated the definition of hypertension.¹¹ Normal BP is now defined as a systolic pressure <120 mm Hg and diastolic pressure <80 mm Hg. Elevated BP is a systolic pressure of 120 to 129 mm Hg and diastolic pressure of <80 mm Hg. Stage I hypertension is a systolic BP from 130 to 139 mm Hg or diastolic blood pressure from 80 to 89 mm Hg. Stage II hypertension is a systolic BP of ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg.¹¹ 

A recent study reported that 90% of women at 12 weeks’ gestation have a BP of ≤130 mm Hg systolic and ≤80 mm Hg diastolic, suggesting that the AHA-ACC criteria for stage I hypertension are reasonable.¹² Obstetricians have not yet fully adopted the AHA-ACC criteria for defining stage I hypertension in pregnant women. Future research may demonstrate that a booking systolic BP 
 ≥130 mm Hg or a diastolic BP ≥80 mm Hg are major risk factors for developing preeclampsia and warrant treatment with low-dose aspirin.

Continue to: Pregnancy resulting from fertility therapy...

Pregnancy resulting from fertility therapy

Current ACOG and USPSTF guidelines do not specifically identify pregnancies resulting from assisted reproductive technology as a major or moderate risk factor for preeclampsia.^2,3 In a study comparing 83,582 births resulting from in vitro fertilization (IVF) and 1,382,311 births to fertile women, treatment with autologous cryopreserved embryos (adjusted odds ratio [aOR], 1.30), fresh donor embryos (aOR, 1.92), and cryopreserved donor embryos (aOR, 1.70) significantly increased the risk of preeclampsia.¹³ However, use of fresh autologous embryos did not increase the risk of preeclampsia (aOR, 1.04). These associations persisted after controlling for diabetes, hypertension, body mass index, and cause of infertility.¹³

Other studies also have reported that use of cryopreserved embryos is associated with a higher rate of preeclampsia than use of fresh autologous embryos. In a study of 825 infertile women undergoing IVF and randomly assigned to single embryo cryopreserved or fresh cycles, the rate of preeclampsia was 3.1% and 1.0% in the pregnancies that resulted from cryopreserved versus fresh cycles.¹⁴ 

What is the optimal dose of aspirin?

ACOG and the USPSTF recommend aspirin 81 mg daily for the prevention of preeclampsia.^2,3 The International Federation of Gynecology and Obstetrics (FIGO) recommends aspirin 150 mg daily for the prevention of preeclampsia.¹⁵ The FIGO recommendation is based, in part, on the results of a large international clinical trial that randomly assigned 1,776 women at high risk for preeclampsia as determined by clinical factors plus biomarker and ultrasound screening to receive aspirin 150 mg daily or placebo daily initiated at 11 to 14 weeks’ gestation and continued until 36 weeks’ gestation.¹⁶ Preeclampsia before 37 weeks’ gestation occurred in 4.3% and 1.6% of women in the placebo and aspirin groups (OR, 0.38; 95% CI, 0.20–0.74; P = .004).¹⁶ FIGO recommends that women at risk for preeclampsia with a body mass <40 kg take aspirin 100 mg daily and women with a body mass ≥40 kg take aspirin at a dose of 150 mg daily. For women who live in a country where aspirin is not available in a pill containing 150 mg, FIGO recommends taking two 81 mg tablets.¹⁵ FIGO recommends initiating aspirin between 11 and 14 weeks and 6 days of gestation and continuing aspirin therapy until 36 weeks of gestation.¹⁵

Aspirin is an inexpensive intervention with many possible benefits

For many nulliparous women and some parous women aspirin treatment initiated early in pregnancy will improve maternal and newborn outcomes, including reducing the risk of preeclampsia, preterm birth, and intrauterine growth restriction.¹ Obstetricians may want to begin to expand the indications for offering aspirin to prevent preeclampsia from those recommended by ACOG and the USPSTF to include nulliparous women with a booking systolic pressure of 120 to 134 mm Hg and women whose pregnancy was the result of an assisted reproduction treatment that used cryopreserved embryos. In addition, obstetricians who currently prescribe 81 mg of aspirin daily might want to consider increasing the prescribed dose to 162 mg of aspirin daily (two 81 mg tablets daily or one-half of a 325 mg tablet). Aspirin costs about less than 5 cents per 81 mg tablet (according to GoodRx website). It is an inexpensive intervention that could benefit many mothers and newborns. ●

Authors of a recent Cochrane review concluded that low-dose aspirin treatment of 1,000 pregnant women at risk of developing preeclampsia resulted in 16 fewer cases of preeclampsia, 16 fewer preterm births, 7 fewer cases of small-for-gestational age newborns, and 5 fewer fetal or neonatal deaths.¹

The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend treatment with 81 mg of aspirin daily, initiated before 16 weeks of pregnancy to prevent preeclampsia in women with one major risk factor (personal history of preeclampsia, multifetal gestation, chronic hypertension, type 1 or 2 diabetes, renal or autoimmune disease) or at least two moderate risk factors (nulliparity; obesity; mother or sister with preeclampsia; a sociodemographic characteristic such as African American race or low socioeconomic status; age ≥35 years; personal history factors such as prior low birth weight infant, previous adverse pregnancy outcome, or >10-year interpregnancy interval).^2,3 Healthy pregnant women with a previous uncomplicated full-term delivery do not need treatment with low-dose aspirin.^2,3

However, evolving data and expert opinion suggest that expanding the indications for aspirin treatment and increasing the recommended dose of aspirin may be warranted. 

Nulliparity

Nulliparity is the single clinical characteristic that is associated with the greatest number of cases of preeclampsia.⁴ Hence, from a public health perspective, reducing the rate of preeclampsia among nulliparous women is a top priority.

ACOG and USPSTF do not recommend aspirin treatment for all nulliparous women because risk factors help to identify those nulliparous women who benefit from aspirin treatment.

However, a recent cost-effectiveness analysis compared the health care costs and rates of preeclampsia for 4 prevention strategies among all pregnant women in the United States (nulliparous and parous)⁵:

1. no aspirin use
2. use of aspirin based on biomarker and ultrasound measurements
3. use of aspirin based on USPSTF guidelines for identifying women at risk
4. prescription of aspirin to all pregnant women.

Health care costs and rates of preeclampsia were lowest with the universal prescription of aspirin to all pregnant women in the United States. Compared with universal prescription of aspirin, the USPSTF approach, the biomarker-ultrasound approach, and the no aspirin approach were associated with 346, 308, and 762 additional cases of preeclampsia per 100,000 women. In sensitivity analyses, universal aspirin was the optimal strategy under most assumptions.

Another cost effectiveness analysis concluded that among nulliparous pregnant women, universal aspirin treatment was superior to aspirin treatment based on biomarker-ultrasound identification of women at high risk.⁶ 

In a recent clinical trial performed in India, Guatemala, Pakistan, Democratic Republic of Congo, Kenya, and Zambia, 14,361 nulliparous women were randomly assigned to placebo or 81 mg of aspirin daily between 6 and 14 weeks of gestation.⁷ Preterm birth (<37 weeks’ gestation) occurred in 13.1% and 11.6% of women treated with placebo or aspirin (relative risk [RR], 0.89; 95% confidence interval [CI], 0.81 to 0.98, P = .012). Most of the decrease in preterm birth appeared to be due to a decrease in the rate of preeclampsia in the aspirin-treated nulliparous women. The investigators also noted that aspirin treatment of nulliparous women resulted in a statistically significant decrease in perinatal mortality (RR, 0.86) and early preterm delivery, <34 weeks’ gestation (RR, 0.75). 

Universal prescription of low-dose aspirin to nulliparous women in order to prevent preeclampsia and preterm birth may become recognized as an optimal public health strategy. As a step toward universal prescription of aspirin to nulliparous women, an opt-out rather than a screen-in strategy might be considered.⁸

Continue to: Booking systolic blood pressure, 120 to 134 mm Hg...

Booking systolic blood pressure, 120 to 134 mm Hg

All obstetricians recognize that women with chronic hypertension should be treated with low-dose aspirin because they are at high risk for preeclampsia. However, there is evidence that nulliparous women with a booking systolic pressure ≥120 mm Hg might also benefit from low-dose aspirin treatment. In one US trial, 3,135 nulliparous normotensive women (booking blood pressure [BP] <135/85 mm Hg) were randomly assigned to treatment with aspirin (60 mg daily) or placebo initiated between 13 and 26 weeks’ gestation. Preeclampsia occurred in 6.3% and 4.6% of the women treated with placebo or aspirin, respectively (RR, 0.7; 95% CI, 0.6–1.0; P = .05).⁹ A secondary analysis showed that, among 519 nulliparous women with a booking systolic BP from 120 to 134 mm Hg, compared with placebo, low-dose aspirin treatment reduced the rate of preeclampsia from 11.9% to 5.6%.⁹ Aspirin did not reduce the rate of preeclampsia among nulliparous women with a booking systolic BP <120 mm Hg.⁹ A systematic review of risk factors for developing preeclampsia reported that a booking diastolic BP of ≥80 mm Hg was associated with an increased risk of developing preeclampsia (RR, 1.38).¹⁰ 

The American Heart Association (AHA) and the American College of Cardiology (ACC) recently updated the definition of hypertension.¹¹ Normal BP is now defined as a systolic pressure <120 mm Hg and diastolic pressure <80 mm Hg. Elevated BP is a systolic pressure of 120 to 129 mm Hg and diastolic pressure of <80 mm Hg. Stage I hypertension is a systolic BP from 130 to 139 mm Hg or diastolic blood pressure from 80 to 89 mm Hg. Stage II hypertension is a systolic BP of ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg.¹¹ 

A recent study reported that 90% of women at 12 weeks’ gestation have a BP of ≤130 mm Hg systolic and ≤80 mm Hg diastolic, suggesting that the AHA-ACC criteria for stage I hypertension are reasonable.¹² Obstetricians have not yet fully adopted the AHA-ACC criteria for defining stage I hypertension in pregnant women. Future research may demonstrate that a booking systolic BP 
 ≥130 mm Hg or a diastolic BP ≥80 mm Hg are major risk factors for developing preeclampsia and warrant treatment with low-dose aspirin.

Continue to: Pregnancy resulting from fertility therapy...

Pregnancy resulting from fertility therapy

Current ACOG and USPSTF guidelines do not specifically identify pregnancies resulting from assisted reproductive technology as a major or moderate risk factor for preeclampsia.^2,3 In a study comparing 83,582 births resulting from in vitro fertilization (IVF) and 1,382,311 births to fertile women, treatment with autologous cryopreserved embryos (adjusted odds ratio [aOR], 1.30), fresh donor embryos (aOR, 1.92), and cryopreserved donor embryos (aOR, 1.70) significantly increased the risk of preeclampsia.¹³ However, use of fresh autologous embryos did not increase the risk of preeclampsia (aOR, 1.04). These associations persisted after controlling for diabetes, hypertension, body mass index, and cause of infertility.¹³

Other studies also have reported that use of cryopreserved embryos is associated with a higher rate of preeclampsia than use of fresh autologous embryos. In a study of 825 infertile women undergoing IVF and randomly assigned to single embryo cryopreserved or fresh cycles, the rate of preeclampsia was 3.1% and 1.0% in the pregnancies that resulted from cryopreserved versus fresh cycles.¹⁴ 

What is the optimal dose of aspirin?

ACOG and the USPSTF recommend aspirin 81 mg daily for the prevention of preeclampsia.^2,3 The International Federation of Gynecology and Obstetrics (FIGO) recommends aspirin 150 mg daily for the prevention of preeclampsia.¹⁵ The FIGO recommendation is based, in part, on the results of a large international clinical trial that randomly assigned 1,776 women at high risk for preeclampsia as determined by clinical factors plus biomarker and ultrasound screening to receive aspirin 150 mg daily or placebo daily initiated at 11 to 14 weeks’ gestation and continued until 36 weeks’ gestation.¹⁶ Preeclampsia before 37 weeks’ gestation occurred in 4.3% and 1.6% of women in the placebo and aspirin groups (OR, 0.38; 95% CI, 0.20–0.74; P = .004).¹⁶ FIGO recommends that women at risk for preeclampsia with a body mass <40 kg take aspirin 100 mg daily and women with a body mass ≥40 kg take aspirin at a dose of 150 mg daily. For women who live in a country where aspirin is not available in a pill containing 150 mg, FIGO recommends taking two 81 mg tablets.¹⁵ FIGO recommends initiating aspirin between 11 and 14 weeks and 6 days of gestation and continuing aspirin therapy until 36 weeks of gestation.¹⁵

Aspirin is an inexpensive intervention with many possible benefits

For many nulliparous women and some parous women aspirin treatment initiated early in pregnancy will improve maternal and newborn outcomes, including reducing the risk of preeclampsia, preterm birth, and intrauterine growth restriction.¹ Obstetricians may want to begin to expand the indications for offering aspirin to prevent preeclampsia from those recommended by ACOG and the USPSTF to include nulliparous women with a booking systolic pressure of 120 to 134 mm Hg and women whose pregnancy was the result of an assisted reproduction treatment that used cryopreserved embryos. In addition, obstetricians who currently prescribe 81 mg of aspirin daily might want to consider increasing the prescribed dose to 162 mg of aspirin daily (two 81 mg tablets daily or one-half of a 325 mg tablet). Aspirin costs about less than 5 cents per 81 mg tablet (according to GoodRx website). It is an inexpensive intervention that could benefit many mothers and newborns. ●

Authors of a recent Cochrane review concluded that low-dose aspirin treatment of 1,000 pregnant women at risk of developing preeclampsia resulted in 16 fewer cases of preeclampsia, 16 fewer preterm births, 7 fewer cases of small-for-gestational age newborns, and 5 fewer fetal or neonatal deaths.¹

The American College of Obstetricians and Gynecologists (ACOG) and the US Preventive Services Task Force (USPSTF) recommend treatment with 81 mg of aspirin daily, initiated before 16 weeks of pregnancy to prevent preeclampsia in women with one major risk factor (personal history of preeclampsia, multifetal gestation, chronic hypertension, type 1 or 2 diabetes, renal or autoimmune disease) or at least two moderate risk factors (nulliparity; obesity; mother or sister with preeclampsia; a sociodemographic characteristic such as African American race or low socioeconomic status; age ≥35 years; personal history factors such as prior low birth weight infant, previous adverse pregnancy outcome, or >10-year interpregnancy interval).^2,3 Healthy pregnant women with a previous uncomplicated full-term delivery do not need treatment with low-dose aspirin.^2,3

However, evolving data and expert opinion suggest that expanding the indications for aspirin treatment and increasing the recommended dose of aspirin may be warranted. 

Nulliparity

Nulliparity is the single clinical characteristic that is associated with the greatest number of cases of preeclampsia.⁴ Hence, from a public health perspective, reducing the rate of preeclampsia among nulliparous women is a top priority.

ACOG and USPSTF do not recommend aspirin treatment for all nulliparous women because risk factors help to identify those nulliparous women who benefit from aspirin treatment.

However, a recent cost-effectiveness analysis compared the health care costs and rates of preeclampsia for 4 prevention strategies among all pregnant women in the United States (nulliparous and parous)⁵:

1. no aspirin use
2. use of aspirin based on biomarker and ultrasound measurements
3. use of aspirin based on USPSTF guidelines for identifying women at risk
4. prescription of aspirin to all pregnant women.

Health care costs and rates of preeclampsia were lowest with the universal prescription of aspirin to all pregnant women in the United States. Compared with universal prescription of aspirin, the USPSTF approach, the biomarker-ultrasound approach, and the no aspirin approach were associated with 346, 308, and 762 additional cases of preeclampsia per 100,000 women. In sensitivity analyses, universal aspirin was the optimal strategy under most assumptions.

Another cost effectiveness analysis concluded that among nulliparous pregnant women, universal aspirin treatment was superior to aspirin treatment based on biomarker-ultrasound identification of women at high risk.⁶ 

In a recent clinical trial performed in India, Guatemala, Pakistan, Democratic Republic of Congo, Kenya, and Zambia, 14,361 nulliparous women were randomly assigned to placebo or 81 mg of aspirin daily between 6 and 14 weeks of gestation.⁷ Preterm birth (<37 weeks’ gestation) occurred in 13.1% and 11.6% of women treated with placebo or aspirin (relative risk [RR], 0.89; 95% confidence interval [CI], 0.81 to 0.98, P = .012). Most of the decrease in preterm birth appeared to be due to a decrease in the rate of preeclampsia in the aspirin-treated nulliparous women. The investigators also noted that aspirin treatment of nulliparous women resulted in a statistically significant decrease in perinatal mortality (RR, 0.86) and early preterm delivery, <34 weeks’ gestation (RR, 0.75). 

Universal prescription of low-dose aspirin to nulliparous women in order to prevent preeclampsia and preterm birth may become recognized as an optimal public health strategy. As a step toward universal prescription of aspirin to nulliparous women, an opt-out rather than a screen-in strategy might be considered.⁸

Continue to: Booking systolic blood pressure, 120 to 134 mm Hg...

Booking systolic blood pressure, 120 to 134 mm Hg

All obstetricians recognize that women with chronic hypertension should be treated with low-dose aspirin because they are at high risk for preeclampsia. However, there is evidence that nulliparous women with a booking systolic pressure ≥120 mm Hg might also benefit from low-dose aspirin treatment. In one US trial, 3,135 nulliparous normotensive women (booking blood pressure [BP] <135/85 mm Hg) were randomly assigned to treatment with aspirin (60 mg daily) or placebo initiated between 13 and 26 weeks’ gestation. Preeclampsia occurred in 6.3% and 4.6% of the women treated with placebo or aspirin, respectively (RR, 0.7; 95% CI, 0.6–1.0; P = .05).⁹ A secondary analysis showed that, among 519 nulliparous women with a booking systolic BP from 120 to 134 mm Hg, compared with placebo, low-dose aspirin treatment reduced the rate of preeclampsia from 11.9% to 5.6%.⁹ Aspirin did not reduce the rate of preeclampsia among nulliparous women with a booking systolic BP <120 mm Hg.⁹ A systematic review of risk factors for developing preeclampsia reported that a booking diastolic BP of ≥80 mm Hg was associated with an increased risk of developing preeclampsia (RR, 1.38).¹⁰ 

The American Heart Association (AHA) and the American College of Cardiology (ACC) recently updated the definition of hypertension.¹¹ Normal BP is now defined as a systolic pressure <120 mm Hg and diastolic pressure <80 mm Hg. Elevated BP is a systolic pressure of 120 to 129 mm Hg and diastolic pressure of <80 mm Hg. Stage I hypertension is a systolic BP from 130 to 139 mm Hg or diastolic blood pressure from 80 to 89 mm Hg. Stage II hypertension is a systolic BP of ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg.¹¹ 

A recent study reported that 90% of women at 12 weeks’ gestation have a BP of ≤130 mm Hg systolic and ≤80 mm Hg diastolic, suggesting that the AHA-ACC criteria for stage I hypertension are reasonable.¹² Obstetricians have not yet fully adopted the AHA-ACC criteria for defining stage I hypertension in pregnant women. Future research may demonstrate that a booking systolic BP 
 ≥130 mm Hg or a diastolic BP ≥80 mm Hg are major risk factors for developing preeclampsia and warrant treatment with low-dose aspirin.

Continue to: Pregnancy resulting from fertility therapy...

Pregnancy resulting from fertility therapy

Current ACOG and USPSTF guidelines do not specifically identify pregnancies resulting from assisted reproductive technology as a major or moderate risk factor for preeclampsia.^2,3 In a study comparing 83,582 births resulting from in vitro fertilization (IVF) and 1,382,311 births to fertile women, treatment with autologous cryopreserved embryos (adjusted odds ratio [aOR], 1.30), fresh donor embryos (aOR, 1.92), and cryopreserved donor embryos (aOR, 1.70) significantly increased the risk of preeclampsia.¹³ However, use of fresh autologous embryos did not increase the risk of preeclampsia (aOR, 1.04). These associations persisted after controlling for diabetes, hypertension, body mass index, and cause of infertility.¹³

Other studies also have reported that use of cryopreserved embryos is associated with a higher rate of preeclampsia than use of fresh autologous embryos. In a study of 825 infertile women undergoing IVF and randomly assigned to single embryo cryopreserved or fresh cycles, the rate of preeclampsia was 3.1% and 1.0% in the pregnancies that resulted from cryopreserved versus fresh cycles.¹⁴ 

What is the optimal dose of aspirin?

ACOG and the USPSTF recommend aspirin 81 mg daily for the prevention of preeclampsia.^2,3 The International Federation of Gynecology and Obstetrics (FIGO) recommends aspirin 150 mg daily for the prevention of preeclampsia.¹⁵ The FIGO recommendation is based, in part, on the results of a large international clinical trial that randomly assigned 1,776 women at high risk for preeclampsia as determined by clinical factors plus biomarker and ultrasound screening to receive aspirin 150 mg daily or placebo daily initiated at 11 to 14 weeks’ gestation and continued until 36 weeks’ gestation.¹⁶ Preeclampsia before 37 weeks’ gestation occurred in 4.3% and 1.6% of women in the placebo and aspirin groups (OR, 0.38; 95% CI, 0.20–0.74; P = .004).¹⁶ FIGO recommends that women at risk for preeclampsia with a body mass <40 kg take aspirin 100 mg daily and women with a body mass ≥40 kg take aspirin at a dose of 150 mg daily. For women who live in a country where aspirin is not available in a pill containing 150 mg, FIGO recommends taking two 81 mg tablets.¹⁵ FIGO recommends initiating aspirin between 11 and 14 weeks and 6 days of gestation and continuing aspirin therapy until 36 weeks of gestation.¹⁵

Aspirin is an inexpensive intervention with many possible benefits

For many nulliparous women and some parous women aspirin treatment initiated early in pregnancy will improve maternal and newborn outcomes, including reducing the risk of preeclampsia, preterm birth, and intrauterine growth restriction.¹ Obstetricians may want to begin to expand the indications for offering aspirin to prevent preeclampsia from those recommended by ACOG and the USPSTF to include nulliparous women with a booking systolic pressure of 120 to 134 mm Hg and women whose pregnancy was the result of an assisted reproduction treatment that used cryopreserved embryos. In addition, obstetricians who currently prescribe 81 mg of aspirin daily might want to consider increasing the prescribed dose to 162 mg of aspirin daily (two 81 mg tablets daily or one-half of a 325 mg tablet). Aspirin costs about less than 5 cents per 81 mg tablet (according to GoodRx website). It is an inexpensive intervention that could benefit many mothers and newborns. ●

As prenatal genetic testing and imaging have advanced, the diagnosis of genetic disorders has moved from the postnatal to the prenatal time frame. This has largely been facilitated by the increasing use of exome sequencing (ES) in the prenatal setting. Two landmark trials published in January 2019 highlighted the overall diagnostic yields of prenatal ES as 8.5% and 10% in fetuses with normal karyotype and microarray.^1,2

Although this is a huge step forward in prenatal diagnosis, ES is currently a manually curated, labor-intensive task. The process involves reviewing thousands of sequence variants for any given sample and prioritizing each variant based on bio­informatic data, prediction models, literature review, and specific patient characteristics. The patient characteristics, or phenotypic information, are critically important in prioritizing candidate variants.

To date, prenatal ES has been limited by the use of inconsistent terminology and the lack of well-understood prenatal phenotypes. In this Update, we highlight how recently published work draws attention to these critical gaps in prenatal diagnosis.

Standardizing phenotyping language in the prenatal setting

Tomar S, Sethi R, Lai PS. Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing. Eur J Hum Genet. 2019;27:1389-1397.

Clinical ES in pediatric and adult populations is enhanced by the use of standardized vocabulary to describe disorders. Standardized language ensures that identified variants are filtered correctly and in a systematic fashion based on the patient characteristics that are provided. One commonly used platform is the Human Phenotype Ontology (HPO).

Tomar and colleagues assessed the impact of HPO-based clinical information on the performance of a gene prioritization tool.³ Gene prioritization (or simulation) tools are used for interpretation of ES data to help analysts efficiently sort through the thousands of variants in an individual’s genetic sequence. The performance, or accuracy, of a prioritization tool can be assessed by looking at the location of the disease-causing gene in the suggested gene list.

Continue to: Cohort of diagnosed patients and gene prioritization...

Cohort of diagnosed patients and gene prioritization

In this experimental model, Tomar and colleagues included 50 cases with neuromuscular disorders; all had available sequencing data, fully described phenotypes, and known causal genes. The authors varied the level of available clinical information in the HPO terms used for simulated variant analysis. Using 3 web-based gene prioritization tools on the 50 cases, they varied the HPO input to include a random selection of 10%, 30%, and 50% of HPO terms derived from deep phenotyping.

The 3 prioritization tools ranked input genes based on gene-phenotype associations that were derived from gene-phenotype databases. The authors then assessed the quality of the candidate gene lists by the location of the known causative gene on the generated rank lists. They repeated this analysis 4 times with different randomly selected HPO terms. 

Inclusion of more HPO terms allowed for more accurate diagnoses in rare disorders

The authors found that the phenotype input for ES matters. When only 10% and 30% of the HPO terms were used to create a candidate gene list, the causative gene was less likely to be in the top portions of gene lists than when 50% or 100% of the available HPO terms were used.

For well-characterized disorders, use of the top 10% HPO terms performed as well as when all available HPO terms were used. For previously undescribed disease-gene associations, identification of the disease gene suffered with more limited HPO term availability.

What this study contributes

This study was a simulation of previously sequenced patients with neuromuscular disorders. It examined a small sample size for a narrow spectrum of disease. However, it clearly illustrated the principle that completeness of phenotypic information for ES pipelines is relevant for interpretation.

Detailed description of prenatal findings is essential to diagnosis

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181.

In a retrospective cohort study, Aarabi and colleagues evaluated the diagnostic utility and limitations of ES in prenatal cases with structural birth defects.⁴

A case series study

The investigators included 20 pregnancies with structural birth defects that were referred to their center for prenatal diagnosis between 12 and 20 weeks’ gestation. All pregnancies had normal karyotype and microarray analyses prior to enrollment.

ES was performed on trio samples, which included fetal and parental DNA samples (extracted from peripheral blood). Reports provided by the commercial laboratories were normal for all cases and included no pathogenic or likely pathogenic variants. The laboratory provided the investigators with the FASTQ (genetic sequence) files for reanalysis, which was performed using both prenatal and postnatal detailed phenotypic information.

Continue to: Use of postnatal information facilitated diagnoses...

Use of postnatal information facilitated diagnoses

Reanalysis of ES data using detailed postnatal findings revealed a possible diagnosis in 20% of cases. Each case in which a diagnosis was made, detailed below, highlights an important limitation in our current ability to make prenatal diagnoses.

Case 1. A fetus was diagnosed prenatally with arthrogryposis, plagiocephaly, and club feet. After birth, the infant also was found to have generalized muscle weakness, elevated creatine phosphokinase, and congenital hip dislocation.

Reanalysis of the ES data revealed compound heterozygous missense variants in the nebulin gene (NEB). Although classified as variants of uncertain significance (VUS), these are consistent with the phenotype, the authors argued, and with the diagnosis of autosomal recessive nemaline myopathy 2.

Case 2. Prenatal diagnosis was made of a right limb anomaly, tetralogy of Fallot, intrauterine growth restriction, ambiguous genitalia, and dextrocardia. Postnatal evaluation revealed absent pulmonary valve syndrome, right arm dysplasia, pectus carinatum deformity, and failure to thrive.

In this case, ES with the postnatal information revealed a VUS in the NOTCH1 gene, which has been associated with Adams-Oliver syndrome. Although by strict criteria this variant is also of uncertain significance, Adams-Oliver syndrome is characterized, in part, by transverse limb defects and congenital heart disease, as was found in the proband.

Case 3. Prenatal ultrasonography revealed microcephaly and absence of the septum pellucidum. Postnatal magnetic resonance imaging revealed semi-lobar holoprosencephaly. A holoprosencephaly-specific gene panel revealed a deletion in the ZIC2 gene, which is known to cause holoprosencephaly.

Careful re-examination of the ES data revealed some abnormality in the ZIC2 signal, which might have been studied in greater detail and thereby detected if the prenatal diagnosis of holoprosencephaly had been made.

Case 4. An ultrasound evaluation at 12 weeks’ gestation revealed a cystic hygroma, short long bones, and possible absent hand and fibula. A postnatal fetal autopsy at 14 weeks showed split-hand and split-foot malformations, which were not appreciated on ultrasonography.

In filtering the ES data with this information, a pathogenic variant in the PRCN gene was identified as causal, and the diagnosis of Goltz syndrome was made.

Challenges facing  prenatal diagnosis

A case series is inherently limited by its small sample size. Nevertheless, the authors suggest 2 major challenges in our ability to make the above diagnoses in the prenatal setting:
1) the prenatal assessment being limited to major structural abnormalities, and 2) commercial laboratories not having enough experience or volume to interpret the limited information provided by prenatal imaging.

Can AI technology be incorporated to make a genetic diagnosis?

Hsieh TC, Mensah MA, Pantel JT, et al. PEDIA: prioritization of exome data by image analysis. Genet Med. 2019;21:2807-2814.

Increasingly, ES is used in all types of undiagnosed, rare genetic diseases. Although there is a high diagnostic yield in many populations, ES’s clinical utility is limited by the labor-intensive process of interpreting each variant in the context of detailed phenotypic information. The widespread use of HPO would be one step toward standardizing the information that is entered into the analysis of ES data, but even HPO cannot capture certain visual clues.

Hsieh and colleagues attempted to use artificial intelligence (AI) for “next-generation phenotyping” to assess facial dysmorphology and integrate the information into variant classification.⁵ The authors described their approach of incorporating AI as “prioritization of exome data by image analysis” (PEDIA).

Continue to: Designing dysmorphology machine learning...

Designing dysmorphology machine learning

The cohort included 679 individuals with 105 different genetic disorders. All individuals had a previously confirmed molecular diagnosis that would be detected by ES. Each individual had a frontal facial photograph analyzed and detailed clinical features documented in HPO terms extracted by 2 clinicians.

A facial analysis software called DeepGestalt, trained on 17,000 patient images, was used to create a Gestalt score. Each individual had 4 different predicted gene scoring approaches:

• a molecular deleteriousness score
• facial analysis with the Gestalt score
• a combination of molecular deleteriousness score and HPO-based gene-prioritization tool (termed semantic similarity score)
• the PEDIA score, which included all 3 prior approaches.

A type of machine learning algorithm (support vector machine, or SVM) was applied, validated, and used to prioritize genes based on the combined scores.

AI seemed to improve diagnostic accuracy

Utilizing the combination of machine learning, HPO terms, and facial analysis software greatly improved the accuracy of variant classification predictions over any approach alone.

Using only the sequence variant and molecular deleteriousness score, the causative variant was ranked in the top 10 of all identified variants in less than 45% of cases. Adding the HPO-based gene prioritization tools increased the accuracy to 63% to 94%. Use of the PEDIA score, which incorporated all 3, increased the accuracy to 99% for the top 10 ranking.

Even more impressive improvements were made in the top 1 ranking accuracy rate, which went from 36% to 74% without facial image information to 86% to 89% with inclusion of DeepGestalt scores.

Study strengths and limitations

This study’s innovative application of facial analysis and machine learning, combined with HPO-driven variant classification, showed added benefit. To achieve this with available patient photographs and thorough phenotyping, previously diagnosed patients were used. Because complete ES information was not available for those patients, their known pathogenic variant was inserted into randomly selected exomes from the 1000 Genomes Project (healthy individuals). The authors additionally noted that the PEDIA score performance was diminished for rare disorders in which limited data were available. 

As prenatal genetic testing and imaging have advanced, the diagnosis of genetic disorders has moved from the postnatal to the prenatal time frame. This has largely been facilitated by the increasing use of exome sequencing (ES) in the prenatal setting. Two landmark trials published in January 2019 highlighted the overall diagnostic yields of prenatal ES as 8.5% and 10% in fetuses with normal karyotype and microarray.^1,2

Although this is a huge step forward in prenatal diagnosis, ES is currently a manually curated, labor-intensive task. The process involves reviewing thousands of sequence variants for any given sample and prioritizing each variant based on bio­informatic data, prediction models, literature review, and specific patient characteristics. The patient characteristics, or phenotypic information, are critically important in prioritizing candidate variants.

To date, prenatal ES has been limited by the use of inconsistent terminology and the lack of well-understood prenatal phenotypes. In this Update, we highlight how recently published work draws attention to these critical gaps in prenatal diagnosis.

Standardizing phenotyping language in the prenatal setting

Tomar S, Sethi R, Lai PS. Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing. Eur J Hum Genet. 2019;27:1389-1397.

Clinical ES in pediatric and adult populations is enhanced by the use of standardized vocabulary to describe disorders. Standardized language ensures that identified variants are filtered correctly and in a systematic fashion based on the patient characteristics that are provided. One commonly used platform is the Human Phenotype Ontology (HPO).

Tomar and colleagues assessed the impact of HPO-based clinical information on the performance of a gene prioritization tool.³ Gene prioritization (or simulation) tools are used for interpretation of ES data to help analysts efficiently sort through the thousands of variants in an individual’s genetic sequence. The performance, or accuracy, of a prioritization tool can be assessed by looking at the location of the disease-causing gene in the suggested gene list.

Continue to: Cohort of diagnosed patients and gene prioritization...

Cohort of diagnosed patients and gene prioritization

In this experimental model, Tomar and colleagues included 50 cases with neuromuscular disorders; all had available sequencing data, fully described phenotypes, and known causal genes. The authors varied the level of available clinical information in the HPO terms used for simulated variant analysis. Using 3 web-based gene prioritization tools on the 50 cases, they varied the HPO input to include a random selection of 10%, 30%, and 50% of HPO terms derived from deep phenotyping.

The 3 prioritization tools ranked input genes based on gene-phenotype associations that were derived from gene-phenotype databases. The authors then assessed the quality of the candidate gene lists by the location of the known causative gene on the generated rank lists. They repeated this analysis 4 times with different randomly selected HPO terms. 

Inclusion of more HPO terms allowed for more accurate diagnoses in rare disorders

The authors found that the phenotype input for ES matters. When only 10% and 30% of the HPO terms were used to create a candidate gene list, the causative gene was less likely to be in the top portions of gene lists than when 50% or 100% of the available HPO terms were used.

For well-characterized disorders, use of the top 10% HPO terms performed as well as when all available HPO terms were used. For previously undescribed disease-gene associations, identification of the disease gene suffered with more limited HPO term availability.

What this study contributes

This study was a simulation of previously sequenced patients with neuromuscular disorders. It examined a small sample size for a narrow spectrum of disease. However, it clearly illustrated the principle that completeness of phenotypic information for ES pipelines is relevant for interpretation.

Detailed description of prenatal findings is essential to diagnosis

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181.

In a retrospective cohort study, Aarabi and colleagues evaluated the diagnostic utility and limitations of ES in prenatal cases with structural birth defects.⁴

A case series study

The investigators included 20 pregnancies with structural birth defects that were referred to their center for prenatal diagnosis between 12 and 20 weeks’ gestation. All pregnancies had normal karyotype and microarray analyses prior to enrollment.

ES was performed on trio samples, which included fetal and parental DNA samples (extracted from peripheral blood). Reports provided by the commercial laboratories were normal for all cases and included no pathogenic or likely pathogenic variants. The laboratory provided the investigators with the FASTQ (genetic sequence) files for reanalysis, which was performed using both prenatal and postnatal detailed phenotypic information.

Continue to: Use of postnatal information facilitated diagnoses...

Use of postnatal information facilitated diagnoses

Reanalysis of ES data using detailed postnatal findings revealed a possible diagnosis in 20% of cases. Each case in which a diagnosis was made, detailed below, highlights an important limitation in our current ability to make prenatal diagnoses.

Case 1. A fetus was diagnosed prenatally with arthrogryposis, plagiocephaly, and club feet. After birth, the infant also was found to have generalized muscle weakness, elevated creatine phosphokinase, and congenital hip dislocation.

Reanalysis of the ES data revealed compound heterozygous missense variants in the nebulin gene (NEB). Although classified as variants of uncertain significance (VUS), these are consistent with the phenotype, the authors argued, and with the diagnosis of autosomal recessive nemaline myopathy 2.

Case 2. Prenatal diagnosis was made of a right limb anomaly, tetralogy of Fallot, intrauterine growth restriction, ambiguous genitalia, and dextrocardia. Postnatal evaluation revealed absent pulmonary valve syndrome, right arm dysplasia, pectus carinatum deformity, and failure to thrive.

In this case, ES with the postnatal information revealed a VUS in the NOTCH1 gene, which has been associated with Adams-Oliver syndrome. Although by strict criteria this variant is also of uncertain significance, Adams-Oliver syndrome is characterized, in part, by transverse limb defects and congenital heart disease, as was found in the proband.

Case 3. Prenatal ultrasonography revealed microcephaly and absence of the septum pellucidum. Postnatal magnetic resonance imaging revealed semi-lobar holoprosencephaly. A holoprosencephaly-specific gene panel revealed a deletion in the ZIC2 gene, which is known to cause holoprosencephaly.

Careful re-examination of the ES data revealed some abnormality in the ZIC2 signal, which might have been studied in greater detail and thereby detected if the prenatal diagnosis of holoprosencephaly had been made.

Case 4. An ultrasound evaluation at 12 weeks’ gestation revealed a cystic hygroma, short long bones, and possible absent hand and fibula. A postnatal fetal autopsy at 14 weeks showed split-hand and split-foot malformations, which were not appreciated on ultrasonography.

In filtering the ES data with this information, a pathogenic variant in the PRCN gene was identified as causal, and the diagnosis of Goltz syndrome was made.

Challenges facing  prenatal diagnosis

A case series is inherently limited by its small sample size. Nevertheless, the authors suggest 2 major challenges in our ability to make the above diagnoses in the prenatal setting:
1) the prenatal assessment being limited to major structural abnormalities, and 2) commercial laboratories not having enough experience or volume to interpret the limited information provided by prenatal imaging.

Can AI technology be incorporated to make a genetic diagnosis?

Hsieh TC, Mensah MA, Pantel JT, et al. PEDIA: prioritization of exome data by image analysis. Genet Med. 2019;21:2807-2814.

Increasingly, ES is used in all types of undiagnosed, rare genetic diseases. Although there is a high diagnostic yield in many populations, ES’s clinical utility is limited by the labor-intensive process of interpreting each variant in the context of detailed phenotypic information. The widespread use of HPO would be one step toward standardizing the information that is entered into the analysis of ES data, but even HPO cannot capture certain visual clues.

Hsieh and colleagues attempted to use artificial intelligence (AI) for “next-generation phenotyping” to assess facial dysmorphology and integrate the information into variant classification.⁵ The authors described their approach of incorporating AI as “prioritization of exome data by image analysis” (PEDIA).

Continue to: Designing dysmorphology machine learning...

Designing dysmorphology machine learning

The cohort included 679 individuals with 105 different genetic disorders. All individuals had a previously confirmed molecular diagnosis that would be detected by ES. Each individual had a frontal facial photograph analyzed and detailed clinical features documented in HPO terms extracted by 2 clinicians.

A facial analysis software called DeepGestalt, trained on 17,000 patient images, was used to create a Gestalt score. Each individual had 4 different predicted gene scoring approaches:

• a molecular deleteriousness score
• facial analysis with the Gestalt score
• a combination of molecular deleteriousness score and HPO-based gene-prioritization tool (termed semantic similarity score)
• the PEDIA score, which included all 3 prior approaches.

A type of machine learning algorithm (support vector machine, or SVM) was applied, validated, and used to prioritize genes based on the combined scores.

AI seemed to improve diagnostic accuracy

Utilizing the combination of machine learning, HPO terms, and facial analysis software greatly improved the accuracy of variant classification predictions over any approach alone.

Using only the sequence variant and molecular deleteriousness score, the causative variant was ranked in the top 10 of all identified variants in less than 45% of cases. Adding the HPO-based gene prioritization tools increased the accuracy to 63% to 94%. Use of the PEDIA score, which incorporated all 3, increased the accuracy to 99% for the top 10 ranking.

Even more impressive improvements were made in the top 1 ranking accuracy rate, which went from 36% to 74% without facial image information to 86% to 89% with inclusion of DeepGestalt scores.

Study strengths and limitations

This study’s innovative application of facial analysis and machine learning, combined with HPO-driven variant classification, showed added benefit. To achieve this with available patient photographs and thorough phenotyping, previously diagnosed patients were used. Because complete ES information was not available for those patients, their known pathogenic variant was inserted into randomly selected exomes from the 1000 Genomes Project (healthy individuals). The authors additionally noted that the PEDIA score performance was diminished for rare disorders in which limited data were available. 

As prenatal genetic testing and imaging have advanced, the diagnosis of genetic disorders has moved from the postnatal to the prenatal time frame. This has largely been facilitated by the increasing use of exome sequencing (ES) in the prenatal setting. Two landmark trials published in January 2019 highlighted the overall diagnostic yields of prenatal ES as 8.5% and 10% in fetuses with normal karyotype and microarray.^1,2

Although this is a huge step forward in prenatal diagnosis, ES is currently a manually curated, labor-intensive task. The process involves reviewing thousands of sequence variants for any given sample and prioritizing each variant based on bio­informatic data, prediction models, literature review, and specific patient characteristics. The patient characteristics, or phenotypic information, are critically important in prioritizing candidate variants.

To date, prenatal ES has been limited by the use of inconsistent terminology and the lack of well-understood prenatal phenotypes. In this Update, we highlight how recently published work draws attention to these critical gaps in prenatal diagnosis.

Standardizing phenotyping language in the prenatal setting

Tomar S, Sethi R, Lai PS. Specific phenotype semantics facilitate gene prioritization in clinical exome sequencing. Eur J Hum Genet. 2019;27:1389-1397.

Clinical ES in pediatric and adult populations is enhanced by the use of standardized vocabulary to describe disorders. Standardized language ensures that identified variants are filtered correctly and in a systematic fashion based on the patient characteristics that are provided. One commonly used platform is the Human Phenotype Ontology (HPO).

Tomar and colleagues assessed the impact of HPO-based clinical information on the performance of a gene prioritization tool.³ Gene prioritization (or simulation) tools are used for interpretation of ES data to help analysts efficiently sort through the thousands of variants in an individual’s genetic sequence. The performance, or accuracy, of a prioritization tool can be assessed by looking at the location of the disease-causing gene in the suggested gene list.

Continue to: Cohort of diagnosed patients and gene prioritization...

Cohort of diagnosed patients and gene prioritization

In this experimental model, Tomar and colleagues included 50 cases with neuromuscular disorders; all had available sequencing data, fully described phenotypes, and known causal genes. The authors varied the level of available clinical information in the HPO terms used for simulated variant analysis. Using 3 web-based gene prioritization tools on the 50 cases, they varied the HPO input to include a random selection of 10%, 30%, and 50% of HPO terms derived from deep phenotyping.

The 3 prioritization tools ranked input genes based on gene-phenotype associations that were derived from gene-phenotype databases. The authors then assessed the quality of the candidate gene lists by the location of the known causative gene on the generated rank lists. They repeated this analysis 4 times with different randomly selected HPO terms. 

Inclusion of more HPO terms allowed for more accurate diagnoses in rare disorders

The authors found that the phenotype input for ES matters. When only 10% and 30% of the HPO terms were used to create a candidate gene list, the causative gene was less likely to be in the top portions of gene lists than when 50% or 100% of the available HPO terms were used.

For well-characterized disorders, use of the top 10% HPO terms performed as well as when all available HPO terms were used. For previously undescribed disease-gene associations, identification of the disease gene suffered with more limited HPO term availability.

What this study contributes

This study was a simulation of previously sequenced patients with neuromuscular disorders. It examined a small sample size for a narrow spectrum of disease. However, it clearly illustrated the principle that completeness of phenotypic information for ES pipelines is relevant for interpretation.

Detailed description of prenatal findings is essential to diagnosis

Aarabi M, Sniezek O, Jiang H, et al. Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet. 2018;137:175-181.

In a retrospective cohort study, Aarabi and colleagues evaluated the diagnostic utility and limitations of ES in prenatal cases with structural birth defects.⁴

A case series study

The investigators included 20 pregnancies with structural birth defects that were referred to their center for prenatal diagnosis between 12 and 20 weeks’ gestation. All pregnancies had normal karyotype and microarray analyses prior to enrollment.

ES was performed on trio samples, which included fetal and parental DNA samples (extracted from peripheral blood). Reports provided by the commercial laboratories were normal for all cases and included no pathogenic or likely pathogenic variants. The laboratory provided the investigators with the FASTQ (genetic sequence) files for reanalysis, which was performed using both prenatal and postnatal detailed phenotypic information.

Continue to: Use of postnatal information facilitated diagnoses...

Use of postnatal information facilitated diagnoses

Reanalysis of ES data using detailed postnatal findings revealed a possible diagnosis in 20% of cases. Each case in which a diagnosis was made, detailed below, highlights an important limitation in our current ability to make prenatal diagnoses.

Case 1. A fetus was diagnosed prenatally with arthrogryposis, plagiocephaly, and club feet. After birth, the infant also was found to have generalized muscle weakness, elevated creatine phosphokinase, and congenital hip dislocation.

Reanalysis of the ES data revealed compound heterozygous missense variants in the nebulin gene (NEB). Although classified as variants of uncertain significance (VUS), these are consistent with the phenotype, the authors argued, and with the diagnosis of autosomal recessive nemaline myopathy 2.

Case 2. Prenatal diagnosis was made of a right limb anomaly, tetralogy of Fallot, intrauterine growth restriction, ambiguous genitalia, and dextrocardia. Postnatal evaluation revealed absent pulmonary valve syndrome, right arm dysplasia, pectus carinatum deformity, and failure to thrive.

In this case, ES with the postnatal information revealed a VUS in the NOTCH1 gene, which has been associated with Adams-Oliver syndrome. Although by strict criteria this variant is also of uncertain significance, Adams-Oliver syndrome is characterized, in part, by transverse limb defects and congenital heart disease, as was found in the proband.

Case 3. Prenatal ultrasonography revealed microcephaly and absence of the septum pellucidum. Postnatal magnetic resonance imaging revealed semi-lobar holoprosencephaly. A holoprosencephaly-specific gene panel revealed a deletion in the ZIC2 gene, which is known to cause holoprosencephaly.

Careful re-examination of the ES data revealed some abnormality in the ZIC2 signal, which might have been studied in greater detail and thereby detected if the prenatal diagnosis of holoprosencephaly had been made.

Case 4. An ultrasound evaluation at 12 weeks’ gestation revealed a cystic hygroma, short long bones, and possible absent hand and fibula. A postnatal fetal autopsy at 14 weeks showed split-hand and split-foot malformations, which were not appreciated on ultrasonography.

In filtering the ES data with this information, a pathogenic variant in the PRCN gene was identified as causal, and the diagnosis of Goltz syndrome was made.

Challenges facing  prenatal diagnosis

A case series is inherently limited by its small sample size. Nevertheless, the authors suggest 2 major challenges in our ability to make the above diagnoses in the prenatal setting:
1) the prenatal assessment being limited to major structural abnormalities, and 2) commercial laboratories not having enough experience or volume to interpret the limited information provided by prenatal imaging.

Can AI technology be incorporated to make a genetic diagnosis?

Hsieh TC, Mensah MA, Pantel JT, et al. PEDIA: prioritization of exome data by image analysis. Genet Med. 2019;21:2807-2814.

Increasingly, ES is used in all types of undiagnosed, rare genetic diseases. Although there is a high diagnostic yield in many populations, ES’s clinical utility is limited by the labor-intensive process of interpreting each variant in the context of detailed phenotypic information. The widespread use of HPO would be one step toward standardizing the information that is entered into the analysis of ES data, but even HPO cannot capture certain visual clues.

Hsieh and colleagues attempted to use artificial intelligence (AI) for “next-generation phenotyping” to assess facial dysmorphology and integrate the information into variant classification.⁵ The authors described their approach of incorporating AI as “prioritization of exome data by image analysis” (PEDIA).

Continue to: Designing dysmorphology machine learning...

Designing dysmorphology machine learning

The cohort included 679 individuals with 105 different genetic disorders. All individuals had a previously confirmed molecular diagnosis that would be detected by ES. Each individual had a frontal facial photograph analyzed and detailed clinical features documented in HPO terms extracted by 2 clinicians.

A facial analysis software called DeepGestalt, trained on 17,000 patient images, was used to create a Gestalt score. Each individual had 4 different predicted gene scoring approaches:

• a molecular deleteriousness score
• facial analysis with the Gestalt score
• a combination of molecular deleteriousness score and HPO-based gene-prioritization tool (termed semantic similarity score)
• the PEDIA score, which included all 3 prior approaches.

A type of machine learning algorithm (support vector machine, or SVM) was applied, validated, and used to prioritize genes based on the combined scores.

AI seemed to improve diagnostic accuracy

Utilizing the combination of machine learning, HPO terms, and facial analysis software greatly improved the accuracy of variant classification predictions over any approach alone.

Using only the sequence variant and molecular deleteriousness score, the causative variant was ranked in the top 10 of all identified variants in less than 45% of cases. Adding the HPO-based gene prioritization tools increased the accuracy to 63% to 94%. Use of the PEDIA score, which incorporated all 3, increased the accuracy to 99% for the top 10 ranking.

Even more impressive improvements were made in the top 1 ranking accuracy rate, which went from 36% to 74% without facial image information to 86% to 89% with inclusion of DeepGestalt scores.

Study strengths and limitations

This study’s innovative application of facial analysis and machine learning, combined with HPO-driven variant classification, showed added benefit. To achieve this with available patient photographs and thorough phenotyping, previously diagnosed patients were used. Because complete ES information was not available for those patients, their known pathogenic variant was inserted into randomly selected exomes from the 1000 Genomes Project (healthy individuals). The authors additionally noted that the PEDIA score performance was diminished for rare disorders in which limited data were available. 

Researchers have been studying the use of exogenous progestins for prevention of preterm delivery (PTD) for almost 60 years, but conflicting results contribute to an ongoing debate. Interpretation of the available data is particularly difficult because different forms and doses of progestins have been used in disparate study populations.

Based on available data, progesterone supplementation is not effective as a primary prevention strategy for PTD in the general low-risk obstetric population. PTD is a complex problem with varied and incompletely elucidated pathogenic pathways, making it unlikely that one interventional approach would be effective for all pregnant women. As a result, emerging indications for the use of progesterone are based on risk factors for PTD (ie, prior PTD and/or short cervix). However, this secondary prevention approach is a limiting factor in itself because 50% of women destined to have a PTD have no identifiable risk factors.¹ In addition, researchers have found that progestins are ineffective at delaying delivery for women with multiple gestation, suggesting that a distinct underlying mechanism of early parturition is present in these women, and that this mechanism is unresponsive to progestins.²

The formulations used in the study of progestin supplementation for PTD prevention have been almost exclusively either the synthetic 17 alpha-hydroxyprogesterone caproate (17-OHPC) or natural progesterone administered orally or vaginally. In 2003, the American College of Obstetricians and Gynecologists (ACOG) supported the use of progesterone to reduce the rate of PTD,³ and in 2011, the US Food and Drug Administration (FDA) approved 17-OHPC for use as prophylaxis against recurrent PTD. As a result, in recent years, the perceived standard of care for a majority of practitioners in the United States had been that all women with a previous preterm birth should be offered 17-OHPC. It may be interesting to note that in other parts of the world, the same enthusiastic adoption did not occur. For example, in Australia and New Zealand in 2007, only 5% of practitioners were using progesterone for this indication.⁴ Further, 17-OHPC is not recommended by professional guidelines in the United Kingdom and has remained unavailable in Germany.

The publication in 2019 of the PROLONG trial called into question the use of 17-OHPC for the prevention of PTD.⁵ In the December 2019 issue of OBG Management (“Managing preterm birth in those at risk: Expert strategies”), I expressed the opinion that with only rare exceptions, 17-OHPC is no longer a viable option for recurrent PTD prevention.⁶ In light of these developments, what scientific evidence is relevant and applicable to the care of women at risk for PTD?

Continue to: Case 1 Previous spontaneous PTD at 31 weeks...

Case 1 Previous spontaneous PTD at 31 weeks

MC is an asymptomatic 32-year-old woman with a singleton pregnancy at 13 weeks’ gestation. You see her for a maternal-fetal medicine consultation because 2 years ago she had a spontaneous PTD at 31 weeks’ gestation. What management recommendations can you make to decrease her risk of recurrent PTD?

Cervical length measurement narrows in on risk

The indication “previous preterm birth” is largely meaningless because of the heterogeneity in preterm birth pathways (preterm birth as a syndrome⁷) and inadequate risk characterization. Among women who experience a spontaneous PTD, 70% to 80% do not deliver prematurely in subsequent pregnancies.⁸ To better characterize the risk of PTD recurrence, ultrasound assessment of cervical length should be used. Research has shown that among women with a prior spontaneous PTD who maintain a normal cervical length until 24 weeks’ gestation, more than 90% will deliver at 35 weeks or after without intervention.⁹ Such an approach not only identifies the subgroup of women at significantly increased risk of recurrence but also eliminates unnecessary interventions.

Cervical ultrasound surveillance should be initiated at 16 weeks’ gestation. A short cervix before 16 weeks is not associated with a statistically significant increase in risk for PTD.¹⁰ Shortening of the cervix begins approximately 10 weeks before delivery in any gestational age group.¹¹ Therefore, ultrasound assessment of the cervix at 28 weeks and after is irrelevant. In addition, after 28 weeks, cervical length varies greatly leading to loss in the predictive power of the cervical measurement.¹² Based on these considerations, cervical surveillance may be extended up to 26 weeks. Although cervical cerclage is not an option in the United States in cases in which a short cervix is detected between 24 and 26 weeks, vaginal progesterone supplementation may still be considered.

Case 1 Continued

MC was started on ultrasound cervical surveillance at 16 weeks’ gestation. Her cervical length was initially normal (> 2.5 cm), but at 18 weeks the measurement was 2.2 cm. What is your recommendation?

The value of vaginal progesterone

There appears to be increasing consensus on the value of vaginal progesterone for women with a midtrimester short cervix on sonography, with or without a history of PTD. An individual patient data meta-analysis demonstrated the benefits of vaginal progesterone.¹³ Although there was no evidence of an effect on PTD at less than 37 weeks, the rates of PTD at less than 36 weeks and spontaneous PTD at less than 34 weeks were significantly reduced (by 20% and 28%, respectively). Also, there was a significant reduction in the risk of respiratory distress syndrome (53%) and composite neonatal morbidity and mortality (41%), with no significant impact on infant development up to the second year of life.¹³

The lack of generalizable evidence of benefit on childhood outcomes, combined with considerable uncertainty about the exact role and mechanism of action of exogenous progestins, contribute to the ongoing debate. Vaginal progesterone dosage regimens have been based on extrapolations from experience with progesterone in nonpregnant women, and recent pharmacokinetic studies have revealed how precarious such extrapolations may be. As an example, in nonpregnant women, the bioavailability of oral and vaginal progesterone is similar.¹⁴ In pregnancy, however, while daily oral progesterone doubles a pregnant woman’s serum progesterone level,¹⁵ daily vaginal administration of progesterone results in only a modest rise in serum progesterone, with a coefficient of variation among individuals that is double that outside of pregnancy.¹⁶ It is, therefore, considered that vaginal progesterone in pregnancy may have a local action secondary to the uterine first-pass effect. The uterine first-pass effect for vaginal progesterone was described in nonpregnant women and is only assumed to occur in pregnancy as well. ¹⁷

After evaluating the data from the largest available study of vaginal progesterone,¹⁸ the FDA concluded in 2012 that the study did not meet the statistical significance generally expected to support the approval of a new product. However, according to a more comprehensive evidence review developed in 2019 by the National Guideline Alliance in the United Kingdom, women with a history of PTD and women with a short cervix derive an important benefit from the use of vaginal progesterone; thus, this intervention should be offered to them.¹⁹ At this time, a short cervix and PTD prevention are not considered FDA-approved indications for progesterone supplementation in pregnancy. However, vaginal progesterone is FDA approved for use in pregnant women with a history of infertility.

Continue to: Case 1 Continued...

Case 1 Continued

MC initiated treatment with daily vaginal progesterone at 18 weeks’ gestation and returned for ultrasound cervical length examination weekly instead of every other week. At 20 weeks’ gestation, cervical length was 2.0 cm; the following week it was 1.4 cm. What would you recommend at this point?

When to consider cerclage

If cervical shortening progresses to about 1.5 cm while a woman is being treated with vaginal progesterone, cerclage may be considered. The benefit of cerclage in patients with prior PTD and a short cervix was highlighted in a 2018 Cochrane Review.²⁰ In this stepwise management approach to a short cervix, waiting for a cervix to be less than 1.5 cm may be unadvisable. Under conditions of a very short cervix that is frequently dilated with exposure of fetal membranes, ascending subclinical intra-amniotic infection may already be present, reducing the efficacy of any preventive measures. Preferential consideration for cerclage from the start over initial vaginal progesterone also may be appropriate when there is a history of 2 spontaneous PTDs or mid-trimester losses, a history of a successful cerclage, or with a very short cervix (< 1.0 cm) at the initial evaluation. As for the latter, a 2018 individual patient data meta-analysis of vaginal progesterone found no benefit when the cervix was less than 1.0 cm.¹³

Progesterone plus cerclage likely to add benefit

The results of an adjusted indirect comparison meta-analysis suggest that both interventions—vaginal progesterone and cerclage—are equally effective.²¹ Assuming that there is no clinically meaningful difference in benefit associated with these 2 treatments, the next logical question is whether combining the 2 therapies provides any added benefit; limited observational data seem to suggest that it does. In a retrospective cohort of 86 consecutive singleton pregnancies among women who underwent ultrasound-indicated cerclage, those who used vaginal progesterone after cerclage (n = 45) had a lower rate of PTD.²² Also, a small (66 cases) case-control study demonstrated the benefit of administration of vaginal progesterone as a rescue intervention in women with cerclage and progressive cervical shortening despite cerclage.²³

Case 2 Woman experiences adverse effects from vaginal progesterone

MS is a 25-year-old G2P0101 who was started on vaginal progesterone as prophylaxis for recurrent PTD. She is now at 20 weeks’ gestation, with a stable remnant cervical length of 2.0 cm. She is reporting an increasing vaginal burning sensation and vaginal discharge caused by the nightly vaginal progesterone applications, to the point that she is unwilling to continue the treatment. She asks if any alternatives to vaginal progesterone are available to decrease her risk of PTD.

Continue to: Is oral progesterone an option?...

Is oral progesterone an option?

In the 1980s and 1990s, oral micronized progesterone was widely used in France at doses of 900 to 1,200 mg/d for women at risk for PTD. The practice was stopped when secondary hepatic effects, including cholestasis of pregnancy, were reported at a higher rate in treated women.²⁴ A rise in the serum concentration of progesterone metabolites has been associated with impaired biliary excretion and subsequent accumulation of bile acids.²⁵ In other reports, elevated serum transaminase activity was found in pregnant women treated with oral micronized progesterone, and withdrawal of treatment frequently has led to improvement in transaminase levels.²⁶ The synthesis of endogenous progesterone during normal pregnancy is between 250 and 500 mg/d,²⁶ and experts have expressed concern that exogenous progesterone supplementation may impose an additional load on the hepatic transport of sulfated metabolites. Unlike orally administered progesterone, progestins given by the vaginal route avoid the hepatic first-pass effect. For this reason, they may be associated with less hepatic dysfunction.

Although not recommended by professional guidelines, oral progesterone administration for the prevention of PTD has been used in the United States. A 2015 survey of Wisconsin prenatal care providers found that of those who prescribed any progesterone for PTD prevention, oral progesterone was prescribed by 13.1% of obstetricians, 24.4% of midwives, and 40.7% of family medicine practitioners.²⁷

Some limited recent evidence from a meta-analysis of 3 trials investigating oral progesterone versus placebo suggests effectiveness in the prevention of recurrent PTD and reduction in perinatal morbidity and mortality.¹⁵ However, the number of cases included in the meta-analysis (386) was too small to support definitive clinical recommendations. Furthermore, questions have been raised in the literature about the reliability of the largest trial included in that meta-analysis.²⁸

Case 3 Two previous spontaneous PTDs

A 29-year-old G3P0201 presents for her first prenatal appointment at 10 weeks’ gestation. With her first pregnancy she had a spontaneous PTD at 23 weeks, and the neonate did not survive. In her second pregnancy, she was treated with 17-OHPC from 16 weeks’ gestation. She had a spontaneous PTD at 29 weeks, and that child is developing normally by her report. She believes that 17-OHPC helped her in her last pregnancy and is anxious about the risk for still another PTD. Consistent with the concept of shared decision-making, you inform her of the results of the recent PROLONG trial and statements on the subject released by professional organizations such as ACOG and the Society for Maternal-Fetal Medicine (SMFM). What options does she have?

17-OHPC may be a possibility in very high-risk women

According to a SMFM statement released in the wake of the PROLONG trial publication, “. . . SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial”.²⁹ Only a few women will have a recurrence risk of PTD over 50%, as was the background event rate in the Meis trial.³⁰ Such a risk level may be suspected, as an example, in women with 2 or more prior early (before 34 weeks) PTDs without intervening term deliveries. Even in those cases, if treatment with 17-OHPC is decided upon, ultrasound cervical surveillance should be added as an additional safety measure. ●

Researchers have been studying the use of exogenous progestins for prevention of preterm delivery (PTD) for almost 60 years, but conflicting results contribute to an ongoing debate. Interpretation of the available data is particularly difficult because different forms and doses of progestins have been used in disparate study populations.

Based on available data, progesterone supplementation is not effective as a primary prevention strategy for PTD in the general low-risk obstetric population. PTD is a complex problem with varied and incompletely elucidated pathogenic pathways, making it unlikely that one interventional approach would be effective for all pregnant women. As a result, emerging indications for the use of progesterone are based on risk factors for PTD (ie, prior PTD and/or short cervix). However, this secondary prevention approach is a limiting factor in itself because 50% of women destined to have a PTD have no identifiable risk factors.¹ In addition, researchers have found that progestins are ineffective at delaying delivery for women with multiple gestation, suggesting that a distinct underlying mechanism of early parturition is present in these women, and that this mechanism is unresponsive to progestins.²

The formulations used in the study of progestin supplementation for PTD prevention have been almost exclusively either the synthetic 17 alpha-hydroxyprogesterone caproate (17-OHPC) or natural progesterone administered orally or vaginally. In 2003, the American College of Obstetricians and Gynecologists (ACOG) supported the use of progesterone to reduce the rate of PTD,³ and in 2011, the US Food and Drug Administration (FDA) approved 17-OHPC for use as prophylaxis against recurrent PTD. As a result, in recent years, the perceived standard of care for a majority of practitioners in the United States had been that all women with a previous preterm birth should be offered 17-OHPC. It may be interesting to note that in other parts of the world, the same enthusiastic adoption did not occur. For example, in Australia and New Zealand in 2007, only 5% of practitioners were using progesterone for this indication.⁴ Further, 17-OHPC is not recommended by professional guidelines in the United Kingdom and has remained unavailable in Germany.

The publication in 2019 of the PROLONG trial called into question the use of 17-OHPC for the prevention of PTD.⁵ In the December 2019 issue of OBG Management (“Managing preterm birth in those at risk: Expert strategies”), I expressed the opinion that with only rare exceptions, 17-OHPC is no longer a viable option for recurrent PTD prevention.⁶ In light of these developments, what scientific evidence is relevant and applicable to the care of women at risk for PTD?

Continue to: Case 1 Previous spontaneous PTD at 31 weeks...

Case 1 Previous spontaneous PTD at 31 weeks

MC is an asymptomatic 32-year-old woman with a singleton pregnancy at 13 weeks’ gestation. You see her for a maternal-fetal medicine consultation because 2 years ago she had a spontaneous PTD at 31 weeks’ gestation. What management recommendations can you make to decrease her risk of recurrent PTD?

Cervical length measurement narrows in on risk

The indication “previous preterm birth” is largely meaningless because of the heterogeneity in preterm birth pathways (preterm birth as a syndrome⁷) and inadequate risk characterization. Among women who experience a spontaneous PTD, 70% to 80% do not deliver prematurely in subsequent pregnancies.⁸ To better characterize the risk of PTD recurrence, ultrasound assessment of cervical length should be used. Research has shown that among women with a prior spontaneous PTD who maintain a normal cervical length until 24 weeks’ gestation, more than 90% will deliver at 35 weeks or after without intervention.⁹ Such an approach not only identifies the subgroup of women at significantly increased risk of recurrence but also eliminates unnecessary interventions.

Cervical ultrasound surveillance should be initiated at 16 weeks’ gestation. A short cervix before 16 weeks is not associated with a statistically significant increase in risk for PTD.¹⁰ Shortening of the cervix begins approximately 10 weeks before delivery in any gestational age group.¹¹ Therefore, ultrasound assessment of the cervix at 28 weeks and after is irrelevant. In addition, after 28 weeks, cervical length varies greatly leading to loss in the predictive power of the cervical measurement.¹² Based on these considerations, cervical surveillance may be extended up to 26 weeks. Although cervical cerclage is not an option in the United States in cases in which a short cervix is detected between 24 and 26 weeks, vaginal progesterone supplementation may still be considered.

Case 1 Continued

MC was started on ultrasound cervical surveillance at 16 weeks’ gestation. Her cervical length was initially normal (> 2.5 cm), but at 18 weeks the measurement was 2.2 cm. What is your recommendation?

The value of vaginal progesterone

There appears to be increasing consensus on the value of vaginal progesterone for women with a midtrimester short cervix on sonography, with or without a history of PTD. An individual patient data meta-analysis demonstrated the benefits of vaginal progesterone.¹³ Although there was no evidence of an effect on PTD at less than 37 weeks, the rates of PTD at less than 36 weeks and spontaneous PTD at less than 34 weeks were significantly reduced (by 20% and 28%, respectively). Also, there was a significant reduction in the risk of respiratory distress syndrome (53%) and composite neonatal morbidity and mortality (41%), with no significant impact on infant development up to the second year of life.¹³

The lack of generalizable evidence of benefit on childhood outcomes, combined with considerable uncertainty about the exact role and mechanism of action of exogenous progestins, contribute to the ongoing debate. Vaginal progesterone dosage regimens have been based on extrapolations from experience with progesterone in nonpregnant women, and recent pharmacokinetic studies have revealed how precarious such extrapolations may be. As an example, in nonpregnant women, the bioavailability of oral and vaginal progesterone is similar.¹⁴ In pregnancy, however, while daily oral progesterone doubles a pregnant woman’s serum progesterone level,¹⁵ daily vaginal administration of progesterone results in only a modest rise in serum progesterone, with a coefficient of variation among individuals that is double that outside of pregnancy.¹⁶ It is, therefore, considered that vaginal progesterone in pregnancy may have a local action secondary to the uterine first-pass effect. The uterine first-pass effect for vaginal progesterone was described in nonpregnant women and is only assumed to occur in pregnancy as well. ¹⁷

After evaluating the data from the largest available study of vaginal progesterone,¹⁸ the FDA concluded in 2012 that the study did not meet the statistical significance generally expected to support the approval of a new product. However, according to a more comprehensive evidence review developed in 2019 by the National Guideline Alliance in the United Kingdom, women with a history of PTD and women with a short cervix derive an important benefit from the use of vaginal progesterone; thus, this intervention should be offered to them.¹⁹ At this time, a short cervix and PTD prevention are not considered FDA-approved indications for progesterone supplementation in pregnancy. However, vaginal progesterone is FDA approved for use in pregnant women with a history of infertility.

Continue to: Case 1 Continued...

Case 1 Continued

MC initiated treatment with daily vaginal progesterone at 18 weeks’ gestation and returned for ultrasound cervical length examination weekly instead of every other week. At 20 weeks’ gestation, cervical length was 2.0 cm; the following week it was 1.4 cm. What would you recommend at this point?

When to consider cerclage

If cervical shortening progresses to about 1.5 cm while a woman is being treated with vaginal progesterone, cerclage may be considered. The benefit of cerclage in patients with prior PTD and a short cervix was highlighted in a 2018 Cochrane Review.²⁰ In this stepwise management approach to a short cervix, waiting for a cervix to be less than 1.5 cm may be unadvisable. Under conditions of a very short cervix that is frequently dilated with exposure of fetal membranes, ascending subclinical intra-amniotic infection may already be present, reducing the efficacy of any preventive measures. Preferential consideration for cerclage from the start over initial vaginal progesterone also may be appropriate when there is a history of 2 spontaneous PTDs or mid-trimester losses, a history of a successful cerclage, or with a very short cervix (< 1.0 cm) at the initial evaluation. As for the latter, a 2018 individual patient data meta-analysis of vaginal progesterone found no benefit when the cervix was less than 1.0 cm.¹³

Progesterone plus cerclage likely to add benefit

The results of an adjusted indirect comparison meta-analysis suggest that both interventions—vaginal progesterone and cerclage—are equally effective.²¹ Assuming that there is no clinically meaningful difference in benefit associated with these 2 treatments, the next logical question is whether combining the 2 therapies provides any added benefit; limited observational data seem to suggest that it does. In a retrospective cohort of 86 consecutive singleton pregnancies among women who underwent ultrasound-indicated cerclage, those who used vaginal progesterone after cerclage (n = 45) had a lower rate of PTD.²² Also, a small (66 cases) case-control study demonstrated the benefit of administration of vaginal progesterone as a rescue intervention in women with cerclage and progressive cervical shortening despite cerclage.²³

Case 2 Woman experiences adverse effects from vaginal progesterone

MS is a 25-year-old G2P0101 who was started on vaginal progesterone as prophylaxis for recurrent PTD. She is now at 20 weeks’ gestation, with a stable remnant cervical length of 2.0 cm. She is reporting an increasing vaginal burning sensation and vaginal discharge caused by the nightly vaginal progesterone applications, to the point that she is unwilling to continue the treatment. She asks if any alternatives to vaginal progesterone are available to decrease her risk of PTD.

Continue to: Is oral progesterone an option?...

Is oral progesterone an option?

In the 1980s and 1990s, oral micronized progesterone was widely used in France at doses of 900 to 1,200 mg/d for women at risk for PTD. The practice was stopped when secondary hepatic effects, including cholestasis of pregnancy, were reported at a higher rate in treated women.²⁴ A rise in the serum concentration of progesterone metabolites has been associated with impaired biliary excretion and subsequent accumulation of bile acids.²⁵ In other reports, elevated serum transaminase activity was found in pregnant women treated with oral micronized progesterone, and withdrawal of treatment frequently has led to improvement in transaminase levels.²⁶ The synthesis of endogenous progesterone during normal pregnancy is between 250 and 500 mg/d,²⁶ and experts have expressed concern that exogenous progesterone supplementation may impose an additional load on the hepatic transport of sulfated metabolites. Unlike orally administered progesterone, progestins given by the vaginal route avoid the hepatic first-pass effect. For this reason, they may be associated with less hepatic dysfunction.

Although not recommended by professional guidelines, oral progesterone administration for the prevention of PTD has been used in the United States. A 2015 survey of Wisconsin prenatal care providers found that of those who prescribed any progesterone for PTD prevention, oral progesterone was prescribed by 13.1% of obstetricians, 24.4% of midwives, and 40.7% of family medicine practitioners.²⁷

Some limited recent evidence from a meta-analysis of 3 trials investigating oral progesterone versus placebo suggests effectiveness in the prevention of recurrent PTD and reduction in perinatal morbidity and mortality.¹⁵ However, the number of cases included in the meta-analysis (386) was too small to support definitive clinical recommendations. Furthermore, questions have been raised in the literature about the reliability of the largest trial included in that meta-analysis.²⁸

Case 3 Two previous spontaneous PTDs

A 29-year-old G3P0201 presents for her first prenatal appointment at 10 weeks’ gestation. With her first pregnancy she had a spontaneous PTD at 23 weeks, and the neonate did not survive. In her second pregnancy, she was treated with 17-OHPC from 16 weeks’ gestation. She had a spontaneous PTD at 29 weeks, and that child is developing normally by her report. She believes that 17-OHPC helped her in her last pregnancy and is anxious about the risk for still another PTD. Consistent with the concept of shared decision-making, you inform her of the results of the recent PROLONG trial and statements on the subject released by professional organizations such as ACOG and the Society for Maternal-Fetal Medicine (SMFM). What options does she have?

17-OHPC may be a possibility in very high-risk women

According to a SMFM statement released in the wake of the PROLONG trial publication, “. . . SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial”.²⁹ Only a few women will have a recurrence risk of PTD over 50%, as was the background event rate in the Meis trial.³⁰ Such a risk level may be suspected, as an example, in women with 2 or more prior early (before 34 weeks) PTDs without intervening term deliveries. Even in those cases, if treatment with 17-OHPC is decided upon, ultrasound cervical surveillance should be added as an additional safety measure. ●

Researchers have been studying the use of exogenous progestins for prevention of preterm delivery (PTD) for almost 60 years, but conflicting results contribute to an ongoing debate. Interpretation of the available data is particularly difficult because different forms and doses of progestins have been used in disparate study populations.

Based on available data, progesterone supplementation is not effective as a primary prevention strategy for PTD in the general low-risk obstetric population. PTD is a complex problem with varied and incompletely elucidated pathogenic pathways, making it unlikely that one interventional approach would be effective for all pregnant women. As a result, emerging indications for the use of progesterone are based on risk factors for PTD (ie, prior PTD and/or short cervix). However, this secondary prevention approach is a limiting factor in itself because 50% of women destined to have a PTD have no identifiable risk factors.¹ In addition, researchers have found that progestins are ineffective at delaying delivery for women with multiple gestation, suggesting that a distinct underlying mechanism of early parturition is present in these women, and that this mechanism is unresponsive to progestins.²

The formulations used in the study of progestin supplementation for PTD prevention have been almost exclusively either the synthetic 17 alpha-hydroxyprogesterone caproate (17-OHPC) or natural progesterone administered orally or vaginally. In 2003, the American College of Obstetricians and Gynecologists (ACOG) supported the use of progesterone to reduce the rate of PTD,³ and in 2011, the US Food and Drug Administration (FDA) approved 17-OHPC for use as prophylaxis against recurrent PTD. As a result, in recent years, the perceived standard of care for a majority of practitioners in the United States had been that all women with a previous preterm birth should be offered 17-OHPC. It may be interesting to note that in other parts of the world, the same enthusiastic adoption did not occur. For example, in Australia and New Zealand in 2007, only 5% of practitioners were using progesterone for this indication.⁴ Further, 17-OHPC is not recommended by professional guidelines in the United Kingdom and has remained unavailable in Germany.

The publication in 2019 of the PROLONG trial called into question the use of 17-OHPC for the prevention of PTD.⁵ In the December 2019 issue of OBG Management (“Managing preterm birth in those at risk: Expert strategies”), I expressed the opinion that with only rare exceptions, 17-OHPC is no longer a viable option for recurrent PTD prevention.⁶ In light of these developments, what scientific evidence is relevant and applicable to the care of women at risk for PTD?

Continue to: Case 1 Previous spontaneous PTD at 31 weeks...

Case 1 Previous spontaneous PTD at 31 weeks

MC is an asymptomatic 32-year-old woman with a singleton pregnancy at 13 weeks’ gestation. You see her for a maternal-fetal medicine consultation because 2 years ago she had a spontaneous PTD at 31 weeks’ gestation. What management recommendations can you make to decrease her risk of recurrent PTD?

Cervical length measurement narrows in on risk

The indication “previous preterm birth” is largely meaningless because of the heterogeneity in preterm birth pathways (preterm birth as a syndrome⁷) and inadequate risk characterization. Among women who experience a spontaneous PTD, 70% to 80% do not deliver prematurely in subsequent pregnancies.⁸ To better characterize the risk of PTD recurrence, ultrasound assessment of cervical length should be used. Research has shown that among women with a prior spontaneous PTD who maintain a normal cervical length until 24 weeks’ gestation, more than 90% will deliver at 35 weeks or after without intervention.⁹ Such an approach not only identifies the subgroup of women at significantly increased risk of recurrence but also eliminates unnecessary interventions.

Cervical ultrasound surveillance should be initiated at 16 weeks’ gestation. A short cervix before 16 weeks is not associated with a statistically significant increase in risk for PTD.¹⁰ Shortening of the cervix begins approximately 10 weeks before delivery in any gestational age group.¹¹ Therefore, ultrasound assessment of the cervix at 28 weeks and after is irrelevant. In addition, after 28 weeks, cervical length varies greatly leading to loss in the predictive power of the cervical measurement.¹² Based on these considerations, cervical surveillance may be extended up to 26 weeks. Although cervical cerclage is not an option in the United States in cases in which a short cervix is detected between 24 and 26 weeks, vaginal progesterone supplementation may still be considered.

Case 1 Continued

MC was started on ultrasound cervical surveillance at 16 weeks’ gestation. Her cervical length was initially normal (> 2.5 cm), but at 18 weeks the measurement was 2.2 cm. What is your recommendation?

The value of vaginal progesterone

There appears to be increasing consensus on the value of vaginal progesterone for women with a midtrimester short cervix on sonography, with or without a history of PTD. An individual patient data meta-analysis demonstrated the benefits of vaginal progesterone.¹³ Although there was no evidence of an effect on PTD at less than 37 weeks, the rates of PTD at less than 36 weeks and spontaneous PTD at less than 34 weeks were significantly reduced (by 20% and 28%, respectively). Also, there was a significant reduction in the risk of respiratory distress syndrome (53%) and composite neonatal morbidity and mortality (41%), with no significant impact on infant development up to the second year of life.¹³

The lack of generalizable evidence of benefit on childhood outcomes, combined with considerable uncertainty about the exact role and mechanism of action of exogenous progestins, contribute to the ongoing debate. Vaginal progesterone dosage regimens have been based on extrapolations from experience with progesterone in nonpregnant women, and recent pharmacokinetic studies have revealed how precarious such extrapolations may be. As an example, in nonpregnant women, the bioavailability of oral and vaginal progesterone is similar.¹⁴ In pregnancy, however, while daily oral progesterone doubles a pregnant woman’s serum progesterone level,¹⁵ daily vaginal administration of progesterone results in only a modest rise in serum progesterone, with a coefficient of variation among individuals that is double that outside of pregnancy.¹⁶ It is, therefore, considered that vaginal progesterone in pregnancy may have a local action secondary to the uterine first-pass effect. The uterine first-pass effect for vaginal progesterone was described in nonpregnant women and is only assumed to occur in pregnancy as well. ¹⁷

After evaluating the data from the largest available study of vaginal progesterone,¹⁸ the FDA concluded in 2012 that the study did not meet the statistical significance generally expected to support the approval of a new product. However, according to a more comprehensive evidence review developed in 2019 by the National Guideline Alliance in the United Kingdom, women with a history of PTD and women with a short cervix derive an important benefit from the use of vaginal progesterone; thus, this intervention should be offered to them.¹⁹ At this time, a short cervix and PTD prevention are not considered FDA-approved indications for progesterone supplementation in pregnancy. However, vaginal progesterone is FDA approved for use in pregnant women with a history of infertility.

Continue to: Case 1 Continued...

Case 1 Continued

MC initiated treatment with daily vaginal progesterone at 18 weeks’ gestation and returned for ultrasound cervical length examination weekly instead of every other week. At 20 weeks’ gestation, cervical length was 2.0 cm; the following week it was 1.4 cm. What would you recommend at this point?

When to consider cerclage

If cervical shortening progresses to about 1.5 cm while a woman is being treated with vaginal progesterone, cerclage may be considered. The benefit of cerclage in patients with prior PTD and a short cervix was highlighted in a 2018 Cochrane Review.²⁰ In this stepwise management approach to a short cervix, waiting for a cervix to be less than 1.5 cm may be unadvisable. Under conditions of a very short cervix that is frequently dilated with exposure of fetal membranes, ascending subclinical intra-amniotic infection may already be present, reducing the efficacy of any preventive measures. Preferential consideration for cerclage from the start over initial vaginal progesterone also may be appropriate when there is a history of 2 spontaneous PTDs or mid-trimester losses, a history of a successful cerclage, or with a very short cervix (< 1.0 cm) at the initial evaluation. As for the latter, a 2018 individual patient data meta-analysis of vaginal progesterone found no benefit when the cervix was less than 1.0 cm.¹³

Progesterone plus cerclage likely to add benefit

The results of an adjusted indirect comparison meta-analysis suggest that both interventions—vaginal progesterone and cerclage—are equally effective.²¹ Assuming that there is no clinically meaningful difference in benefit associated with these 2 treatments, the next logical question is whether combining the 2 therapies provides any added benefit; limited observational data seem to suggest that it does. In a retrospective cohort of 86 consecutive singleton pregnancies among women who underwent ultrasound-indicated cerclage, those who used vaginal progesterone after cerclage (n = 45) had a lower rate of PTD.²² Also, a small (66 cases) case-control study demonstrated the benefit of administration of vaginal progesterone as a rescue intervention in women with cerclage and progressive cervical shortening despite cerclage.²³

Case 2 Woman experiences adverse effects from vaginal progesterone

MS is a 25-year-old G2P0101 who was started on vaginal progesterone as prophylaxis for recurrent PTD. She is now at 20 weeks’ gestation, with a stable remnant cervical length of 2.0 cm. She is reporting an increasing vaginal burning sensation and vaginal discharge caused by the nightly vaginal progesterone applications, to the point that she is unwilling to continue the treatment. She asks if any alternatives to vaginal progesterone are available to decrease her risk of PTD.

Continue to: Is oral progesterone an option?...

Is oral progesterone an option?

In the 1980s and 1990s, oral micronized progesterone was widely used in France at doses of 900 to 1,200 mg/d for women at risk for PTD. The practice was stopped when secondary hepatic effects, including cholestasis of pregnancy, were reported at a higher rate in treated women.²⁴ A rise in the serum concentration of progesterone metabolites has been associated with impaired biliary excretion and subsequent accumulation of bile acids.²⁵ In other reports, elevated serum transaminase activity was found in pregnant women treated with oral micronized progesterone, and withdrawal of treatment frequently has led to improvement in transaminase levels.²⁶ The synthesis of endogenous progesterone during normal pregnancy is between 250 and 500 mg/d,²⁶ and experts have expressed concern that exogenous progesterone supplementation may impose an additional load on the hepatic transport of sulfated metabolites. Unlike orally administered progesterone, progestins given by the vaginal route avoid the hepatic first-pass effect. For this reason, they may be associated with less hepatic dysfunction.

Although not recommended by professional guidelines, oral progesterone administration for the prevention of PTD has been used in the United States. A 2015 survey of Wisconsin prenatal care providers found that of those who prescribed any progesterone for PTD prevention, oral progesterone was prescribed by 13.1% of obstetricians, 24.4% of midwives, and 40.7% of family medicine practitioners.²⁷

Some limited recent evidence from a meta-analysis of 3 trials investigating oral progesterone versus placebo suggests effectiveness in the prevention of recurrent PTD and reduction in perinatal morbidity and mortality.¹⁵ However, the number of cases included in the meta-analysis (386) was too small to support definitive clinical recommendations. Furthermore, questions have been raised in the literature about the reliability of the largest trial included in that meta-analysis.²⁸

Case 3 Two previous spontaneous PTDs

A 29-year-old G3P0201 presents for her first prenatal appointment at 10 weeks’ gestation. With her first pregnancy she had a spontaneous PTD at 23 weeks, and the neonate did not survive. In her second pregnancy, she was treated with 17-OHPC from 16 weeks’ gestation. She had a spontaneous PTD at 29 weeks, and that child is developing normally by her report. She believes that 17-OHPC helped her in her last pregnancy and is anxious about the risk for still another PTD. Consistent with the concept of shared decision-making, you inform her of the results of the recent PROLONG trial and statements on the subject released by professional organizations such as ACOG and the Society for Maternal-Fetal Medicine (SMFM). What options does she have?

17-OHPC may be a possibility in very high-risk women

According to a SMFM statement released in the wake of the PROLONG trial publication, “. . . SMFM believes that it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial”.²⁹ Only a few women will have a recurrence risk of PTD over 50%, as was the background event rate in the Meis trial.³⁰ Such a risk level may be suspected, as an example, in women with 2 or more prior early (before 34 weeks) PTDs without intervening term deliveries. Even in those cases, if treatment with 17-OHPC is decided upon, ultrasound cervical surveillance should be added as an additional safety measure. ●

The Food and Drug Administration has updated the labels for peginterferon beta-1a (Plegridy) and interferon beta-1a (Avonex) to include more information about usage of these medications during pregnancy and breastfeeding in women with multiple sclerosis (MS).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The FDA based the decision on data from more than 1,000 real-world pregnancies, including pregnancies from a large epidemiologic study and published studies over several decades, which found no connection between use of interferon-beta products during early pregnancy and an increased risk of major birth defects, according to the FDA.

As a result, the labels for both medications will no longer have the pregnancy category C designation; however, patients should continue to notify their health care provider if they are pregnant or plan to become pregnant.

The FDA decision to remove the warning follows a similar decision by the European Medicines Agency last year.

“Many women with MS are diagnosed during their childbearing years. With this important update for Plegridy and Avonex, healthcare providers have more data to inform appropriate treatment paths for patients who may be pregnant or planning for pregnancy,” said Bernd Kieseier, MD, MHBA, executive director and head of global MS at Worldwide Medical, Biogen, in a press release.

[email protected]

The Food and Drug Administration has updated the labels for peginterferon beta-1a (Plegridy) and interferon beta-1a (Avonex) to include more information about usage of these medications during pregnancy and breastfeeding in women with multiple sclerosis (MS).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The FDA based the decision on data from more than 1,000 real-world pregnancies, including pregnancies from a large epidemiologic study and published studies over several decades, which found no connection between use of interferon-beta products during early pregnancy and an increased risk of major birth defects, according to the FDA.

As a result, the labels for both medications will no longer have the pregnancy category C designation; however, patients should continue to notify their health care provider if they are pregnant or plan to become pregnant.

The FDA decision to remove the warning follows a similar decision by the European Medicines Agency last year.

“Many women with MS are diagnosed during their childbearing years. With this important update for Plegridy and Avonex, healthcare providers have more data to inform appropriate treatment paths for patients who may be pregnant or planning for pregnancy,” said Bernd Kieseier, MD, MHBA, executive director and head of global MS at Worldwide Medical, Biogen, in a press release.

[email protected]

The Food and Drug Administration has updated the labels for peginterferon beta-1a (Plegridy) and interferon beta-1a (Avonex) to include more information about usage of these medications during pregnancy and breastfeeding in women with multiple sclerosis (MS).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The FDA based the decision on data from more than 1,000 real-world pregnancies, including pregnancies from a large epidemiologic study and published studies over several decades, which found no connection between use of interferon-beta products during early pregnancy and an increased risk of major birth defects, according to the FDA.

As a result, the labels for both medications will no longer have the pregnancy category C designation; however, patients should continue to notify their health care provider if they are pregnant or plan to become pregnant.

The FDA decision to remove the warning follows a similar decision by the European Medicines Agency last year.

“Many women with MS are diagnosed during their childbearing years. With this important update for Plegridy and Avonex, healthcare providers have more data to inform appropriate treatment paths for patients who may be pregnant or planning for pregnancy,” said Bernd Kieseier, MD, MHBA, executive director and head of global MS at Worldwide Medical, Biogen, in a press release.

[email protected]

Exposure during pregnancy to a specific per- and polyfluoroalkyl substance (PFAS), combined with a low cholesterol level, is linked to a heightened risk of abdominal and whole-body obesity in granddaughters, according to a new analysis of the Child Health and Development Studies, which have been ongoing since the 1960s.

Researchers directly measured levels of N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA) in blood samples from the grandmothers, which had been taken shortly after delivery, and then analyzed measures of obesity and other metabolic factors in their daughters at ages 30 years and 50 years, and their granddaughters at age 20.

PFASs are synthetic compounds commonly used as oil and water repellents; coatings for cookware, carpets, and textiles; and as firefighting foams. The compounds do not break down in the environment or the human body and accumulate over time. They are known to disrupt the endocrine system.

EtFOSAA is a metabolite of a raw material used in the manufacturing of packaging and paper products, and itself gets converted to perfluorooctane sulfonic acid (PFOS), which is extremely stable in the environment and within organisms, leading to bioaccumulation that has the potential to span generations, Barbara A. Cohn, PhD, director of child health and development studies at the Public Health Institute in Berkeley, Calif., said during a virtual press conference held by The Endocrine Society. The study was slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

Abdominal obesity was defined as a waist circumference of more than 34.6 inches (88 cm), and whole-body obesity was defined as a body mass index of more than 30 kg/m². Findings from a previous study drawn from the same cohort showed that exposure to EtFOSAA, combined with high maternal cholesterol levels, was linked to increased risk of breast cancer in daughters.

“I want to emphasize that we don’t understand the mechanism, but we do know that this finding [from the current study], if it is confirmed, has implications for the current epidemic of obesity. Exposure to these compounds is very widespread, [having] started in the 1940s and 50s, and is consistent with the timing of the obesity epidemic,” said Dr. Cohn, during the virtual press conference.

Robert Sargis, MD, professor of endocrinology, diabetes, and metabolism at the University of Illinois at Chicago, said the mechanistic connection could be complex. “It’s a combination of the possibility that the chemicals themselves are passed down either through breast milk or across the placenta, or that the biological impact is somehow coded epigenetically, and then that epigenetic code is somehow passed on to subsequent generations,” he said in an interview. He was not associated with the research.

Dr. Cohn said her team is investigating both of those possibilities through analysis of the existing blood samples. “There are implications for PFAS clean-up if [these findings are] confirmed, and there’s an opportunity for setting up precautions for pregnant women on how they can try to avoid this contamination to [offset] a rekindling of this generational effect 60 years down the road,” Dr. Cohn added.

Daughters of the original participants (now grandmothers) were measured at an average age of 50, and the granddaughters, at an average of 20 (219 dyads, 657 women in total). Daughters also reported their weight at age 30, which was close to the mean age at which they had given birth. This allowed the researchers to control for obesity present during gestation of the granddaughters.

The researchers analyzed EtFOSAA, PFOS, and cholesterol levels from archived blood samples taken from grandmothers within 3 days of delivery. There was an association between EtFOSAA and self-reported obesity at age 30 in daughters, as well as measured abdominal, whole-body obesity, and blood pressure at age 20 in granddaughters, and all were modified by low cholesterol levels (25% interquartile) in grandmothers (P < .05).

In granddaughters, the combined risk of abdominal and whole-body obesity was 2.3-fold higher in those whose grandmothers were in the top 25% of EtFOSAA exposure, compared with those whose grandmothers were in the lowest 25% (95% confidence interval, 1.1-4.8). Those associations remained after adjustments for race, being overweight in early pregnancy (BMI, >25 kg/m²), and serum PFOS levels.

Although the weight of daughters did not affect the association between the granddaughters’ risk for obesity risk and EtFOSAA levels in grandmothers, it did predict high metabolic risk in granddaughters. That suggests that the burden may be building over generations. “Independently, their mothers themselves are heavier and fatter, and that heaviness of the mother is also a source of increasing body size for the granddaughter. We have a multiplying, very ugly situation that may be helping us to understand this really quick rise of obesity,” said Dr. Cohn.

She also emphasized that PFAS may not be the only culprit in fueling obesity. “Most of us believe that there is sufficient data in the animal studies and, now, growing data in human studies, to suggest that these obesogens exist and are contributing to the health problems that are going to be following the obesity epidemic in young people now.”

Dr. Cohn noted that the study is limited by its lack of a control group.

The California Breast Research Foundation, the National Institutes of Health, and the State of California funded the study. Dr. Cohn and Dr. Sargis reported no relevant financial disclosures.

The study abstract will be published in the Journal of the Endocrine Society. In addition to a series of news conferences held on March 30-31, the society will host ENDO Online 2020 during June 8-22 with programming for clinicians and researchers.
 

SOURCE: Cohn B et al. ENDO 2020, Abstract LB132.

Exposure during pregnancy to a specific per- and polyfluoroalkyl substance (PFAS), combined with a low cholesterol level, is linked to a heightened risk of abdominal and whole-body obesity in granddaughters, according to a new analysis of the Child Health and Development Studies, which have been ongoing since the 1960s.

Researchers directly measured levels of N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA) in blood samples from the grandmothers, which had been taken shortly after delivery, and then analyzed measures of obesity and other metabolic factors in their daughters at ages 30 years and 50 years, and their granddaughters at age 20.

PFASs are synthetic compounds commonly used as oil and water repellents; coatings for cookware, carpets, and textiles; and as firefighting foams. The compounds do not break down in the environment or the human body and accumulate over time. They are known to disrupt the endocrine system.

EtFOSAA is a metabolite of a raw material used in the manufacturing of packaging and paper products, and itself gets converted to perfluorooctane sulfonic acid (PFOS), which is extremely stable in the environment and within organisms, leading to bioaccumulation that has the potential to span generations, Barbara A. Cohn, PhD, director of child health and development studies at the Public Health Institute in Berkeley, Calif., said during a virtual press conference held by The Endocrine Society. The study was slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

Abdominal obesity was defined as a waist circumference of more than 34.6 inches (88 cm), and whole-body obesity was defined as a body mass index of more than 30 kg/m². Findings from a previous study drawn from the same cohort showed that exposure to EtFOSAA, combined with high maternal cholesterol levels, was linked to increased risk of breast cancer in daughters.

“I want to emphasize that we don’t understand the mechanism, but we do know that this finding [from the current study], if it is confirmed, has implications for the current epidemic of obesity. Exposure to these compounds is very widespread, [having] started in the 1940s and 50s, and is consistent with the timing of the obesity epidemic,” said Dr. Cohn, during the virtual press conference.

Robert Sargis, MD, professor of endocrinology, diabetes, and metabolism at the University of Illinois at Chicago, said the mechanistic connection could be complex. “It’s a combination of the possibility that the chemicals themselves are passed down either through breast milk or across the placenta, or that the biological impact is somehow coded epigenetically, and then that epigenetic code is somehow passed on to subsequent generations,” he said in an interview. He was not associated with the research.

Dr. Cohn said her team is investigating both of those possibilities through analysis of the existing blood samples. “There are implications for PFAS clean-up if [these findings are] confirmed, and there’s an opportunity for setting up precautions for pregnant women on how they can try to avoid this contamination to [offset] a rekindling of this generational effect 60 years down the road,” Dr. Cohn added.

Daughters of the original participants (now grandmothers) were measured at an average age of 50, and the granddaughters, at an average of 20 (219 dyads, 657 women in total). Daughters also reported their weight at age 30, which was close to the mean age at which they had given birth. This allowed the researchers to control for obesity present during gestation of the granddaughters.

The researchers analyzed EtFOSAA, PFOS, and cholesterol levels from archived blood samples taken from grandmothers within 3 days of delivery. There was an association between EtFOSAA and self-reported obesity at age 30 in daughters, as well as measured abdominal, whole-body obesity, and blood pressure at age 20 in granddaughters, and all were modified by low cholesterol levels (25% interquartile) in grandmothers (P < .05).

In granddaughters, the combined risk of abdominal and whole-body obesity was 2.3-fold higher in those whose grandmothers were in the top 25% of EtFOSAA exposure, compared with those whose grandmothers were in the lowest 25% (95% confidence interval, 1.1-4.8). Those associations remained after adjustments for race, being overweight in early pregnancy (BMI, >25 kg/m²), and serum PFOS levels.

Although the weight of daughters did not affect the association between the granddaughters’ risk for obesity risk and EtFOSAA levels in grandmothers, it did predict high metabolic risk in granddaughters. That suggests that the burden may be building over generations. “Independently, their mothers themselves are heavier and fatter, and that heaviness of the mother is also a source of increasing body size for the granddaughter. We have a multiplying, very ugly situation that may be helping us to understand this really quick rise of obesity,” said Dr. Cohn.

She also emphasized that PFAS may not be the only culprit in fueling obesity. “Most of us believe that there is sufficient data in the animal studies and, now, growing data in human studies, to suggest that these obesogens exist and are contributing to the health problems that are going to be following the obesity epidemic in young people now.”

Dr. Cohn noted that the study is limited by its lack of a control group.

The California Breast Research Foundation, the National Institutes of Health, and the State of California funded the study. Dr. Cohn and Dr. Sargis reported no relevant financial disclosures.

The study abstract will be published in the Journal of the Endocrine Society. In addition to a series of news conferences held on March 30-31, the society will host ENDO Online 2020 during June 8-22 with programming for clinicians and researchers.
 

SOURCE: Cohn B et al. ENDO 2020, Abstract LB132.

Exposure during pregnancy to a specific per- and polyfluoroalkyl substance (PFAS), combined with a low cholesterol level, is linked to a heightened risk of abdominal and whole-body obesity in granddaughters, according to a new analysis of the Child Health and Development Studies, which have been ongoing since the 1960s.

Researchers directly measured levels of N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA) in blood samples from the grandmothers, which had been taken shortly after delivery, and then analyzed measures of obesity and other metabolic factors in their daughters at ages 30 years and 50 years, and their granddaughters at age 20.

PFASs are synthetic compounds commonly used as oil and water repellents; coatings for cookware, carpets, and textiles; and as firefighting foams. The compounds do not break down in the environment or the human body and accumulate over time. They are known to disrupt the endocrine system.

EtFOSAA is a metabolite of a raw material used in the manufacturing of packaging and paper products, and itself gets converted to perfluorooctane sulfonic acid (PFOS), which is extremely stable in the environment and within organisms, leading to bioaccumulation that has the potential to span generations, Barbara A. Cohn, PhD, director of child health and development studies at the Public Health Institute in Berkeley, Calif., said during a virtual press conference held by The Endocrine Society. The study was slated for presentation during ENDO 2020, the society’s annual meeting, which was canceled because of the COVID-19 pandemic.

Abdominal obesity was defined as a waist circumference of more than 34.6 inches (88 cm), and whole-body obesity was defined as a body mass index of more than 30 kg/m². Findings from a previous study drawn from the same cohort showed that exposure to EtFOSAA, combined with high maternal cholesterol levels, was linked to increased risk of breast cancer in daughters.

“I want to emphasize that we don’t understand the mechanism, but we do know that this finding [from the current study], if it is confirmed, has implications for the current epidemic of obesity. Exposure to these compounds is very widespread, [having] started in the 1940s and 50s, and is consistent with the timing of the obesity epidemic,” said Dr. Cohn, during the virtual press conference.

Robert Sargis, MD, professor of endocrinology, diabetes, and metabolism at the University of Illinois at Chicago, said the mechanistic connection could be complex. “It’s a combination of the possibility that the chemicals themselves are passed down either through breast milk or across the placenta, or that the biological impact is somehow coded epigenetically, and then that epigenetic code is somehow passed on to subsequent generations,” he said in an interview. He was not associated with the research.

Dr. Cohn said her team is investigating both of those possibilities through analysis of the existing blood samples. “There are implications for PFAS clean-up if [these findings are] confirmed, and there’s an opportunity for setting up precautions for pregnant women on how they can try to avoid this contamination to [offset] a rekindling of this generational effect 60 years down the road,” Dr. Cohn added.

Daughters of the original participants (now grandmothers) were measured at an average age of 50, and the granddaughters, at an average of 20 (219 dyads, 657 women in total). Daughters also reported their weight at age 30, which was close to the mean age at which they had given birth. This allowed the researchers to control for obesity present during gestation of the granddaughters.

The researchers analyzed EtFOSAA, PFOS, and cholesterol levels from archived blood samples taken from grandmothers within 3 days of delivery. There was an association between EtFOSAA and self-reported obesity at age 30 in daughters, as well as measured abdominal, whole-body obesity, and blood pressure at age 20 in granddaughters, and all were modified by low cholesterol levels (25% interquartile) in grandmothers (P < .05).

In granddaughters, the combined risk of abdominal and whole-body obesity was 2.3-fold higher in those whose grandmothers were in the top 25% of EtFOSAA exposure, compared with those whose grandmothers were in the lowest 25% (95% confidence interval, 1.1-4.8). Those associations remained after adjustments for race, being overweight in early pregnancy (BMI, >25 kg/m²), and serum PFOS levels.

Although the weight of daughters did not affect the association between the granddaughters’ risk for obesity risk and EtFOSAA levels in grandmothers, it did predict high metabolic risk in granddaughters. That suggests that the burden may be building over generations. “Independently, their mothers themselves are heavier and fatter, and that heaviness of the mother is also a source of increasing body size for the granddaughter. We have a multiplying, very ugly situation that may be helping us to understand this really quick rise of obesity,” said Dr. Cohn.

She also emphasized that PFAS may not be the only culprit in fueling obesity. “Most of us believe that there is sufficient data in the animal studies and, now, growing data in human studies, to suggest that these obesogens exist and are contributing to the health problems that are going to be following the obesity epidemic in young people now.”

Dr. Cohn noted that the study is limited by its lack of a control group.

The California Breast Research Foundation, the National Institutes of Health, and the State of California funded the study. Dr. Cohn and Dr. Sargis reported no relevant financial disclosures.

The study abstract will be published in the Journal of the Endocrine Society. In addition to a series of news conferences held on March 30-31, the society will host ENDO Online 2020 during June 8-22 with programming for clinicians and researchers.
 

SOURCE: Cohn B et al. ENDO 2020, Abstract LB132.

As the COVID-19 pandemic continues to spread across the United States, several members of the Ob.Gyn. News Editorial Advisory Board shared their experiences.

• One person will cover labor and delivery.
• One person will cover triage and help on labor and delivery.
• One person will be assigned to the resident office.
• One person will be assigned to cover the team of the post call attending (Sunday through Thursday call).
• One person will be assigned to gynecology coverage, consults, and postpartum rounds.

To further minimize the patient interactions, when possible, each patient should be seen by the attending physician with the resident. This is a change from usual practice, where the patient is first seen by the resident, who reports back to the attending, and then both physicians see the patient together.

The network’s offices now open from 9 a.m. (many offices had been offering early-morning hours starting at 7 a.m.), and the physicians and advanced practice providers will work through the last scheduled patient appointment, Dr. Jaspan explained. “The office-based team will preferentially see in-person visits.”

Several offices have been closed so that ob.gyns. and staff can be reassigned to telehealth. The remaining five offices generally have one attending physician and one advanced practice provider.

The remaining team of ob.gyns. provides telehealth with the help of staff members. This involves an initial call to the patient by staff letting them know the doctor will be calling, checking them in, verifying insurance, and collecting payment, followed by the actual telehealth visit. If follow-up is needed, the staff member schedules the follow-up.

Dr. Jaspan called the new approach to prenatal care because of COVID-19 a “cataclysmic change in how we care for our patients. We have decided to further limit our obstetrical in-person visits. It is our feeling that these changes will enable patients to remain outside of the office and in the safety of their homes, provide appropriate social distancing, and diminish potential exposures to the office staff providers and patients.”

In-person visits will occur at: the initial visit, between 24 and 28 weeks, at 32 weeks, and at 36 or 37 weeks; if the patient at 36/37 has a blood pressure cuff, they will not have additional scheduled in-patient visits. We have partnered with the insurance companies to provide more than 88% of obstetrical patients with home blood pressure cuffs.

Obstetrical visits via telehealth will continue at our standard intervals: monthly until 26 weeks; twice monthly during 26-36 weeks; and weekly from 37 weeks to delivery. These visits should use a video component such as Zoom, Doxy.me, or FaceTime.

“If the patient has concerns or problems, we will see them at any time. However, the new standard will be telehealth visits and the exception will be the in-person visit,” Dr. Jaspan said.

In addition, we have worked our division of maternal-fetal medicine to adjust the antenatal testing schedules, and we have curtailed the frequency of ultrasound, he noted.

He emphasized the importance of documenting telehealth interactions with obstetrical patients, in addition to “providing adequate teaching and education for patients regarding kick counts to ensure fetal well-being.” It also is key to “properly document conversations with patients regarding bleeding, rupture of membranes, fetal movement, headache, visual changes, fevers, cough, nausea and vomiting, diarrhea, fatigue, muscle aches, etc.”

The residents’ schedule also has been modified to diminish their exposure. Within our new paradigm, we have scheduled video conferences to enable our program to maintain our commitment to academics.

It is imperative that we keep our patients safe, and it is critical to protect our staff members. Those who provide women’s health cannot be replaced by other nurses or physicians.

• Suspend initiation of new treatment cycles, including ovulation induction, intrauterine inseminations, in vitro fertilization including retrievals and frozen embryo transfers, and nonurgent gamete cryopreservation.
• Strongly consider cancellation of all embryo transfers, whether fresh or frozen.
• Continue to care for patients who are currently “in cycle” or who require urgent stimulation and cryopreservation.
• Suspend elective surgeries and nonurgent diagnostic procedures.
• Minimize in-person interactions and increase utilization of telehealth.

As a member of ASRM for more than 2 decades and a participant of several of their committees, my practice immediately ceased treatment cycles to comply with this guidance.

Then on March 20, 2020, the Florida governor’s executive order 20-72 was released, stating, “All hospitals, ambulatory surgical centers, office surgery centers, dental, orthodontic and endodontic offices, and other health care practitioners’ offices in the State of Florida are prohibited from providing any medically unnecessary, nonurgent or nonemergency procedure or surgery which, if delayed, does not place a patient’s immediate health, safety, or well-­being at risk, or will, if delayed, not contribute to the worsening of a serious or life-threatening medical condition.”

As a result, my practice has been limited to telemedicine consultations. While the ASRM guidance and the gubernatorial executive order pose a significant financial hardship on my center and all applicable medical clinics in my state, resulting in expected layoffs, salary reductions, and requests for government stimulus loans, the greater good takes priority and we pray for all the victims of this devastating pandemic.

The governor’s current executive order is set to expire on May 9, 2020, unless it is extended.

ASRM released an update of their guidance on March 30, 2020, offering no change from their prior recommendations. The organization plans to reevaluate the guidance at 2-week intervals.

Sangeeta Sinha, MD, an ob.gyn. in private practice at Stone Springs Hospital Center, Dulles, Va. said in an interview, “COVID 19 has put fear in all aspects of our daily activities which we are attempting to cope with.”

She related several changes made to her office and hospital environments. “In our office, we are now wearing a mask at all times, gloves to examine every patient. We have staggered physicians in the office to take televisits and in-office patients. We are screening all new patients on the phone to determine if they are sick, have traveled to high-risk, hot spot areas of the country, or have had contact with someone who tested positive for COVID-19. We are only seeing our pregnant women and have also pushed out their return appointments to 4 weeks if possible. There are several staff who are not working due to fear or are in self quarantine so we have shortage of staff in the office. At the hospital as well we are wearing a mask at all times, using personal protective equipment for deliveries and C-sections.

“We have had several scares, including a new transfer of an 18-year-old pregnant patient at 30 weeks with cough and sore throat, who later reported that her roommate is very sick and he works with someone who has tested positive for COVID-19. Thankfully she is healthy and well. We learned several lessons from this one.”

As the COVID-19 pandemic continues to spread across the United States, several members of the Ob.Gyn. News Editorial Advisory Board shared their experiences.

• One person will cover labor and delivery.
• One person will cover triage and help on labor and delivery.
• One person will be assigned to the resident office.
• One person will be assigned to cover the team of the post call attending (Sunday through Thursday call).
• One person will be assigned to gynecology coverage, consults, and postpartum rounds.

To further minimize the patient interactions, when possible, each patient should be seen by the attending physician with the resident. This is a change from usual practice, where the patient is first seen by the resident, who reports back to the attending, and then both physicians see the patient together.

The network’s offices now open from 9 a.m. (many offices had been offering early-morning hours starting at 7 a.m.), and the physicians and advanced practice providers will work through the last scheduled patient appointment, Dr. Jaspan explained. “The office-based team will preferentially see in-person visits.”

Several offices have been closed so that ob.gyns. and staff can be reassigned to telehealth. The remaining five offices generally have one attending physician and one advanced practice provider.

The remaining team of ob.gyns. provides telehealth with the help of staff members. This involves an initial call to the patient by staff letting them know the doctor will be calling, checking them in, verifying insurance, and collecting payment, followed by the actual telehealth visit. If follow-up is needed, the staff member schedules the follow-up.

Dr. Jaspan called the new approach to prenatal care because of COVID-19 a “cataclysmic change in how we care for our patients. We have decided to further limit our obstetrical in-person visits. It is our feeling that these changes will enable patients to remain outside of the office and in the safety of their homes, provide appropriate social distancing, and diminish potential exposures to the office staff providers and patients.”

In-person visits will occur at: the initial visit, between 24 and 28 weeks, at 32 weeks, and at 36 or 37 weeks; if the patient at 36/37 has a blood pressure cuff, they will not have additional scheduled in-patient visits. We have partnered with the insurance companies to provide more than 88% of obstetrical patients with home blood pressure cuffs.

Obstetrical visits via telehealth will continue at our standard intervals: monthly until 26 weeks; twice monthly during 26-36 weeks; and weekly from 37 weeks to delivery. These visits should use a video component such as Zoom, Doxy.me, or FaceTime.

“If the patient has concerns or problems, we will see them at any time. However, the new standard will be telehealth visits and the exception will be the in-person visit,” Dr. Jaspan said.

In addition, we have worked our division of maternal-fetal medicine to adjust the antenatal testing schedules, and we have curtailed the frequency of ultrasound, he noted.

He emphasized the importance of documenting telehealth interactions with obstetrical patients, in addition to “providing adequate teaching and education for patients regarding kick counts to ensure fetal well-being.” It also is key to “properly document conversations with patients regarding bleeding, rupture of membranes, fetal movement, headache, visual changes, fevers, cough, nausea and vomiting, diarrhea, fatigue, muscle aches, etc.”

The residents’ schedule also has been modified to diminish their exposure. Within our new paradigm, we have scheduled video conferences to enable our program to maintain our commitment to academics.

It is imperative that we keep our patients safe, and it is critical to protect our staff members. Those who provide women’s health cannot be replaced by other nurses or physicians.

• Suspend initiation of new treatment cycles, including ovulation induction, intrauterine inseminations, in vitro fertilization including retrievals and frozen embryo transfers, and nonurgent gamete cryopreservation.
• Strongly consider cancellation of all embryo transfers, whether fresh or frozen.
• Continue to care for patients who are currently “in cycle” or who require urgent stimulation and cryopreservation.
• Suspend elective surgeries and nonurgent diagnostic procedures.
• Minimize in-person interactions and increase utilization of telehealth.

As a member of ASRM for more than 2 decades and a participant of several of their committees, my practice immediately ceased treatment cycles to comply with this guidance.

Then on March 20, 2020, the Florida governor’s executive order 20-72 was released, stating, “All hospitals, ambulatory surgical centers, office surgery centers, dental, orthodontic and endodontic offices, and other health care practitioners’ offices in the State of Florida are prohibited from providing any medically unnecessary, nonurgent or nonemergency procedure or surgery which, if delayed, does not place a patient’s immediate health, safety, or well-­being at risk, or will, if delayed, not contribute to the worsening of a serious or life-threatening medical condition.”

As a result, my practice has been limited to telemedicine consultations. While the ASRM guidance and the gubernatorial executive order pose a significant financial hardship on my center and all applicable medical clinics in my state, resulting in expected layoffs, salary reductions, and requests for government stimulus loans, the greater good takes priority and we pray for all the victims of this devastating pandemic.

The governor’s current executive order is set to expire on May 9, 2020, unless it is extended.

ASRM released an update of their guidance on March 30, 2020, offering no change from their prior recommendations. The organization plans to reevaluate the guidance at 2-week intervals.

Sangeeta Sinha, MD, an ob.gyn. in private practice at Stone Springs Hospital Center, Dulles, Va. said in an interview, “COVID 19 has put fear in all aspects of our daily activities which we are attempting to cope with.”

She related several changes made to her office and hospital environments. “In our office, we are now wearing a mask at all times, gloves to examine every patient. We have staggered physicians in the office to take televisits and in-office patients. We are screening all new patients on the phone to determine if they are sick, have traveled to high-risk, hot spot areas of the country, or have had contact with someone who tested positive for COVID-19. We are only seeing our pregnant women and have also pushed out their return appointments to 4 weeks if possible. There are several staff who are not working due to fear or are in self quarantine so we have shortage of staff in the office. At the hospital as well we are wearing a mask at all times, using personal protective equipment for deliveries and C-sections.

“We have had several scares, including a new transfer of an 18-year-old pregnant patient at 30 weeks with cough and sore throat, who later reported that her roommate is very sick and he works with someone who has tested positive for COVID-19. Thankfully she is healthy and well. We learned several lessons from this one.”

As the COVID-19 pandemic continues to spread across the United States, several members of the Ob.Gyn. News Editorial Advisory Board shared their experiences.

• One person will cover labor and delivery.
• One person will cover triage and help on labor and delivery.
• One person will be assigned to the resident office.
• One person will be assigned to cover the team of the post call attending (Sunday through Thursday call).
• One person will be assigned to gynecology coverage, consults, and postpartum rounds.

To further minimize the patient interactions, when possible, each patient should be seen by the attending physician with the resident. This is a change from usual practice, where the patient is first seen by the resident, who reports back to the attending, and then both physicians see the patient together.

The network’s offices now open from 9 a.m. (many offices had been offering early-morning hours starting at 7 a.m.), and the physicians and advanced practice providers will work through the last scheduled patient appointment, Dr. Jaspan explained. “The office-based team will preferentially see in-person visits.”

Several offices have been closed so that ob.gyns. and staff can be reassigned to telehealth. The remaining five offices generally have one attending physician and one advanced practice provider.

The remaining team of ob.gyns. provides telehealth with the help of staff members. This involves an initial call to the patient by staff letting them know the doctor will be calling, checking them in, verifying insurance, and collecting payment, followed by the actual telehealth visit. If follow-up is needed, the staff member schedules the follow-up.

Dr. Jaspan called the new approach to prenatal care because of COVID-19 a “cataclysmic change in how we care for our patients. We have decided to further limit our obstetrical in-person visits. It is our feeling that these changes will enable patients to remain outside of the office and in the safety of their homes, provide appropriate social distancing, and diminish potential exposures to the office staff providers and patients.”

In-person visits will occur at: the initial visit, between 24 and 28 weeks, at 32 weeks, and at 36 or 37 weeks; if the patient at 36/37 has a blood pressure cuff, they will not have additional scheduled in-patient visits. We have partnered with the insurance companies to provide more than 88% of obstetrical patients with home blood pressure cuffs.

Obstetrical visits via telehealth will continue at our standard intervals: monthly until 26 weeks; twice monthly during 26-36 weeks; and weekly from 37 weeks to delivery. These visits should use a video component such as Zoom, Doxy.me, or FaceTime.

“If the patient has concerns or problems, we will see them at any time. However, the new standard will be telehealth visits and the exception will be the in-person visit,” Dr. Jaspan said.

In addition, we have worked our division of maternal-fetal medicine to adjust the antenatal testing schedules, and we have curtailed the frequency of ultrasound, he noted.

He emphasized the importance of documenting telehealth interactions with obstetrical patients, in addition to “providing adequate teaching and education for patients regarding kick counts to ensure fetal well-being.” It also is key to “properly document conversations with patients regarding bleeding, rupture of membranes, fetal movement, headache, visual changes, fevers, cough, nausea and vomiting, diarrhea, fatigue, muscle aches, etc.”

The residents’ schedule also has been modified to diminish their exposure. Within our new paradigm, we have scheduled video conferences to enable our program to maintain our commitment to academics.

It is imperative that we keep our patients safe, and it is critical to protect our staff members. Those who provide women’s health cannot be replaced by other nurses or physicians.

• Suspend initiation of new treatment cycles, including ovulation induction, intrauterine inseminations, in vitro fertilization including retrievals and frozen embryo transfers, and nonurgent gamete cryopreservation.
• Strongly consider cancellation of all embryo transfers, whether fresh or frozen.
• Continue to care for patients who are currently “in cycle” or who require urgent stimulation and cryopreservation.
• Suspend elective surgeries and nonurgent diagnostic procedures.
• Minimize in-person interactions and increase utilization of telehealth.

As a member of ASRM for more than 2 decades and a participant of several of their committees, my practice immediately ceased treatment cycles to comply with this guidance.

Then on March 20, 2020, the Florida governor’s executive order 20-72 was released, stating, “All hospitals, ambulatory surgical centers, office surgery centers, dental, orthodontic and endodontic offices, and other health care practitioners’ offices in the State of Florida are prohibited from providing any medically unnecessary, nonurgent or nonemergency procedure or surgery which, if delayed, does not place a patient’s immediate health, safety, or well-­being at risk, or will, if delayed, not contribute to the worsening of a serious or life-threatening medical condition.”

As a result, my practice has been limited to telemedicine consultations. While the ASRM guidance and the gubernatorial executive order pose a significant financial hardship on my center and all applicable medical clinics in my state, resulting in expected layoffs, salary reductions, and requests for government stimulus loans, the greater good takes priority and we pray for all the victims of this devastating pandemic.

The governor’s current executive order is set to expire on May 9, 2020, unless it is extended.

ASRM released an update of their guidance on March 30, 2020, offering no change from their prior recommendations. The organization plans to reevaluate the guidance at 2-week intervals.

Sangeeta Sinha, MD, an ob.gyn. in private practice at Stone Springs Hospital Center, Dulles, Va. said in an interview, “COVID 19 has put fear in all aspects of our daily activities which we are attempting to cope with.”

She related several changes made to her office and hospital environments. “In our office, we are now wearing a mask at all times, gloves to examine every patient. We have staggered physicians in the office to take televisits and in-office patients. We are screening all new patients on the phone to determine if they are sick, have traveled to high-risk, hot spot areas of the country, or have had contact with someone who tested positive for COVID-19. We are only seeing our pregnant women and have also pushed out their return appointments to 4 weeks if possible. There are several staff who are not working due to fear or are in self quarantine so we have shortage of staff in the office. At the hospital as well we are wearing a mask at all times, using personal protective equipment for deliveries and C-sections.

“We have had several scares, including a new transfer of an 18-year-old pregnant patient at 30 weeks with cough and sore throat, who later reported that her roommate is very sick and he works with someone who has tested positive for COVID-19. Thankfully she is healthy and well. We learned several lessons from this one.”

In 2019, the Food and Drug Administration approved 42 drugs, 6 of which will not be discussed here because of space limitations: recarbrio, a three-drug combination, containing imipenem, cilastatin, and relebactam; polatuzumab (Polivy) combined with bendamustine and a rituximab product; pretomanid combined with bedaquiline and linezolid; romosozumab (Evenity) for postmenopausal women; and alpelisib (Piqray) for postmenopausal women. In addition, darolutamide (Nubeqa) will not be included because it is indicated for the treatment of patients with prostate cancer. The remaining 36 agents are listed alphabetically below with the trade names in parentheses.

PhotoDisk

The molecular weights (if available), rounded to the nearest whole number, are shown in parentheses. As with nearly all drugs, avoiding these agents in pregnancy is the best choice.

Air polymer-type a intrauterine foam (ExEm Foam), an ultrasound contrast agent, is indicated for sonohysterosalpingography to assess fallopian tube patency in women with known or suspected infertility. Animal studies have not been conducted, and the agent is contraindicated in pregnancy.

Afamelanotide implant (Scenesse) (1,647) is a melanocortin 1 receptor agonist that is indicated to increase pain-free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria. The drug caused no embryofetal toxicity in two species of rats. The molecular weight suggests that it will not cross the placenta, at least early in pregnancy.

Alpelisib (Piqray) (441) is a kinase inhibitor that is combined with fulvestrant for the treatment of advanced breast cancer in women and men. The molecular weight suggests that it can cross the human placenta. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Bremelanotide (Vyleesi) (1,025) is indicated for the treatment of premenopausal women with hypoactive sexual disorder. The drug caused fetal harm in dogs and mice. If a pregnant woman is exposed to the drug, health care providers are encouraged to call the VYLEESI Pregnancy Exposure Registry at 877-411-2510.

Brolucizumab (Beovu) (26,000) is a human vascular endothelial growth factor that is indicated for the treatment of neovascular age-related macular degeneration. In animals, it caused malformations, embryofetal resorption, and decreased fetal weight. Other adverse effects were follicular development, corpus luteum function, and fertility.

Caplacizumab (Cablivi) (28,000) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura, in combination with plasma exchange and immunosuppressive therapy. If used in pregnancy, there is a risk of hemorrhage in the mother and fetus. In guinea pigs given intramuscular doses of the drug, there was no evidence of adverse developmental outcomes.

Cefiderocol (Fetroja) (3,044) is an IV cephalosporin antibiotic indicated for the treatment of urinary tract infections, including pyelonephritis. The manufacturer states that it should be used in patients 18 years of age or older who have limited or no alternative treatment options. Consistent with other cephalosporins, no developmental adverse effects were observed in rats and mice.

Cenobamate (Xcopri) (268) is indicated for the treatment of partial-onset seizures in adults. In pregnant animals given the drug, there was increased embryo-fetal mortality, decreased fetal and offspring body weight, and neurobehavioral and reproductive impairment in offspring. If a pregnant woman receives this drug, encourage her to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling the toll-free number 1-888-233-2334.

Crizanlizumab (Adakveo) (146,000) is indicated to reduce the frequency of vaso-occlusive crises in patients with sickle cell disease. In monkeys given doses slightly higher than those given to humans, there was increased fetal loss (abortions/stillbirths).

Entrectinib (Rozlytrek) (561) is a kinase inhibitor indicated for the treatment of cancer. The drug was teratogenic in rats. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Erdafitinib (Balversa) (447), a kinase inhibitor, is indicated for the treatment of locally advanced or metastatic urothelial carcinoma. In rats given doses during organogenesis with maternal exposures less than human exposures, the drug was teratogenic and caused embryofetal death. The manufacturer states that women of reproductive potential should use effective contraception during treatment and for 1 month after the last dose. The same advice was provided for male patients with female partners of reproductive potential. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fedratinib (Inrebic) (616), a kinase inhibitor, is indicated for patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The drug was teratogenic in rats when doses that were about 0.1 times the human exposure based on AUC (area under the curve) at the recommended daily dose during organogenesis. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fluorodopa f18 (214) is a radioactive diagnostic agent. It is indicated for use in positron emission tomography to visualize dopaminergic nerve terminals in the striatum for evaluation of adult patients with suspected parkinsonian syndromes. The potential for adverse pregnant outcomes is based on the radiation dose and the gestational timing of exposure.

Givosiran sodium (Givlaari) (17,2460) is an aminolevulinate synthase 1-directed small interfering RNA given subcutaneously. It is indicated for the treatment of adults with acute hepatic porphyria. Doses less than 10 times the human dose in rats and rabbits produced maternal toxicity. In rats there was increased postimplantation loss, and in rats there was skeletal variation (incomplete ossification of pubes).

Golodirsen (Vyondys 53) (8,647) is indicated for the treatment of Duchenne muscular dystrophy given intravenously. There are no human or animal data available to assess the use of this drug during pregnancy.

Istradefylline (Nourianz) (384) is an adenosine receptor antagonist given orally. It is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. In pregnant rats and rabbits, the drug was related to teratogenicity, embryo-fetal and offspring mortality, and growth deficits at clinically relevant exposures.

Lasmiditan (Reyvow) (436), a serotonin receptor agonist, is indicated for acute treatment of migraine with or without aura. In animals, the drug caused increased incidences of fetal defects, increased embryo-fetal and offspring mortality, and decreased fetal body weight at maternal exposures less than (rabbits) or greater than (rat) those observed clinically.

Lefamulin (Xenleta) (568) is an antibacterial agent available for oral and IV administration. They are indicated for the treatment of community-acquired bacterial pneumonia. The drug was teratogenic in rats at systemic exposures lower than those in humans, an increased incidence of post-implantation fetal loss and stillbirths, and decreased fetal body weights and ossification. There was also an apparent delay in sexual maturation in rats.

Luspatercept (Reblozyl) (76,000) is given subcutaneously for the treatment of anemia in patients with beta thalassemia who require regular red blood cell transfusions. In rats and rabbits, the drug cause increased embryo-fetal mortality, alteration to growth, and structural defects at exposures (based on AUC) that were about 13 times (rats) and 18 times (rabbits) the maximum recommended human dose.

Pexidartinib (Turalio) (454) is an oral kinase inhibitor that is indicated for the treatment of symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable with surgery. In rats and rabbits, the drug caused malformations, increased post-implantation loss, and abortion at exposures nearly equal to the human exposure. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Pitolisant HCl (Wakix) (296) is an histamine-3 receptor antagonist/inverse agonist indicated for the treatment of excessive daytime sleepiness in patients with narcolepsy. The drug has caused maternal and embryofetal toxicity in rats and rabbits at doses greater than and equal to 13 times and greater than 4 times the maximum human dose, respectively. The manufacturer has a pregnancy exposure registry that patients can contact at 1-800-833-7460.

Prabotulinum toxin A (Jeuveau) (900,000) is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity. The drug caused no adverse embryo-fetal in rats with doses up to 12 times the human dose.

Risankizumab-rzaa (Skyrizi) (molecular weight unknown), an interleukin-23 antagonist, is used for the treatment of moderate-to-severe plaque psoriasis. In pregnant monkeys, doses that were 20 times the maximum human dose increased fetal/infant loss.

Selinexor (Xpovio) (443) is an oral nuclear export inhibitor given in combination with dexamethasone for the treatment of relapsed or refractory myeloma. At doses lower than those used clinically, the drug caused structural abnormalities and alterations to growth in fetal rats.

Siponimod (Mayzent) (1,149) is an oral sphingosine 1-phosphate receptor modulator. It is indicated for the treatment of relapsing forms of multiple sclerosis. At low doses, the drug caused embryotoxicity and fetotoxicity in rats and rabbits including embryofetal deaths and abortions. The drug was teratogenic in both species.

Solriamfetol (Sunosi) (231) is an oral dopamine and norepinephrine reuptake inhibitor that is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. The drug caused maternal and fetal toxicities in rats and rabbits and was teratogenic. The manufacturer has a pregnancy exposure registry to monitor pregnancy outcomes. Health care providers or patients can enroll in the program by calling 1-877-283-6220 or contacting the company.

Tafamidis meglumine (Vyndaqel) (503) and tafamidis (Vyndamax) (308) are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis to reduce cardiovascular mortality and cardiovascular-related hospitalization. In rabbits and rats, use of the drugs during pregnancy caused birth defects, embryo-fetal mortality, and fetal body weight reduction. Limited available data with Vyndaqel use in human pregnancy at a dose of 20 mg/day have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see package insert).

Tenapanor (Ibsrela) (1,218) is indicated for the treatment of irritable bowel syndrome with constipation. The drug is minimally absorbed systemically, with plasma concentrations below the limit of quantification. No adverse maternal or fetal outcomes in rats or rabbits were observed. As reported by the manufacturer, in a small number of pregnant women, no drug-induced adverse maternal or fetal outcomes were identified.

Triclabendazole (Egaten) (360), an oral anthelmintic, is indicated for the treatment of fascioliasis. The drug was not teratogenic in mice and rabbits.

Trifarotene (Aklief) (460) cream is a retinoid that is indicated for the topical treatment of acne vulgaris. Animal data was related to oral retinoids and it not applicable to this agent. The manufacturer reported that available data from the use of the cream in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Upadacitinib (Rinvoq) (389) is an oral Janus inhibitor. It is indicated for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate. The drug caused increases in fetal malformations when given to rats and rabbits during organogenesis.

Voxelotor (Oxbryta) (337) is an oral hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease. In rats and rabbits, there was no evidence of adverse developmental outcomes.

Zanubrutinib (Brukinsa) (472), an oral kinase inhibitor, is indicated for the treatment of mantle cell lymphoma. The drug caused embryofetal toxicity in pregnant rats, including malformations. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Breastfeeding

Brexanolone (Zulresso) (319) is indicated for the treatment of postpartum depression. It is given as a continuous IV infusion over 60 hours. The drug, at exposures close to those seen in humans, did not cause structural defects in rabbits and rats, but did cause fetal toxicity. Because patients are at risk of excessive sedation or sudden loss of consciousness when receiving the drug, it is only available through a restricted program called the ZULRESSO REMS. Health care providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 844-405-6185. To obtain a list of health care facilities enrolled in the program call 844-472-4379.

Nearly all of the above drugs will cross into a woman’s colostrum during the first 48 hours post partum. These amounts should be very small, but not breastfeeding is the best choice.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

In 2019, the Food and Drug Administration approved 42 drugs, 6 of which will not be discussed here because of space limitations: recarbrio, a three-drug combination, containing imipenem, cilastatin, and relebactam; polatuzumab (Polivy) combined with bendamustine and a rituximab product; pretomanid combined with bedaquiline and linezolid; romosozumab (Evenity) for postmenopausal women; and alpelisib (Piqray) for postmenopausal women. In addition, darolutamide (Nubeqa) will not be included because it is indicated for the treatment of patients with prostate cancer. The remaining 36 agents are listed alphabetically below with the trade names in parentheses.

PhotoDisk

The molecular weights (if available), rounded to the nearest whole number, are shown in parentheses. As with nearly all drugs, avoiding these agents in pregnancy is the best choice.

Air polymer-type a intrauterine foam (ExEm Foam), an ultrasound contrast agent, is indicated for sonohysterosalpingography to assess fallopian tube patency in women with known or suspected infertility. Animal studies have not been conducted, and the agent is contraindicated in pregnancy.

Afamelanotide implant (Scenesse) (1,647) is a melanocortin 1 receptor agonist that is indicated to increase pain-free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria. The drug caused no embryofetal toxicity in two species of rats. The molecular weight suggests that it will not cross the placenta, at least early in pregnancy.

Alpelisib (Piqray) (441) is a kinase inhibitor that is combined with fulvestrant for the treatment of advanced breast cancer in women and men. The molecular weight suggests that it can cross the human placenta. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Bremelanotide (Vyleesi) (1,025) is indicated for the treatment of premenopausal women with hypoactive sexual disorder. The drug caused fetal harm in dogs and mice. If a pregnant woman is exposed to the drug, health care providers are encouraged to call the VYLEESI Pregnancy Exposure Registry at 877-411-2510.

Brolucizumab (Beovu) (26,000) is a human vascular endothelial growth factor that is indicated for the treatment of neovascular age-related macular degeneration. In animals, it caused malformations, embryofetal resorption, and decreased fetal weight. Other adverse effects were follicular development, corpus luteum function, and fertility.

Caplacizumab (Cablivi) (28,000) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura, in combination with plasma exchange and immunosuppressive therapy. If used in pregnancy, there is a risk of hemorrhage in the mother and fetus. In guinea pigs given intramuscular doses of the drug, there was no evidence of adverse developmental outcomes.

Cefiderocol (Fetroja) (3,044) is an IV cephalosporin antibiotic indicated for the treatment of urinary tract infections, including pyelonephritis. The manufacturer states that it should be used in patients 18 years of age or older who have limited or no alternative treatment options. Consistent with other cephalosporins, no developmental adverse effects were observed in rats and mice.

Cenobamate (Xcopri) (268) is indicated for the treatment of partial-onset seizures in adults. In pregnant animals given the drug, there was increased embryo-fetal mortality, decreased fetal and offspring body weight, and neurobehavioral and reproductive impairment in offspring. If a pregnant woman receives this drug, encourage her to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling the toll-free number 1-888-233-2334.

Crizanlizumab (Adakveo) (146,000) is indicated to reduce the frequency of vaso-occlusive crises in patients with sickle cell disease. In monkeys given doses slightly higher than those given to humans, there was increased fetal loss (abortions/stillbirths).

Entrectinib (Rozlytrek) (561) is a kinase inhibitor indicated for the treatment of cancer. The drug was teratogenic in rats. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Erdafitinib (Balversa) (447), a kinase inhibitor, is indicated for the treatment of locally advanced or metastatic urothelial carcinoma. In rats given doses during organogenesis with maternal exposures less than human exposures, the drug was teratogenic and caused embryofetal death. The manufacturer states that women of reproductive potential should use effective contraception during treatment and for 1 month after the last dose. The same advice was provided for male patients with female partners of reproductive potential. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fedratinib (Inrebic) (616), a kinase inhibitor, is indicated for patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The drug was teratogenic in rats when doses that were about 0.1 times the human exposure based on AUC (area under the curve) at the recommended daily dose during organogenesis. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fluorodopa f18 (214) is a radioactive diagnostic agent. It is indicated for use in positron emission tomography to visualize dopaminergic nerve terminals in the striatum for evaluation of adult patients with suspected parkinsonian syndromes. The potential for adverse pregnant outcomes is based on the radiation dose and the gestational timing of exposure.

Givosiran sodium (Givlaari) (17,2460) is an aminolevulinate synthase 1-directed small interfering RNA given subcutaneously. It is indicated for the treatment of adults with acute hepatic porphyria. Doses less than 10 times the human dose in rats and rabbits produced maternal toxicity. In rats there was increased postimplantation loss, and in rats there was skeletal variation (incomplete ossification of pubes).

Golodirsen (Vyondys 53) (8,647) is indicated for the treatment of Duchenne muscular dystrophy given intravenously. There are no human or animal data available to assess the use of this drug during pregnancy.

Istradefylline (Nourianz) (384) is an adenosine receptor antagonist given orally. It is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. In pregnant rats and rabbits, the drug was related to teratogenicity, embryo-fetal and offspring mortality, and growth deficits at clinically relevant exposures.

Lasmiditan (Reyvow) (436), a serotonin receptor agonist, is indicated for acute treatment of migraine with or without aura. In animals, the drug caused increased incidences of fetal defects, increased embryo-fetal and offspring mortality, and decreased fetal body weight at maternal exposures less than (rabbits) or greater than (rat) those observed clinically.

Lefamulin (Xenleta) (568) is an antibacterial agent available for oral and IV administration. They are indicated for the treatment of community-acquired bacterial pneumonia. The drug was teratogenic in rats at systemic exposures lower than those in humans, an increased incidence of post-implantation fetal loss and stillbirths, and decreased fetal body weights and ossification. There was also an apparent delay in sexual maturation in rats.

Luspatercept (Reblozyl) (76,000) is given subcutaneously for the treatment of anemia in patients with beta thalassemia who require regular red blood cell transfusions. In rats and rabbits, the drug cause increased embryo-fetal mortality, alteration to growth, and structural defects at exposures (based on AUC) that were about 13 times (rats) and 18 times (rabbits) the maximum recommended human dose.

Pexidartinib (Turalio) (454) is an oral kinase inhibitor that is indicated for the treatment of symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable with surgery. In rats and rabbits, the drug caused malformations, increased post-implantation loss, and abortion at exposures nearly equal to the human exposure. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Pitolisant HCl (Wakix) (296) is an histamine-3 receptor antagonist/inverse agonist indicated for the treatment of excessive daytime sleepiness in patients with narcolepsy. The drug has caused maternal and embryofetal toxicity in rats and rabbits at doses greater than and equal to 13 times and greater than 4 times the maximum human dose, respectively. The manufacturer has a pregnancy exposure registry that patients can contact at 1-800-833-7460.

Prabotulinum toxin A (Jeuveau) (900,000) is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity. The drug caused no adverse embryo-fetal in rats with doses up to 12 times the human dose.

Risankizumab-rzaa (Skyrizi) (molecular weight unknown), an interleukin-23 antagonist, is used for the treatment of moderate-to-severe plaque psoriasis. In pregnant monkeys, doses that were 20 times the maximum human dose increased fetal/infant loss.

Selinexor (Xpovio) (443) is an oral nuclear export inhibitor given in combination with dexamethasone for the treatment of relapsed or refractory myeloma. At doses lower than those used clinically, the drug caused structural abnormalities and alterations to growth in fetal rats.

Siponimod (Mayzent) (1,149) is an oral sphingosine 1-phosphate receptor modulator. It is indicated for the treatment of relapsing forms of multiple sclerosis. At low doses, the drug caused embryotoxicity and fetotoxicity in rats and rabbits including embryofetal deaths and abortions. The drug was teratogenic in both species.

Solriamfetol (Sunosi) (231) is an oral dopamine and norepinephrine reuptake inhibitor that is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. The drug caused maternal and fetal toxicities in rats and rabbits and was teratogenic. The manufacturer has a pregnancy exposure registry to monitor pregnancy outcomes. Health care providers or patients can enroll in the program by calling 1-877-283-6220 or contacting the company.

Tafamidis meglumine (Vyndaqel) (503) and tafamidis (Vyndamax) (308) are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis to reduce cardiovascular mortality and cardiovascular-related hospitalization. In rabbits and rats, use of the drugs during pregnancy caused birth defects, embryo-fetal mortality, and fetal body weight reduction. Limited available data with Vyndaqel use in human pregnancy at a dose of 20 mg/day have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see package insert).

Tenapanor (Ibsrela) (1,218) is indicated for the treatment of irritable bowel syndrome with constipation. The drug is minimally absorbed systemically, with plasma concentrations below the limit of quantification. No adverse maternal or fetal outcomes in rats or rabbits were observed. As reported by the manufacturer, in a small number of pregnant women, no drug-induced adverse maternal or fetal outcomes were identified.

Triclabendazole (Egaten) (360), an oral anthelmintic, is indicated for the treatment of fascioliasis. The drug was not teratogenic in mice and rabbits.

Trifarotene (Aklief) (460) cream is a retinoid that is indicated for the topical treatment of acne vulgaris. Animal data was related to oral retinoids and it not applicable to this agent. The manufacturer reported that available data from the use of the cream in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Upadacitinib (Rinvoq) (389) is an oral Janus inhibitor. It is indicated for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate. The drug caused increases in fetal malformations when given to rats and rabbits during organogenesis.

Voxelotor (Oxbryta) (337) is an oral hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease. In rats and rabbits, there was no evidence of adverse developmental outcomes.

Zanubrutinib (Brukinsa) (472), an oral kinase inhibitor, is indicated for the treatment of mantle cell lymphoma. The drug caused embryofetal toxicity in pregnant rats, including malformations. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Breastfeeding

Brexanolone (Zulresso) (319) is indicated for the treatment of postpartum depression. It is given as a continuous IV infusion over 60 hours. The drug, at exposures close to those seen in humans, did not cause structural defects in rabbits and rats, but did cause fetal toxicity. Because patients are at risk of excessive sedation or sudden loss of consciousness when receiving the drug, it is only available through a restricted program called the ZULRESSO REMS. Health care providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 844-405-6185. To obtain a list of health care facilities enrolled in the program call 844-472-4379.

Nearly all of the above drugs will cross into a woman’s colostrum during the first 48 hours post partum. These amounts should be very small, but not breastfeeding is the best choice.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

In 2019, the Food and Drug Administration approved 42 drugs, 6 of which will not be discussed here because of space limitations: recarbrio, a three-drug combination, containing imipenem, cilastatin, and relebactam; polatuzumab (Polivy) combined with bendamustine and a rituximab product; pretomanid combined with bedaquiline and linezolid; romosozumab (Evenity) for postmenopausal women; and alpelisib (Piqray) for postmenopausal women. In addition, darolutamide (Nubeqa) will not be included because it is indicated for the treatment of patients with prostate cancer. The remaining 36 agents are listed alphabetically below with the trade names in parentheses.

PhotoDisk

The molecular weights (if available), rounded to the nearest whole number, are shown in parentheses. As with nearly all drugs, avoiding these agents in pregnancy is the best choice.

Air polymer-type a intrauterine foam (ExEm Foam), an ultrasound contrast agent, is indicated for sonohysterosalpingography to assess fallopian tube patency in women with known or suspected infertility. Animal studies have not been conducted, and the agent is contraindicated in pregnancy.

Afamelanotide implant (Scenesse) (1,647) is a melanocortin 1 receptor agonist that is indicated to increase pain-free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria. The drug caused no embryofetal toxicity in two species of rats. The molecular weight suggests that it will not cross the placenta, at least early in pregnancy.

Alpelisib (Piqray) (441) is a kinase inhibitor that is combined with fulvestrant for the treatment of advanced breast cancer in women and men. The molecular weight suggests that it can cross the human placenta. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Bremelanotide (Vyleesi) (1,025) is indicated for the treatment of premenopausal women with hypoactive sexual disorder. The drug caused fetal harm in dogs and mice. If a pregnant woman is exposed to the drug, health care providers are encouraged to call the VYLEESI Pregnancy Exposure Registry at 877-411-2510.

Brolucizumab (Beovu) (26,000) is a human vascular endothelial growth factor that is indicated for the treatment of neovascular age-related macular degeneration. In animals, it caused malformations, embryofetal resorption, and decreased fetal weight. Other adverse effects were follicular development, corpus luteum function, and fertility.

Caplacizumab (Cablivi) (28,000) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura, in combination with plasma exchange and immunosuppressive therapy. If used in pregnancy, there is a risk of hemorrhage in the mother and fetus. In guinea pigs given intramuscular doses of the drug, there was no evidence of adverse developmental outcomes.

Cefiderocol (Fetroja) (3,044) is an IV cephalosporin antibiotic indicated for the treatment of urinary tract infections, including pyelonephritis. The manufacturer states that it should be used in patients 18 years of age or older who have limited or no alternative treatment options. Consistent with other cephalosporins, no developmental adverse effects were observed in rats and mice.

Cenobamate (Xcopri) (268) is indicated for the treatment of partial-onset seizures in adults. In pregnant animals given the drug, there was increased embryo-fetal mortality, decreased fetal and offspring body weight, and neurobehavioral and reproductive impairment in offspring. If a pregnant woman receives this drug, encourage her to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling the toll-free number 1-888-233-2334.

Crizanlizumab (Adakveo) (146,000) is indicated to reduce the frequency of vaso-occlusive crises in patients with sickle cell disease. In monkeys given doses slightly higher than those given to humans, there was increased fetal loss (abortions/stillbirths).

Entrectinib (Rozlytrek) (561) is a kinase inhibitor indicated for the treatment of cancer. The drug was teratogenic in rats. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Erdafitinib (Balversa) (447), a kinase inhibitor, is indicated for the treatment of locally advanced or metastatic urothelial carcinoma. In rats given doses during organogenesis with maternal exposures less than human exposures, the drug was teratogenic and caused embryofetal death. The manufacturer states that women of reproductive potential should use effective contraception during treatment and for 1 month after the last dose. The same advice was provided for male patients with female partners of reproductive potential. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fedratinib (Inrebic) (616), a kinase inhibitor, is indicated for patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The drug was teratogenic in rats when doses that were about 0.1 times the human exposure based on AUC (area under the curve) at the recommended daily dose during organogenesis. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fluorodopa f18 (214) is a radioactive diagnostic agent. It is indicated for use in positron emission tomography to visualize dopaminergic nerve terminals in the striatum for evaluation of adult patients with suspected parkinsonian syndromes. The potential for adverse pregnant outcomes is based on the radiation dose and the gestational timing of exposure.

Givosiran sodium (Givlaari) (17,2460) is an aminolevulinate synthase 1-directed small interfering RNA given subcutaneously. It is indicated for the treatment of adults with acute hepatic porphyria. Doses less than 10 times the human dose in rats and rabbits produced maternal toxicity. In rats there was increased postimplantation loss, and in rats there was skeletal variation (incomplete ossification of pubes).

Golodirsen (Vyondys 53) (8,647) is indicated for the treatment of Duchenne muscular dystrophy given intravenously. There are no human or animal data available to assess the use of this drug during pregnancy.

Istradefylline (Nourianz) (384) is an adenosine receptor antagonist given orally. It is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. In pregnant rats and rabbits, the drug was related to teratogenicity, embryo-fetal and offspring mortality, and growth deficits at clinically relevant exposures.

Lasmiditan (Reyvow) (436), a serotonin receptor agonist, is indicated for acute treatment of migraine with or without aura. In animals, the drug caused increased incidences of fetal defects, increased embryo-fetal and offspring mortality, and decreased fetal body weight at maternal exposures less than (rabbits) or greater than (rat) those observed clinically.

Lefamulin (Xenleta) (568) is an antibacterial agent available for oral and IV administration. They are indicated for the treatment of community-acquired bacterial pneumonia. The drug was teratogenic in rats at systemic exposures lower than those in humans, an increased incidence of post-implantation fetal loss and stillbirths, and decreased fetal body weights and ossification. There was also an apparent delay in sexual maturation in rats.

Luspatercept (Reblozyl) (76,000) is given subcutaneously for the treatment of anemia in patients with beta thalassemia who require regular red blood cell transfusions. In rats and rabbits, the drug cause increased embryo-fetal mortality, alteration to growth, and structural defects at exposures (based on AUC) that were about 13 times (rats) and 18 times (rabbits) the maximum recommended human dose.

Pexidartinib (Turalio) (454) is an oral kinase inhibitor that is indicated for the treatment of symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable with surgery. In rats and rabbits, the drug caused malformations, increased post-implantation loss, and abortion at exposures nearly equal to the human exposure. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Pitolisant HCl (Wakix) (296) is an histamine-3 receptor antagonist/inverse agonist indicated for the treatment of excessive daytime sleepiness in patients with narcolepsy. The drug has caused maternal and embryofetal toxicity in rats and rabbits at doses greater than and equal to 13 times and greater than 4 times the maximum human dose, respectively. The manufacturer has a pregnancy exposure registry that patients can contact at 1-800-833-7460.

Prabotulinum toxin A (Jeuveau) (900,000) is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity. The drug caused no adverse embryo-fetal in rats with doses up to 12 times the human dose.

Risankizumab-rzaa (Skyrizi) (molecular weight unknown), an interleukin-23 antagonist, is used for the treatment of moderate-to-severe plaque psoriasis. In pregnant monkeys, doses that were 20 times the maximum human dose increased fetal/infant loss.

Selinexor (Xpovio) (443) is an oral nuclear export inhibitor given in combination with dexamethasone for the treatment of relapsed or refractory myeloma. At doses lower than those used clinically, the drug caused structural abnormalities and alterations to growth in fetal rats.

Siponimod (Mayzent) (1,149) is an oral sphingosine 1-phosphate receptor modulator. It is indicated for the treatment of relapsing forms of multiple sclerosis. At low doses, the drug caused embryotoxicity and fetotoxicity in rats and rabbits including embryofetal deaths and abortions. The drug was teratogenic in both species.

Solriamfetol (Sunosi) (231) is an oral dopamine and norepinephrine reuptake inhibitor that is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. The drug caused maternal and fetal toxicities in rats and rabbits and was teratogenic. The manufacturer has a pregnancy exposure registry to monitor pregnancy outcomes. Health care providers or patients can enroll in the program by calling 1-877-283-6220 or contacting the company.

Tafamidis meglumine (Vyndaqel) (503) and tafamidis (Vyndamax) (308) are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis to reduce cardiovascular mortality and cardiovascular-related hospitalization. In rabbits and rats, use of the drugs during pregnancy caused birth defects, embryo-fetal mortality, and fetal body weight reduction. Limited available data with Vyndaqel use in human pregnancy at a dose of 20 mg/day have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see package insert).

Tenapanor (Ibsrela) (1,218) is indicated for the treatment of irritable bowel syndrome with constipation. The drug is minimally absorbed systemically, with plasma concentrations below the limit of quantification. No adverse maternal or fetal outcomes in rats or rabbits were observed. As reported by the manufacturer, in a small number of pregnant women, no drug-induced adverse maternal or fetal outcomes were identified.

Triclabendazole (Egaten) (360), an oral anthelmintic, is indicated for the treatment of fascioliasis. The drug was not teratogenic in mice and rabbits.

Trifarotene (Aklief) (460) cream is a retinoid that is indicated for the topical treatment of acne vulgaris. Animal data was related to oral retinoids and it not applicable to this agent. The manufacturer reported that available data from the use of the cream in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Upadacitinib (Rinvoq) (389) is an oral Janus inhibitor. It is indicated for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate. The drug caused increases in fetal malformations when given to rats and rabbits during organogenesis.

Voxelotor (Oxbryta) (337) is an oral hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease. In rats and rabbits, there was no evidence of adverse developmental outcomes.

Zanubrutinib (Brukinsa) (472), an oral kinase inhibitor, is indicated for the treatment of mantle cell lymphoma. The drug caused embryofetal toxicity in pregnant rats, including malformations. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Breastfeeding

Brexanolone (Zulresso) (319) is indicated for the treatment of postpartum depression. It is given as a continuous IV infusion over 60 hours. The drug, at exposures close to those seen in humans, did not cause structural defects in rabbits and rats, but did cause fetal toxicity. Because patients are at risk of excessive sedation or sudden loss of consciousness when receiving the drug, it is only available through a restricted program called the ZULRESSO REMS. Health care providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 844-405-6185. To obtain a list of health care facilities enrolled in the program call 844-472-4379.

Nearly all of the above drugs will cross into a woman’s colostrum during the first 48 hours post partum. These amounts should be very small, but not breastfeeding is the best choice.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].