FDA clears first ever test that aids in the detection of cytomegalovirus in newborn

The US Food and Drug Administration announced Friday that it had completed the de novo premarket review and cleared Meridian Bioscience's cytomegalovirus assay for marketing for newborns less than 21 days of age.

The Alethia CMV Assay Test System detects CMV deoxyribonucleic acid (DNA) from a saliva swab from the newborn, but the diagnosis is confirmed after taking into consideration the results of other diagnostic tests and clinical presentation. 

The FDA clearance was based on results of a prospective clinical trial which showed that Alethia test correctly identified 1,472 out of 1,475 saliva samples collected as negative for CMV. Only three samples were incorrectly identified as positive when they were negative, the FDA said.

Further, the test correctly identified 34 archived samples from babies known to be infected with CMV as positive for the virus.

“Although most people who become infected with cytomegalovirus face little to no risk of serious illness, the virus has the potential to cause serious illness for people with weak immune systems and in newborn babies," said Tim Stenzel, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health in a news release.

 "This test for detecting the virus, when used in conjunction with the results of other diagnostic tests, may help health care providers more quickly identify the virus in newborns and determine the best approach for the child,” he further added.

 In the US, about 50% of adult get CMV infection by the time they reach the age of 40. Once a person is infected with the virus, the virus stays there for life and can be reactivated. Most people with CMV infection do not experience any symptoms, but the virus can cause serious illness in some newborn, adults, and immunocompromised population. 

CMV is the most common cause of congenital infection worldwide, and its prevalence varies between 0.2 % and 2.2 % of all infants born. In the US, about 30,000 babies are born each year with congenital CMV infection. Most babies with congenital infection do not show any signs of infection and do not have any sequelae of CMV infection in later life.

About 8000 babies are born with in utero growth restriction (IUGR), liver and spleen disease, petechiae, thrombocytopenia, congenital and progressive hearing loss, vision loss, brain maldevelopment syndromes, microcephaly, and permanent neurodevelopmental and motor disabilities such as cerebral palsy.

Severe in utero infection leads to the death of about 400 still-births every year.

FDA press release

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Should universal serological screening for Toxoplasmosis be recommended during pregnancy?

Toxoplama gondii is ubiquitous in nature and infects animals and human alike. In immunocompetent host the infection is typically asymptomatic; however, in congenital settings, toxoplasmosis causes a range of manifestations in the fetus and newborn including but not limited to prematurity, IUGR, microcephaly, seizures, myocarditis, and life-long neurological and ophthalmologic sequelae.

The global incidence of congenital toxoplasmosis has been estimated to be 190,100 cases annually which corresponds to a burden of 1.20 million disability-adjusted life years. Yet only a few countries in the world have policies about universal serologic screening during gestation, followed by treatment of women who seroconvert. France is one of such countries where routine serologic screening is performed monthly during pregnancy. 

Surprisingly, In USA, serological screening is not universally recommended, although some obstetric practices do the screening. The current issue of American Journal of Obstetrics and Gynecology reports the results of first RCT Toxogest (ClinicalTrials.gov Identifier: NCT01189448) compare the efficacy and tolerance of pyrimethamine + sulfadiazine(PS) vs spiramycin to reduce placental transmission with an accompanying editorial about the systematic screening of toxoplasmosis during pregnancy.

Since placebo-controlled RCT was not possible, the trial compared the potential of spiramycin vs. PS to treat congenital toxoplasmosis in 150 women who have seroconverted during their second trimester of gestation or later.

Unfortunately, the trial was terminated early because of insufficient participants and problems with funds, but there were fewer transmission and no fetal cerebral toxoplasmosis lesions in the PS group, prompting to perform further research on prevention of congenital toxoplasmosis.

However, there is a lot to learn from results of Toxogest trial write Jose G. Montoya from Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA in the accompanying editorial.

Based on results of study and literature review so far, the author advises systematic screening for toxoplasmosis in every pregnant woman where Toxoplasma infection is known to occur because of devastating consequences of congenital toxoplasmosis. Further, congenital toxoplasmosis is preventable and treatable in utero.

If a woman tests positive or seroconverts during pregnancy, the question is not about to treat or not to treat, but what to treat with. The author proposed a simple algorithm for serological screening and follow up of pregnant women who were identified to be at risk for seroconversion during gestation (negative for Toxoplasma immunoglobulin G and M).  

If Toxoplasma IgM/IgG remains negative along with normal fetal ultrasound till term, no further treatment is needed. If the patient seroconverts and tests positive for IgM/IgG, follow the following algorithm.

At 18 weeks of pregnancy, do amniotic fluid PCR in patients on Spiramycin or pyrimethamine +sulfadiazine(PS) and follow the algorithm.

Algorithm  after amniotic fluid PCR in Spiramycin group

Algorithm  after amniotic fluid PCR in pyrimethamine +sulfadiazine(PS) group

The author concludes, “It is time to not leave anymore pregnant women who silently seroconvert for toxoplasmosis during gestation in the equivalence of a placebo arm.”

Abstract

Editorial full text

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ACOG/AHA calls for including a ‘Heart-talk’ during the annual well-woman visit

A joint advisory issued by American College of Obstetrician and Gynecologists (ACOG) and American Heart Association(AHA) calls for all gynecologist to screen women for signs of cardiovascular disease and risk factors during their annual ‘well-woman’ visit.

The presidential advisory published 10 May in Journal Circulation calls for a collaboration between cardiologists and Ob/Gyn physicians to use these visits as an opportunity to screen, counsel and educate women about lifestyle factors that influence the risk of heart diseases.

This is important because, for more than 50% of women, their Ob/Gyn physician is the only primary care doctor they visit every year.

“OB/GYNs are primary care providers for many women, and the annual ‘well woman’ visit provides a powerful opportunity to counsel patients about achieving and maintaining a heart-healthy lifestyle, which is a cornerstone of maintaining heart health” said John Warner, M.D. president of the American Heart Association, executive vice president for Health System Affairs at University of Texas Southwestern Medical Center in Dallas, Texas.

Dr. Stacey Rosen, MD, a cardiologist, co-author of the advisory and vice president of The Katz Institute for Women's Health at Northwell Health said, "We know that 90 percent of women have at least one risk factor for heart disease and that 80 percent of heart disease is preventable through a heart-healthy lifestyle.”

A post-partum visit is an ideal opportunity to identify women with pregnancy complications like pre-eclampsia, eclampsia, chronic hypertension, gestational diabetes, gestational hypertension, pre-term delivery, and low-for-estimated-gestational-age birth weight which all indicate a subsequent increase in the mother’s cardiovascular risk.

Preeclampsia and gestational hypertension impart a three- to six-fold excess risk of subsequent hypertension and a two-fold risk for subsequent heart disease.

In 2001, the Institute of Medicine now the National Academy of Sciences, issued a monograph" Exploring the Biological Contributions to Human Health: Does Sex Matter?" This initiated research on gender-specific risk factors for chronic diseases and development of guidelines that are distinct for men and women based on their unique health risks.

This has considerably helped in bringing down the morbidity and mortality associated with cardiac disease in women in last two decades.

Despite this progress, gender-specific inequalities continue when it comes to managing risk factors for cardiac disease. For example, women who have diabetes are at increased risk of CVD as compared to men (19% vs 10%) but they are far less likely to receive preventive treatment as compared to men.

Similarly, only 29% of older women have a well-controlled blood pressure as compared to 41% of older men.

In women, the CVD risk factors are often related to hormonal or pregnancy influences, such as pregnancy complications and polycystic ovary syndrome, menopausal status and hormone use, but these are seldom considered when calculating the risk of CVD.

Some of the common recommendations in the advisory include:

• All women should be weighed at every visit and diet assessment should be performed through a predetermined questionnaire.
• Women are advised to perform 150 minutes per week of moderate-intensity physical activity, 75 minutes per week of vigorous-intensity aerobic physical activity or a combination of both levels. Women should also walk 10,000 steps per day.
• Presence of behavioral risk factors like smoking and alcohol should be assessed.
• Screening for Glucose intolerance should be done in women 40 to 70 years with obesity or overweight, a history of gestational diabetes, a family history of diabetes or established CVD.
• All women above 20 years of age with a family history of CVD, should undergo lipid screening. Lifestyle modification followed by statins is advised in those with elevated lipids.
• Women with family history of CVD should also be screened for blood pressure every 2 years and annually after 40 years of age.
• Medical therapy would be considered for women without CVD or elevated risk for the disease and with BP measurements greater than 140 mm Hg/90 mm Hg.
• Ob/Gyn and cardiologist should make sure that patients Electronic Health Record (EHR) is complete during each visit and is something does not look good, patients should be referred to a specialist.

The clinicians and patients can visit the following websites to get patient education material.

AHA Life's Simple 7 

AHA's Go Red for Women

ACOG's patient page

Full Text

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Here is one video from  AHA series ' Life's Simple 7'

New use of old drug: Sildenafil Citrate (Viagra) improves amniotic fluid index in oligohydramnios.

Pfizer.com 

Sildenafil Citrate (Viagra) improves amniotic fluid index in pregnancies complicated by oligohydramnios according to a new study published ahead of print on March 6,2017 in Journal of Obstetrics and Gynecology.[1]

Viagra, a specific phosphodiesterase-5 inhibitor, has recently been proposed as a potential therapeutic strategy to maintain placental function and increase the amniotic fluid index (AFI).

This was an open-label randomized trial, carried out over a period of one year and recruited a total of 184 women. The study included all women at 30 weeks or more in pregnancy with oligohydramnios detected during routine sonography. No specific cause or etiology was detected for oligohydramnios in all these women.

The women were randomized to receive either Sildenafil Citrate 25 mg three times a day along with intravenous infusion of 2 L isotonic solution (82 women) or just fluids only (84 women). All women were hospitalized for initial 24 hours and received the IV fluids.  

The women were followed up for 6 weeks on the basis of outpatient monitoring with NST, USG and biophysical profile. Patient is readmitted if the AFI drops below 5 for Intravenous fluid therapy. Final assessment of the amniotic fluid volume is done at 6 weeks or before delivery if she went into labor before completing 6 weeks.

It was seen that women who received Sildenafil have considerable good amniotic fluid at follow up with AFI of 11.5 vs 5.4 in the control group. (P=.02).

The women in sildenafil group also went further into pregnancy with mean gestational age of 38.3 weeks as compared to 36 weeks. (P=.001). These women had one third the rate of Cesarean section and one fourth neonatal intensive care admission as compared to placebo group.

The authors concluded that “Sildenafil citrate increases amniotic fluid volume in pregnancies complicated by oligohydramnios.”

The proposed mechanism is vasodilatation of small myometrial vessels, thereby increasing the placental perfusion which leads to improvement in amniotic fluid index, fetal weight, and even uterine and umbilical artery Doppler patterns.

Currently there is no effective therapy for early onset IUGR or oligohydramnios.

Sildenafil citrate in the same dose has also shown promising results in improving the birth outcomes in early and late onset IUGR.[2]

Preliminary studies have also shown that it is effective in early onset preeclampsia to improve fetal growth retardation, but more randomized trials are needed.[3]

The trial is registered with Clinicaltrials.gov number NCT02372487

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[1] http://journals.lww.com/greenjournal/toc/publishahead

[2] http://www.ijrcog.org/index.php/ijrcog/article/viewFile/1603/1429

[3] https://obgynupdated.blogspot.com/2016/07/new-use-of-old-drug-sildenafil-citrate.html

ACOG recommendations for management of suboptimally dated pregnancies.

courtesy:Pexels.com  

The American College of Obstetricians and Gynecologists (ACOG) recently published its recommendations regarding management and delivery of pregnancies in whom the best clinical estimation of gestational dates is not confirmed in forthcoming March 2017 issue of Obstetrics and Gynecology Journal. 

ACOG has always strived to curb elective deliveries before 39 weeks of pregnancy and spread awareness among obstetricians about the negative effects of elective delivery before 39 weeks, which increases neonatal respiratory and nonrespiratory morbidities.[1] 

The article can be accessed here.

This topic was also debated at the ACOG Annual Clinical and Scientific Meeting 2016.[2]

The most accurate method of gestational dating is a first trimester sonography. As the woman advances into second and third trimester the reliability of USG for the purpose of dating decreases linearly.  Pregnancies without an USG performed to confirm or revise the gestational dating before 22 0/7 weeks are labeled as suboptimally dated.

The guidelines for management are:

1. The decision about timing the delivery in a suboptimally dated pregnancy should be based on the best clinical estimate of the gestational age.
2. There is no role for elective delivery in suboptimally dated pregnancies to avoid the neonatal morbidity because the pregnancy may be earlier in gestation than believed to be. Decision to administer antenatal corticosteroids should be based on the best clinical judgement if a woman with suboptimally dated pregnancy is identified to be at risk for preterm delivery.
3. Amniocentesis to determine fetal lung maturity should not be used to decide the time of delivery in suboptimally dated pregnancies because  it is not reliable in predicting pulmonary maturity and other non-respiratory outcomes.
4. A follow-up sonography after 3-4 weeks of the initial one is always advisable in women with suboptimally dated pregnancies. It helps to support the prediction of gestational dating as well as fetal well-being in terms of weight gain. If IUGR is suspected, a close surveillance with umbilical cord Doppler should be considered.
5. It is always difficult to manage a presumably late-term pregnancy that lacks accurate dating because of the risk of overlooking post maturity and associated fetal morbidity and mortality. Therefore, is advised to begin antepartum fetal surveillance at 39–40 weeks of gestation and to deliver at 41 weeks using the best clinical judgement because it could be more postdated than it is believed to be.
6. In women with suboptimally dated pregnancy with a previous history of low transverse C-section incision a trial of labor can be given based on the clinical assessment of gestational age. If a woman requests a repeat elective C-section, it should be planned around 39 weeks based on best clinical judgement.
7. Women with suboptimally dated pregnancy should be well informed about the risks of neonatal morbidity and mortality because of inaccurate dating.

The full text of the  journal article can be accessed here.  

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[1] https://obgynupdated.blogspot.com/2017/01/choosing-wisely-and-acog-advises.html

[2] https://obgynupdated.blogspot.com/2016/05/elective-induction-of-labor-iol-at-39.html

Vitamin D and Human Reproduction—Evolving perspectives

We are all well versed with the role of Vitamin D in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. Its deficiency is linked to many chronic diseases of the cardiovascular and metabolic systems.

Evidence from animal and human studies suggests that vitamin D plays a very important role in human fertility and neonatal development. This steroid hormone has Vitamin D receptors (VDR) at multiple sites in the body including ovary, particularly the granulosa cells, endometrium and placenta.

It plays a very important role in ovarian steroidogenesis. [1] It deficiency contribute to development of insulin resistance and impaired glucose metabolism in patients with Polycystic Ovary Syndrome (PCOS). Therapeutic efficacy of supplementation with Vitamin D to improve insulin resistance, bring about ovulation and regularize menstruation in PCOs patients have been documented.[2] [3]

Observations also shows that lower 25(OH)D levels put women at higher risk of developing uterine fibroids, both in black and white ethnicities. In these women, the growth and size of the fibroid is also directly related to decreased levels of Vitamin D. Animal studies and human in vitro studies have shown the beneficial effect Vitamin D supplementation in inhibition of development and/or growth of uterine fibroids.[4] [5]

A recent study by Harris HR et al demonstrated that women within the highest quintile of Vitamin D blood values have one fourth the risk of developing endometriosis as compared to those in lowest quintile.[6]

It also plays a role in Body Mass Index (BMI) as per a recent meta-analysis, every 10% increase in BMI leads to 4% decrees in Vitamin D concentration.[7]

It’s role in male reproductive physiology is well documented by the fact that it’s level directly correlate with sperm motility and morphology.

As per Hill’s criteria a causal relationship between Vitamin D deficiency and negative outcome in IVF is explained but further research into knowing the magnitude of association is needed.[8]

A systemic review and meta-analysis by Lerchbaum E and Obermayer-Pietsch B published in Eur J Endocrinol May 1, 2012 concludes that Vitamin D plays an important role in Human reproduction and advocates the need of further research in therapeutic benefits of Vitamin D supplementation in such patients.  

Another review by Vanni et al published in the Reproductive Biology and Endocrinology, 2014 emphasizes the importance of supplementation of Vitamin D in IVF settings because consisting evidence documenting the increase incidence of gestational diabetes, IUGR, pre-eclampsia and preterm births in patients deficient in Vitamin D.[9]

The authors opine that although drastic improvements in reproductive failure may not be achieved solely by supplementing Vitamin D, but its addition to any fertility regimen is cheap, effective and without any side effects. It is easily correctable by simple oral supplementation.

Dosage up to 4000 IU is safe, without any side effects and effectively improve maternal vitamin D status. [10]

Results of double blind randomized trial entitled “Vitamin D during IVF” is still awaited.[11]

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[1]Anagnostis P, Karras S, Goulis DG: Vitamin D in human reproduction: a narrative review. Int J Clin Pract. 2013, 67 (3): 225-235

[2] Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E, Erturk E, Imamoglu S: The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010, 33 (4): 234-238.

[3] Wehr E, Pieber TR, Obermayer-Pietsch B: Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest. 2011, 34 (10): 757-63.

[4] Bläuer M, Rovio PH, Ylikomi T, Heinonen PK: Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro. Fertil Steril. 2009, 91 (5): 1919-1925.

[5] Halder SK, Osteen KG, Al-Hendy A: Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and −9 in human uterine fibroid cells. Hum Reprod. 2013, 28 (9): 2407-2416.

[6]  Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA: Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013, 177 (5): 420-430.

[7] Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Kiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaëlsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, et al: Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013, 10 (2): e1001383-

[8] Hill AB: The environment and disease: association or causation?. Proc R Soc Med. 1965, 58: 295-300.

[9] Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM: Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013, 26 (346): f1169-

[10] Wagner CL, McNeil R, Johnson DD, Husley TC, Ebeling M, Robinson C, Hamilton SA, Hollis BW: Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol. 2013, 136: 313-320.

[11] https://clinicaltrials.gov/ct2/show/NCT01019785

First baby born with ZIKA related microcephaly in Continental US

Tuesday saw the birth of first baby born with Zika related microcephaly at the  Hackensack University Medical Center, New Jersey. This is the second known case of a baby born with Zika-related birth defects in the United States. The first baby was born in Hawaii.

The mother is from Honduras and travelled to US to her relatives in hope of better medical care. Doctors in US believe that she contracted the disease probably in second trimester when she had fever and rash, which are symptoms of viral infection.

Her OBGYN  in Honduras suspected that she  had a baby with IUGR  and coordinated with CDC to send the samples for testing. As expected the results came back positive.

A last trimester ultrasound  revealed that baby had abnormalities including severe microcephaly, calcification of the brain, bowel problems and restricted growth.

Baby was delivered by emergency C-section and also suspected to suffer from other problems.

Honduras is one of half a dozen Latin American and Caribbean countries where abortion is not legal with no exceptions, not even to save a woman’s life, according to reproductive rights advocacy groups.

 As of May 12, 2016, the two Zika virus infection surveillance systems are monitoring 157 pregnant women in the U.S. states and 122 pregnant women in the U.S. territories with laboratory evidence of possible Zika virus infection.  That is a total of 279 pregnant women in U.S. states and territories who are followed closely as a part of national registry.

Till date almost 600 cases of Zika have been diagnosed in the US, but all sufferers have travelled to an infected country and none of them got infected in US.

According to the World Health Organization (WHO), women planning to become pregnant should wait at least eight weeks before trying to conceive if they or their partner live in or are returning from Zika virus hotspots.

The case comes at a time when Congress has yet to approve new funding to fight the virus, despite months of White House pressure. Congressional Republicans have rejected the White House’s request for $1.9 billion in new funds. 

References:

http://www.cdc.gov/media/releases/2016/s0520-pregnant-women-zika.html

http://www.cdc.gov/zika/hc-providers/registry.html