Trying to Understand Stillbirths

Stillbirths affects 1% of all pregnancies in US, amounting to nearly 24,000 deaths every year. Recent advances in medicine has brought down the neonatal and infant mortality considerably in last decade, but the decline is still birth rate is very slow.

A lack of understanding of the mechanisms behind it coupled with inability to predict stillbirth has prevented significant improvement in stillbirths’ rate.

Although altered fetal growth and placental abnormalities are strongest predictors of stillbirths but all patients with placental abnormalities do not end up in stillbirths, reflecting our lack of understanding of this interrelationship.

This population based case control study included 613 women who had stillbirths and 1747 women who had live births and who consented to placental pathological examination from 59 hospitals in 5 geographic areas in the U.S.

Study was published online August 18, 2017 in Journal PloS one.

About 15 placental pathologies were most prevalent in women with stillbirths and fetal growth abnormalities.

Out of 15, ten were also associated with fetal growth retardations. These are: single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight)

The other 5 (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate) resulted in stillbirths without altered fetal growth.  

Terminal villous hypoplasia was equally common in live born and still born fetuses with altered fetal growth.

Maternal factors associated with still births were gestational hypertension/pre-eclampsia (20% versus 11%, p<0.001), hypertension before pregnancy (11% versus 5%, p<0.001), and pregestational diabetes (7% versus 2%, p<0.001)

Fetal factors associated with still births were congenital malformations (13% versus 3%, p<0.001), lower birth weight (median 1,949 versus 3,321 grams, p<0.001), and lower GA (median 33 versus 39 weeks, p<0.001).

The study results suggest that different mechanisms exist for disruption in placental function and the results vary according to timing of gestation. An acute insult results in still births but no fetal growth alterations while a chronic, low level insult results in fetal growth retardation which may end up in still births.

Some of these placental findings can be diagnosed with prenatal ultrasound and pregnancies managed accordingly, Similarly, birth weight to placental weight ratio could be estimated antenatally by ultrasound and those pregnancies with abnormal ratio and at risk of stillbirths could benefit from early  term delivery.

Access the abstract, Full Text.

Older paternal age does not increase risk of adverse perinatal outcome

Couples can now be reassured regarding their concerns for adverse perinatal outcomes because of advancing paternal age says the results of recent study in press in American Journal of Obstetrics and Gynecology (ACOG).

The abstract for this study was presented as a poster presentation at the American Society for Reproductive Medicine Scientific Meeting October 15-19, 2016 in Salt Lake City, Utah, USA.

The adverse effects of increasing maternal age and ARTs are well known, but data on effects of increased paternal age is scarce.

This is a large population-based retrospective cohort study, stretching across 7 years that examined 1,034,552 live births in state of Ohio.

The data was stratified according to natural conception or use of ARTs.

It was seen that:

The paternal age varied between 12-87 years, mean 30 years.

Maternal age ranged from 11-62 years, median 27 years.

ARTs were used in 3118 pregnancies while 830,609 were due to natural conception.

Statistically significant increased need for ARTs was observed with increasing paternal age: 0.1% <30 years vs. 2.5% > 60 years, p<0.001.

After considering increasing maternal age and other confounders, increased paternal age was not significantly associated with preterm births, preeclampsia, Intrauterine growth retardation (IUGR), congenital anomalies, genetic disorders or increased NICU admissions. 

These results were also same when the data was stratified according to the use of ARTs or not.

The only limitation of the study was data was derived from births register, only shortterm outcome was looked at and compared to total sample size, pregnancies with advanced paternal age was small.

The authors concluded that, “Older paternal age does not appear to pose an independent risk of adverse perinatal outcomes, either in pregnancies achieved with or without ART.”

Obstructive sleep apnea in pregnancy linked to higher risk of congenital malformations: News from the sleep conference.

 Newborns of mothers with sleep apnea have higher chances of requiring resuscitation at birth, longer hospital stay and 26% higher risk of being born with a congenital malformation reports a study result presented at the 31st Annual Meeting of the Associated Professional Sleep Societies LLC (APSS), Boston.

This is first of its kind study linking Obstructive Sleep Apnea (OSA) in pregnancy and its effect on newborn.

The researchers looked at data from more than 1.4 million linked maternal and newborn records from National Perinatal Information Center over a period of 4 years from 2010-2014.

More than 17% of babies born to mother with OSA had congenital malformations. These mothers were also more likely to be tobacco and drug user, older, obese, and with pre-gestational hypertension and diabetes.

Only 10% of babies born to mother with no OSA had congenital anomalies (P < 0.001).

Most common anomalies were those related to circulatory system, nervous system and musculoskeletal.

Moreover, these newborns also had 2.76 times the risk of requiring resuscitation at birth and 2.25 times more likelihood of being in hospital for extended period of time.

“Our results have shown that babies born to mothers with a diagnosis of obstructive sleep apnea are more likely to require resuscitative efforts at birth, be born preterm, and to require a stay in the neonatal intensive care unit compared to babies who were not exposed to maternal sleep apnea,” said principal investigator and lead author Dr. Ghada Bourjeily, associate professor of medicine at Brown University and the Women’s Medicine Collaborative at The Miriam Hospital in Providence, Rhode Island.

“These findings add to our understanding of the extent of morbidities of maternal sleep apnea for the mother as well as the baby,” said Bourjeily. “The results further highlight the importance of identifying this condition in pregnancy and testing the impact of therapy on these complications.”

Dr. Bourjeily opined that results of this single study do not prove causation.

“We know that women who have sleep apnea also often have other morbidities, so we don’t know what might have contributed to the congenital outcomes,” said Dr. Bourjeily.

“We also don’t know if treating sleep apnea can reverse or prevent birth complications or even maternal complications, like preeclampsia or gestational diabetes.”

Studies are underway to look at maternal continuous positive airway pressure therapy use and neonatal outcomes.

Dr. Bourjeily received research equipment support from Respironics.

Baby born with absent nose dies at age two: A review of literature about this extremely rare anomaly

Baby Eli who was born with a absent nose died recently at age two. Absent nose or Arhinia is congenital absence of external nose, nasal cavities, and olfactory apparatus. It is extremely rare craniofacial anomaly with 47 reported cases in history of medicine. It was first described in the French literature in the 1800’s.

Baby Eli received a tracheotomy on day 5 of his birth and was learning to communicate with the help of sign language.

It is associated with other anomalies of central nervous system and genital and hormonal problems

Phenotypically it may present in a less sever form like hyporhinia, manifested as lack of external nasal structures.

Embryologically, formation of external nose and bony canal is completed between 3 to 8 weeks of intrauterine life. It occurs because of failure of maxillary and lateral nasal process, along with cribriform plate anomaly resulting in olfactory agenesis.

Chromosomal aberration such as inversion and trisomy 9 have been found in some cases of arrhinia. It may present as a part of syndrome or an isolated entity. The syndrome it is associated with is Bosma arhinia microphthalmia (BAM) syndrome. The Syndrome has 3 major features: 1) complete absence of the nose, 2) eye defects, and 3) absent sexual maturation.

Antenatal Ultrasound, preferably 3D can detect it earliest by 12 to 16 weeks of gestation. So far, antenatal diagnosis was possible in only one case. If diagnosed at appropriate gestational age, parents can have a choice of termination of pregnancy as prognosis of such children is poor in terms of mental and physical development as well as cosmetic and functional outcomes.

Arhinia is apparent at birth, with only a depression located between the eyes and mouth (at the normal position of the external nose)

The management at birth involves creating a functional airway and dealing with the feeding difficulties. Neonates are obligate nasal breathers, so the simultaneous action of sucking and breathing leads to respiratory distress.  In these neonates, the maxilla is underdeveloped with a high arch palate.

Surgically created nasal airway or tracheotomy forms an important part of management at birth.

Surgical reconstruction begins at 4-5 years of age and completed near puberty. Now it is possible to create much more cosmetically appealing nose because of newer nasal prostheses for these children.

Most patient will require ongoing medical care by a team of medical and surgical sub-specialists, including plastic or maxillofacial surgeons, ophthalmologists, and endocrinologists.

Tessa Evans was another baby born in Ireland with Arrhinia, undergone pioneering surgery in which a custom-built 3D printed mould was inserted into her face, to stretch her skin and slowly build the missing facial feature.

Her arrhinia was diagnosed antenatally at 20-weeks, with a follow up 3D scan revealed no other abnormalities. Her parents decided to continue the pregnancy.

No evidence of congenital anomalies with Zika infection in third trimester.

The first outbreak of Zika virus occurred in South America occurred in Brazil in May 2015 subsequently in October Columbia confirmed 156 cases of Zika in 13 municipalities.[1]  Neurological abnormalities and other adverse pregnancy outcomes are associated with Zika infection in first and second trimester of pregnancy.

A recent surveillance report from the Colombian Instituto Nacional de Salud (INS) suggested that Zika infection in the last trimester of pregnancy does not cause any structural fetal defect. The report of this study was published in recent online edition of New England Journal of Medicine.[2]

A total of 65,726 cases of ZVD were reported in Colombia during the study period from August 9, 2015, through April 2, 2016. Out of these 2485 (4%) were found positive on RT-PCR assay. Zika infection was widespread in Colombia with 11,944 pregnant women affected, of which 1484 (12%) were confirmed on RT-PCR assay.

Out of 11,944 infected pregnant women, INS had complete data on for a subgroup of 1850 women correlating gestational age and the onset of symptoms of Zika infection. Out of these 1850 women, 616 women got infection in third trimester and in nearly 89-90% of these women no congenital anomalies were detected at birth.

The remaining women were infected in first and second trimester, so they still had ongoing pregnancy when the cut-off date of the study was reached. 

The number of cases reported in the study does not show the true magnitude of the Zika infection as the surveillance system does not include asymptomatic women or those women who do not go to healthcare provider.

The authors stressed the importance of healthcare providers in educating the patients about the vector and sexual mode of transmission of the Zika infection.

The INS and CDC jointly are implementing intensified surveillance in places with Zika infections to determine the full spectrum of disease in mother and infants in relation to gestational age at infection. 

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[1] http://www.who.int/emergencies/zika-virus/history/en/

[2] http://www.nejm.org/doi/full/10.1056/NEJMoa1604037#t=article

CDC Confirms the link between Zika infection and microcephaly.

Zika has been linked to microcephaly since Brazil reported a sudden increase in number of infants born with microcephaly in September 2015, but causation was not established. CDC today made an important announcement after careful review of all the possible evidence that Zika virus is a cause of microcephaly and other severe fetal brain defects.

The study is published online in the New England Journal of  Medicine today.

“This study marks a turning point in the Zika outbreak.  It is now clear that the virus causes microcephaly.  We are also launching further studies to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain and other developmental problems,” said Tom Frieden, M.D., M.P.H., director of the CDC. “We’ve now confirmed what mounting evidence has suggested, affirming our early guidance to pregnant women and their partners to take steps to avoid Zika infection and to health care professionals who are talking to patients every day. We are working to do everything possible to protect the American public.”

The investigators examined the causality evidence in light of Shepard’s criterias, which is set of rules that must be satisfied before labeling  an agent being ‘ teratogenic’  and causing  congenital malformations. According to the Shepard’s criterias, causality is established when either criteria 1, 3, and 4 (rare exposure–rare defect approach) or criteria 1, 2, and 3 (epidemiologic approach) are fulfilled.

So, the relationship between Zika infection and microcephaly was termed casual under the rare exposure–rare defect approach as criteria 1, 3 and 4 were fulfilled:

1. Proven exposure must occur at a critical time during prenatal exposure: The microcephaly and other anomalies occur when the exposure occurs during first trimester or early second trimester. 
2. Careful delineation of clinical cases with the finding of a specific defect or syndrome: Infants with Zika infection do have a typical pattern which includes severe microcephaly, intracranial calcifications, and other brain anomalies, sometimes accompanied by eye findings, redundant scalp skin, arthrogryposis, and clubfoot which led the scientist to coin a term “Congenital Zika Syndrome.”
3. Rare exposure and a rare defect: This criterion was met because microcephaly is a rare defect with an incidence of 6 infants per 10,000 liveborn infants in the United States and infection in travelers who spent a limited amount of time in Brazil with active infection, constitute rare exposure for the patients.

Also supportive of causation is lack of alternative explanation for sudden increase in microcephaly cases in Brazil, French Polynesia and Colombia.

But, proving the causation is not enough in the fight against Zika infection. Many key questions are yet to be answered that have important implications.

CDC's director, Tom Frieden, MD said “We are launching further studies to determine whether children who have microcephaly born to mothers infected by the Zika virus is the tip of the iceberg of what we could see in damaging effects on the brain and other developmental problems," in a statement.

In addition to this researchers are also interested in knowing relative and absolute risk of infection and malformation. At present 1% to 29% of babies are born with microcephaly of all the mothers infected with the virus. They are also looking at other factors that modify the risk and severity of infections, such as gestational week at infection, additional morbidities and co-viral infection like Dengue fever.

CDC has not changed the travel warning or guidelines related to Zika infection after this publication.

Mark S. DeFrancesco, MD, MBA, President of the American College of Obstetricians and Gynecologists (ACOG), released the following statement regarding the U.S. Centers for Disease and Control and Prevention (CDC) paper addressing Zika virus “The message of the CDC paper underscores the importance of ongoing research into this outbreak. We once again encourage Congress to act swiftly to pass emergency funding to enhance our public health preparedness and enable America’s researchers to lead the charge in the development of a vaccine or treatment for this virus. Ongoing support for Zika virus research will protect American families and, indeed, families around the world."

References:

http://www.nejm.org/doi/full/10.1056/NEJMsr1604338?query=featured_home&

http://www.acog.org/About-ACOG/News-Room/Statements/2016/ACOG-Statement-on-the-CDC-Update-on-Zika-Virus

http://www.cdc.gov/media/releases/2016/s0413-zika-microcephaly.html

Oral contraceptives use around and during pregnancy does not appear to be teratogenic.

Image in the public domain, courtesy of Wikimedia Commons

2010 saw the 50^th anniversary of the contraceptive pill.

‘The pill’ as it is commonly known was a key player in building women’s current economic role in society as it gave women an unprecedented control over their own fertility.

Oral contraceptives remain the most common method of contraception in most part of the world. According to a CDC Faststats:

• Leading contraceptive method among women aged 15-29: Pill
• Percent of women aged 15-44 currently using the pill: 17.1%

Although the failure rate is 0.1 percent when pills are taken perfectly (same time every day, no missed pills), the actual failure rate is 9 percent over the first year, due primarily to the missed pills, drug interactions, forgetting to restart the pill after the seven-day pill-free interval or illness and results in what is known as breakthrough pregnancy.

photo courtesy: http://www.catholicmatch.com

Studies conducted in the past with high dose preparations have linked various birth defects with first trimester exposure to oral contraceptives. These birth defects involved the vertebrae, anus, heart, trachea, esophagus, kidney and limbs (VACTERL syndrome) (Nora et al, 1976).

After thorough investigation in the later years, these associations have not been substantiated. These studies were mainly focused on use of the OC during the first trimester.  No studies were found that studied the effect of exogenous hormones immediately before and around the time of conception or immediately after conception.

This prospective observational cohort study conducted by Brittany M Charlton from the Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts and her colleagues from Denmark was published on line on January 6, 2016 in British Medical Journal and aims to study the association between use of oral contraceptives around pregnancy time and resulting congenital malformations in the fetus.

They used Medical Birth Register records from 1997 to 2011 (880,694 live births) and Danish National Prescription Register and collected prescription data on the use of oral contraceptives. The investigators assumed that women who filled their prescriptions were exposed to oral contraceptives.

The women were divided into 4 groups, No oral contraceptive exposure, >3 months before pregnancy onset (reference group), 0-3 months before pregnancy onset (that is, recent use), and after conception. The two primary exposures of interest were after conception and recent use before pregnancy onset.

Any major birth defect was the primary outcome and subgroups of major birth defects categorized by organ system were the secondary outcomes.

Previous studies have observed associations between oral contraceptive exposure and 4 subgroups of congenital anomalies of hypoplastic left heart syndrome, gastroschisis, limb defects, and urinary tract anomalies.

Logistic regression was used to o estimate prevalence odds ratios of any major birth defect as well as categories of birth defect subgroups.

It was seen that the prevalence of major birth defect was consistent at 25 per 1000 live births across all the four groups. The study did not find any increase in the 4 birth defects that earlier studies have shown a link with.

The study lacked the statistical power for different formulations of oral contraceptives and specific subgroup of birth defects, but was very strong when it comes to examining the association between birth defects and the timing of oral contraceptives use.

It also stands at par with other studies conducted earlier, documenting no increase in birth defects after the use of oral contraceptives.

It also assures the patients and healthcare providers about no association between the oral contraceptive use and increased risks of malformation, as estimated 9% of oral contraceptive users become pregnant in the first year of use; many more women will stop using oral contraceptives when planning a pregnancy and conceive within a few menstrual cycles.

The study also postulate that future research could examine the different formulations of oral contraceptives as other health outcomes, such as breast cancer risk have varied by formulation—with triphasic levonorgestrel formulations driving the increased breast cancer risk.

References:

http://www.webmd.com/sex/birth-control/news/20141211/the-pill-remains-most-common-method-of-birth-control-us-report-shows

http://www.cdc.gov/nchs/fastats/contraceptive.htm

http://www.uptodate.com/contents/hormonal-methods-of-birth-control-beyond-the-basics

http://www.bmj.com/content/352/bmj.h6712

Mosher WD, Jones J. Use of contraception in the United States: 1982-2008. Vital Health Stat 23 2010:1-44.

Skouby SO. Contraceptive use and behavior in the 21st century: a comprehensive study across five European countries. Eur J Contracept Reprod Health Care 2004;9:57-68.

http://prospect.rsc.org/blogs/cw/2011/01/11/my-hero-carl-djerassi/#more-6286

http://cebp.aacrjournals.org/content/19/10/2496