Screening for Fetal Abnormalities 1

1 Running head: Screening for Fetal Abnormalities

SCREENING FOR FETAL ABNORMALITIES

Sonia Donaires

Applied Research Project Paper Submitted in Partial Fulfillment Of the Requirements

For the Degree of Master in Public Health MPH 500

Concordia University Nebraska

Dr. Evelyn Davila

February 23, 2015 SCREENING FOR FETAL ABNORMALITIES 2

Executive Summary

This is a study of fetal abnormalities in pregnancy from the point of view of screening aspects of clinical epidemiology. The purpose of this research is to evaluate and interpret data and statistics about the efficacy of screening in a case study. The population selected is pregnant women in the United States.

According to Word Health Organization, fetal abnormalities and congenital anomalies are defects that affect an estimated 270,000 newborns (World Health Organization, 2015). The most common anomalies are heart defects, neural tube defects and Down syndrome. Fetal anomalies are difficult to identify the exact cause and sometimes difficult to treat, and most of fetuses with abnormalities end in neonatal deaths because of the complicated condition. Risk factor is related to socioeconomic, genetic, infections, maternal nutrition status, and environmental factors.

For the purpose of this study, I selected a retrospective study conducted by Von Dorsten in the

State of South Carolina. This study begun in 1993 and end in 1996. The results show that the specificity

(99.9%) was higher than the sensitivity (47.6%) and the screening had a 99.3% of accuracy (Parker, et al,

Some issues related to ethical and legal issues are the uncontrolled use of ultrasound screening that pregnant women get. Ethical issues related with selective abortion of females in India and China, and legal issues because of the misdiagnosed of the condition of the fetuses. The lack of guidelines and restrictions for the use of ultrasound scan are limited. This is one of the reasons for which ultrasound scan become in commercial interest and not only for health purposes.

Recommendation of ultrasound scan is especially for high risk population such as, women that are exposed to contaminants in the environment, couples that have close consanguinity, and pregnant women with advance age. Also, it is recommended that all pregnant women have at least one ultrasound scan during pregnancy in week 15-20 or in the second semester to detect fetal anomalous (Centers for

Diseases Control and Prevention, 2014). Inform and educate about the benefits of ultrasound scan is important that ensure all women prevent fetal abnormalities. SCREENING FOR FETAL ABNORMALITIES 3

Screening for Fetal Abnormalities

Fetal abnormalities or congenital anomalies are also known as birth defects, congenital disorders of congenital malformations. Congenital anomalies can be defined as structural or functional anomalies, including metabolic disorders, which are present at the time of birth (World Health Organization, 2015).

Causes of 2.7 million neonatal deaths in 193 countries in 2010 SCREENING FOR FETAL ABNORMALITIES 4

Today congenital anomalies and preterm birth are important causes of childhood death, chronic illness, and disability in many countries.

Compared with infants of non-Hispanic white mothers,

Infants of non-Hispanic black or Infants of Hispanic mothers had

African-American mothers had

Higher birth Lower birth Higher birth Lower birth prevalence of these birth defects prevalence of prevalence of these prevalence of these birth birth defects these birth defects: defects:

Tetralogy of Cleft palate Anencephaly Tetralogy of Fallot

Fallot Cleft lip with or Spina bifida Hypoplastic left heart syndrome

Lower limb without cleft palate Encephalocele Cleft palate reduction Esophageal atresia Gastroschisis Esophageal atresia or tracheoesophageal fistula defects or tracheoesophageal Down syndrome Trisomy 18 fistula

Gastroschisis

Down syndrome

Source: http://www.ncbi.nlm.nih.gov/pubmed/17051527?log$=activity

The prevalence of birth defects in the United States for 1999- 2001 ranged from 0.82 ore 10,000 live births for truncus arteriosus to 13.65 per 10,000 live births for Down syndrome. Compared with infants of non-Hispanic (NH) white mothers, infants of NH black mothers had a significantly higher birth SCREENING FOR FETAL ABNORMALITIES 5 prevalence of tetralogy of Fallot, lower limb reduction defects, and trisomy 18, and a significantly lower birth prevalence of cleft palate, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, gastroschisis, and Down syndrome. Infants of Hispanic mothers, compared with infants of NH white mothers, had a significantly higher birth prevalence of anencephalus, spina bifida, encephalocele, gastroschisis, and Down syndrome, and a significantly lower birth prevalence of tetralogy of Fallot, hypoplastic left heart syndrome, cleft palate without cleft lip, and esophageal atresia/tracheoesophageal fistula. (Parker, et al, 2010)

Causes and risk factors

According the World Health Organization, there are approximately 50% of all congenital anomalies, cannot be linked to a specific cause, but there are some known causes or risk factors:

Socioeconomic Factors

Developing countries have a 95% higher incidence of severe birth defects than in developed countries.

Mothers that are susceptible to malnutrition have increased exposure to agents that increase the incidence of abnormal prenatal development. Another risk factor is advanced maternal age in develop countries.

Having a baby in advance age increases the risk of some chromosomal abnormalities such as Down syndrome.

Genetic factors

Consanguinity (relationship by blood) increases the prevalence of rare genetic congenital anomalies and nearly doubles the risk for neonatal and childhood death, intellectual disability and serious birth anomalies in first cousin unions.

Infections

Maternal infections such as syphilis and rubella are a significant cause of birth defects in low- and middle-income countries. SCREENING FOR FETAL ABNORMALITIES 6

Maternal nutritional status

Iodine deficiency, folate insufficiency, obesity, or diabetes mellitus are linked to some congenital anomalies. For example folate insufficiency increases the risk of having a baby with neural tube defects.

Environmental factors

Mothers that are exposes to pesticides, medications, alcohol, Tabaco, chemicals in the environment during pregnancy increases the risk of having fetus affected by congenital anomalies.

Working or living near or in waste sites, smelters, or mines may also be a risk factor.

Common Fetal Anomalies

Anencephaly - the absence of the cranial vault

Spina Bifida - a midline defect of the vertebrae that results in exposure of the contents of the neural canal

Cleft lip - 2nd common congenital malformation. It can be causes by both genetic and environmental factors. It is a malformation of the primitive oral cavity of the lip. Usually lip defect on nose and mouth.

Gastroschisis – is a paraumbilical defect of the anterior abdominal wall.

Omphalocele - a ventral wall defect where there is herniation of the intra abdominal contents into the base of the umbilical cord.

Trisomy 18 - called Edwards Syndrome. There are three 18th chromosomes instead of two.

Conjoined Twins - sporadic event caused by an incomplete division of the embryonic cell mass.

(American Medical Technologists, n.d).

Common Congenital Anomalies in the Newborn

• Respiratory system: SCREENING FOR FETAL ABNORMALITIES 7

- Laryngeal stridor

- Choanal atresia

• Gastrointestinal system:

- Anomalies of the mouth (cleft lip & cleft palate)

- Anomalies of the esophagus (esophageal atresia & chalasia of the esophagus).

• Anomalies of the stomach and duodenum:

- pyloric stenosis

- duodenal obstruction

- hiatus hernia

• Anomalies of the intestine:

- Imperforated anus

- Omphalocele.

- Intestinal atresia

- Diaphragmatic hernia

- Hirschsprung’s disease (congenital aganglionic megacolon)

- Intussusception (Centers for Disease Control and Prevention, 2014)

Ultrasound Screening for Pregnant Women in USA

The population selected is pregnant women in the United States, specifically South Carolina State where Von Dorsten developed the research that begun in 1993 and end 1996. SCREENING FOR FETAL ABNORMALITIES 8

What is an Ultrasound Screening?

Ultrasound scan is a machine that sends sound waves to the womb of a pregnant woman. These waves produce echoes that turned into an image on a screen that shows the fetus. This type of screen is used for identify potential problems in the fetus and improve the safety of birth. Between the several uses of the screening of different stages of the pregnancy the main use is to detect the common fetal anomalies to prevent morbidity and mortality in high-risk population.

Ultrasound Screening Epidemiological Data and Studies

For the purpose of this research I will review a retrospective case study conducted by Van

Dorsten in a period of four years from 1993 to 1996. This study is an excerpt of 11 studies around the world conducted by the Royal College of Obstetrician and Gynecologists in London (RCOG). This was a diagnostic value of routine ultrasound in the second trimester, including both multi-stage ultrasound screening.

The table showed below is a description of included studies and detection rates of structural anomalies by antenatal ultrasound (first and second trimester).

Description

Ultrasound screening by registered diagnostic medical sonographers. Scanned at 15-22 weeks. Soft markers: no

Number of fetuses 1611 (twins excluded)

Prevalence of anomalous 1.30% (21 fetuses) fetuses/anomalies Anomalies: (29 anomalies)

Detection < 15 0 SCREENING FOR FETAL ABNORMALITIES 9

Detection <24 weeks 10 ST: 47.6% SP: 99.90%

Detection > 24 weeks 0

Overall detection 10 FP: 1 ST: 47.6% SP: 99.90%

Termination of Pregnancy 4 (0.25%) Source: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0009593/

Meta-analysis of positive likelihood ratios by routine ultrasound to detect fetal anomalies before 24 weeks.

Outcomes: 01 Positive likelihood ratio

Anomalous fetuses: 10/21

Normal Fetuses: 1/1590

RR (fixed) 95% CI

757.14 (101.44, 5651.03)

Weight: 0.88%

Meta-analysis of negative likelihood ratios by routine ultrasound to detect fetal anomalies before 24 weeks.

Outcome: 02 Negative likelihood ratios

Normal fetuses: 1589/1590

Weight: 1.15%

RR (fixed) 95% CI

0.52 (0.35,0.79) SCREENING FOR FETAL ABNORMALITIES 10

Meta-analysis of overall positive likelihood ratios by routine ultrasound to detect fetal anomalies.

Outcome: 01 Positive likelihood ratios

Weight: 0.15

RR (fixed) 95% CI

757.14 (101.44, 5651.03)

Meta-analysis of overall negative likelihood ratios by routine ultrasound to detect fetal anomalies.

Outcome: 02 Negative likelihood ratios

Weight: 0.35

RR (fixed) 95% CI

0.52 (0.35,0.79)

Findings

The results presented above show that the sensitivity and specificity of detecting fetal structural anomalies before 24 weeks of gestation reported from the study was 47.6% and 99.90% respectively.

Meta-analysis of likelihoods ratios showed positive and negative likelihood ratios before 24 weeks of

757.14 (95% CI 101.44 to 5651.03) and 0.52 (95% CI 0.35 to 0.79), respectively. Meta-analysis of likelihood ratios showed overall positive and negative likelihood ratios was 757.14 (05% CI 101.44 to

5651.03) and 0.52 (95% CI 0.35 to 0.79) respectively. SCREENING FOR FETAL ABNORMALITIES 11

Prevalence and detection of congenital anomalies at second-trimester antenatal ultrasound

according to RCOG subgroup

Prevalence for 1000 Van Dorsten

Number of fetuses 1611

Lethal anomalies (total) 0

Possible survival and 1.57 13/16 long-term morbidity

Spine bifida 0.47 2/2

Hydrocephalus 0.49 4/5

Complex cardiac 0.35 4/5 malformations

Anterior abdominal wall 0.33 1/1 defects

- Gastrochisis 0.19 1/1

Congenital cystic 0.15 1/2 adenomatous malformation

Trachea-esophageal 0.03 1/1 atresia

Renal dysplasia 0.77 N/A (bilateral)

Anomalies associated 0/38 0/3 with possible short- term/immediate morbidity Source: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0009593/ SCREENING FOR FETAL ABNORMALITIES 12

Overall sensitivity for lethal anomalies was 0% that for possible survival and long-term morbidity was 81% that for Hydrocephalus and Complex cardiac malformations were 8%. In conclusion, the second trimester ultrasound shows high specificity but low sensitivity.

Common Ultrasound Screening Tests for Pregnant Women

According to the CDC, second trimester screening is recommended. It is between weeks 15 and

20 of pregnancy. This is the period in which the ultrasound scan can detect defects in the fetus.

There are two types of screening:

 Maternal Serum Screen is simple blood test used to identify if a woman is at increased rick for

having a baby with certain birth defects, such as chromosomal disorders such as Down syndrome. It

is also known as a “triple screen” or “quad screen” depending on the number of proteins measured in

the mother’s blood. For example, a quad screen tests the levels of 4 proteins AFP (alpha-fetoprotein),

hCG, estriol, and inhibin-A (CDC, 2014).

 Anomaly Ultrasound. This test is usually completed around 18–20 weeks of pregnancy. This

ultrasound creates pictures of the baby that helps to check the size of the baby and looks for birth

defects or other problems with the baby (CDC, 2014).

Measures of the Validity of Ultrasound Screening Tests for Pregnant Women

2X2 Table

Present Absent Total Positive 10 1 11 Negative 11 1589 1600 21 1590 1611 SCREENING FOR FETAL ABNORMALITIES 13

Sensitivity: 47.6%

Specificity: 99.9%

Predictive value positive: 90%

Predictive value negative: 99%

This study show high specificity and low sensitivity meaning that there were 99.9% pregnant women with normal fetuses and 47.6% patients identified with anomalous fetuses. The predictive value positive and negative show that the screening was positive in a 90% detecting pregnant women with anomalous fetuses and 99% screened normal respectively. Measuring the accuracy of the degree of agreement between the screening test and the gold standard is 99.3%, which means that the outcomes of the screening were effective. Based in the results of this study, I conclude that, the validity of ultrasound scan presented above show that the screening was 99.3% accurate. Bias in a ultrasound scan can lead to misdiagnose to the normal or anomalous fetuses.

Considering that no screening test is perfect. Bias in a ultrasound scan can lead to misdiagnose to the normal or anomalous fetuses.

Ultrasound Screening tests and Population

Ultrasound scan is especially for pregnant women that live on environmental risk factors. As a result, most pregnant women should have at least one ultrasound scan during their pregnancy. It usually takes place between 18 weeks and 21 weeks. It’s called the anomaly scan because it checks for structural abnormalities (anomalies in the baby). Ultrasound scans are offered to all women, but not everyone chooses to have them because of the lack of information.

According to Wilson and Jungner (1968) to evaluate the validity of any screening program is that disorders to be screened for should be clinically well defined SCREENING FOR FETAL ABNORMALITIES 14

- The incidence of the condition (individual malformations) should be known

- Disorders should be associated with significant morbidity or mortality

- Effective treatment should be available, e.g. intrauterine treatment, birth managed in a specialist

center, or termination of pregnancy

- There should be a period before onset of the disorder (the antenatal period) during which

intervention is possible to improve outcome or allow informed choice

- There should be an ethical, safe, simple and robust screening test, e.g. ultrasound appears safe,

ethical and acceptable

- Screening should be cost-effective (Wilson & Jungner, 1968).

Ethical Considerations

Modern equipment of today has been made possible to identify accurately fetal anomalies and fetal growth problems for the unborn. Ultrasound scan gives you the possibility to know beforehand if a child has certain anomalies giving you the option to terminate the pregnancy. This type of scan become in a difficult decisions for the couple and in a potential cause of anxiety throughout the remaining weeks of pregnancy if the couple decide continue with the pregnancy or terminate.

Although this may be true that the medical advances have improved treatment options and quality of life for infants with abnormalities. It also gives you the option to correct abnormalities through a surgery such as cleft lip, cleft palate and many heart defects. However, some concerns of today related to ethical and legal issues has been arise with birth abnormalities that led to legal issues because of misdiagnoses, failure to diagnose ectopic pregnancy, to diagnose twins, and to detect fetal anomalies. SCREENING FOR FETAL ABNORMALITIES 15

In addition, ultrasound scan is used no longer for diagnostic test applied to a few pregnancies that is necessary to detect defects in the fetus of the population at higher risk. Today, the increasing and uncontrolled use of the ultrasound scans become in commercial interests that not only doctors and nurses use in the hospitals, it also become in a widespread business around the world that with the solely purpose to give a baby look, a fun ultrasound in order to meet your baby with photograph and home videos

(Wagner, 1999).

According to the American College of Obstetricians and Gynecologists, ultrasound scan are recommended only for specific reasons. On the other hand, ultrasound screening on pregnant women in many countries does not have any restrictions to contain the over use of this type of screening. This is one of the reasons why women get multiple screening. This of course is an unjustified advice because women should have only one screening or two when physicians detect some problem in the fetus.

For instance, poor countries such as India and China, the ultrasound scan in pregnancy become in one of the most controversial topics because of the ethic issues. Ultrasound scan is used regularly to determine sex of the fetus and then to selectively abort female fetuses. The economic and social reasons are the basis for which there is preference of male children than females. In both countries there are high incidence of female fetuses aborted (in India, 250,000 abortions per year). Girls are more expensive because girls once they married, they won’t be able to take care of their parents. It is cheaper to get an ultrasound scan to abort females and keep the males fetuses because males will take care of their parents

(Boughton, 2013).

Recommendations

Ultrasound Screening for the Target Population

My target populations are pregnant woman in USA. The United State is a develop country that regulate the use of screenings. The CDC has a main role to establish the necessary recommendations to prevent fetal abnormalities. SCREENING FOR FETAL ABNORMALITIES 16

 Ultrasound screening is for high-risk population. Women that are exposed to

contaminants in the environment.

 Ultrasound scan are recommended for couples that have close consanguinity such

as, cousins of 1st degree.

 Pregnant woman with advance age, especially to detect down syndrome

 Pregnant woman at least should have one ultrasound scan to detect fetal

abnormalities

 The prenatal Screening Program should consist of three types of screening test:

- Quad Marker Screening – one blood specimen drain at 15 weeks – 20 weeks of

pregnancy (second trimester)

- Serum Integrated Screening – combines first trimester blood test results with

second trimester blood test results

- Sequential Integrated Screening – combines Nuchal Translucency with first and

second trimester blood test results (Genetic Disease Screening Program, n.d.).

Increasing the participation of Ultrasound Scan

First of all, focusing on the population of high risk, I will develop programs of health and promotion about fetal abnormalities. Promoting the primary prevention as one of my priorities to ensure that all pregnant women in USA stay well informed about the risk factors, how to prevent fetal abnormalities and educating about the benefits of ultrasound scan. This programs would be available to all women without consider their condition (pregnant or not). I also will promote SCREENING FOR FETAL ABNORMALITIES 17 education about fetal abnormalities and the risk factors in teenagers including females and males at the high school level.

Role of Public Health and Increasing Participation

The role of public health in relation to increasing screening participation of pregnant women is focused on developing programs of screening for genetic disorders that are, for the most part preventable or remediable by an early intervention and provide clinical oversight for the follow-up services, which include genetic counseling, confirmatory testing, including ultrasound an diagnostic procedures, establishing a primary prevention and making available ultrasound scans to all women

(Genetic Disease Screening Program, n.d.).

There are two programs that will enhance the screening participation are:

- Promote the Genetic Disease Screening Program (GDSP) which main function is

improving health and birth outcomes of all newborns in high-risk population.

- Newborn Screenings (NBS) is an essential program of preventive public health

measure.

Early identification and initiation of ongoing treatment of disorders identified through

newborn screening can prevent severe mental retardation, delayed body growth, damage to

major organs, and death (Genetic Disease Screening Program, n.d.).

The impact of the early treatment will ensure reduce the prevalence of fetal abnormalities.

Equally important is evaluate the technology that provide ultrasound screening, verify if this type of screening is harmful for the fetus and ensure that ultrasound screening should be only once or twice during pregnancy.

References

Data and Statistics. (2014, October 20). Retrieved from Centers for Disease Control and Prevention: http://www.cdc.gov/ncbddd/birthdefects/data.html SCREENING FOR FETAL ABNORMALITIES 18

Genetic Disease Screening Program. (n.d.) California Department of Public Health GDSP Fact Sheet. Retrieved from http://www.cdph.ca.gov/PROGRAMS/CENTERFORFAMILYHEALTH/Pages/GDSPFactSheet.asp x

Parker S.E., Mai C.T., Canfield M.A., Rickard R., Wang Y, Meyer R.E., Anderson P, Mason C.A,. Collins J.S., Kirby R.S., Correa A. (2010, December). Updated National Birth Prevalence Estimates for Selected Birth Defects in the United States, 2004-2006. 88(12):1008-16. doi: 10.1002/bdra.20735. Epub 2010 Sep 28.

Screening for Fetal Anomalies (2008, March). Retrieved from Royal College of Obstetrician and Gynecologists: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0009593/

Wilson J.M., Jungner G. (2008, April). Principles and practice of screening for disease. WHO Chronicle. 1968;22(11):473. Retrieved from http://www.scielosp.org/scielo.php?script=sci_arttext&pid=S0042-96862008000400018