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Motherisk Newsletters: Spring 1998, No. 8Spring 1998, No. 8
THE NEW SELECTIVE SEROTONIN REUPTAKE INHIBITORS
Are they safe in pregnancy?
A decade after the introduction of the first selective serotonin reuptake inhibitor (SSRI) fluoxetine into clinical use, this class of antidepressants is being used by millions of men and women worldwide. Because more than half of all pregnancies are unplanned and an estimated 8-20% of all women suffer from depression, fetal safety is a primary concern.
During the last few years new SSRIs have been introduced into the market with purportedly less adverse effects than fluoxetine. Presently, while a large number of women of reproductive age use newer SSRIs for depression and other indications (such as obsessive compulsive disorder), no human data on their reproductive safety exist.
We have recently completed the first prospective, controlled, cohort study of pregnancy outcome following fetal exposure to the new SSRIs.( 1 )
Patients and Methods
This prospective cohort included all women who contacted one of 9 participating Teratology Information Services (TIS) regarding exposure to fluvoxamine, sertraline or paroxetine during the first trimester of pregnancy for depression.
The primary endpoint of interest was the rates of major malformations, defined as structural or functional anomalies which have significant medical or social consequences.
A total of 267 women met the study inclusion criteria (92 from Toronto, 66 from Tampa, 46 from Philadelphia, 32 from Farmington, 11 from Salt Lake City, 7 from Burlington, 6 from London, Ont., 4 from Chicago, and 3 from Indianapolis). One hundred forty-seven women used sertraline, 97 paroxetine and 26 fluvoxamine.
Of the 267 women exposed to a SSRI, 49 used the drug throughout pregnancy. The majority of women used sertraline at 50 mg/day (range 25-250 mg), paroxetine at 30 mg (range 10 to 60 mg) and fluvoxamine at 50 mg (range 25 to 200 mg).
Women exposed to a SSRI were significantly less likely to be primigravid, and significantly more likely to smoke cigarettes and to have had a previous TA ( Table 1 ). These trends were homogeneous among the three SSRIs.
Pregnancy outcome did not differ between the groups, with similar rates of major malformations, spontaneous and elective abortions and stillbirth, and similar mean birthweight and gestational age (Table 2 ).
Pregnancy outcome among women who took a SSRI throughout pregnancy did not differ from those who took the drug only during the first trimester. Among SSRI users, there were no differences in outcome measures between smokers and non-smokers (data not shown).
Our study confirms animal experiments in showing that, when used in the recommended doses,
the new SSRIs do not appear to increase the risk of congenital malformations.(2-4) Our sample size was large enough to detect a relative risk of 2.5 for major malformations with a power of 80% and an alpha of 0.05.
In summary, this study indicates that the new SSRIs sertraline, paroxetine and fluvoxamine do not appear to increase the teratogenic risk when used in their recommended doses.
Nathalie A. Kulin M.Sc.
Anne Pastuszak M.Sc.
Gideon Koren MD
Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldcamp M,
et al: Pregnancy outcome following maternal
use of the new selective seratonin reuptake inhibitors. A prospective
controlled multicenter study. JAMA 1998; 279; 609-610.
Product information. Luvox. Solvay Kingswood, 1991.
Product information. Paxil. SmithKline Beecham Pharmaceuticals, 1995.
- Product information. Zoloft. Pfizer Pharmaceuticals, 1994.
Excerpts from the program's recent 3-year evaluation report
Breaking the Cycle (BTC) is a unique early identification and prevention program designed to serve a high-risk population: pregnant women and drug-involved families with young children who are living near-the-street and experiencing chaotic, transient, unstable and often very violent environments. The program is a "one-stop" model organized by six partner agencies that offer integrated addiction, parenting, health and child development services at a downtown site. It is funded by Health Canada's Community Action Program for Children.
BTC's target population is women from Toronto or surrounding areas who meet the following three criteria:
They are pregnant and/or the parent of at least one child under the age of 6
They are using substances or in recovery from substance use, and
- They desire support to reduce or cease their substance use and/or to maintain recovery.
Mothers who do not become
involved with the program beyond one visit or a few phone calls. Some
of these mothers may have been referred to more appropriate programs.
They may also be mothers who were not yet ready for involvement.
Children and mothers who attended the program for less than three visits.
Children and mothers who attended the program
for more than three visits.
32 Non-client families
57 Non-engaged families
121 Engaged families
The demographic profile of clients presented in the following discussion is based on information drawn from the Intake Forms for:
27 Non-engaged families
93 Engaged families
120 Total client families examined through this evaluation
Table 1: Services Provided On Site by Breaking the Cycle Partners
|SERVICES||DELIVERED by||SUPERVISED by|
|Support Group||Breaking the Cycle||Jean Tweed Centre|
|Relapse Prevention Group||Breaking the Cycle||Jean Tweed Centre|
|Recovery Group||Breaking the Cycle||Jean Tweed Centre|
|Individual Counselling||Breaking the Cycle||Jean Tweed Centre|
|New Moms' Support Group||Dept. of Public Health/Mothercraft||Dept. of Public Health/Mothercraft|
|Nobody's Perfect Parenting Program||Dept. of Public Health||Dept. of Public Health|
|Community Kitchen||Dept. of Public Health||Dept. of Public Health|
|Parent-Child Program||Breaking the Cycle||Mothercraft|
|Parent-Child Counselling||Breaking the Cycle||Mothercraft|
|Hanen "You Make the Difference" Group||Breaking the Cycle/ Mothercraft||Mothercraft|
|Supervised Access Visits||Breaking the Cycle/CAS||Mothercraft/CAS|
|Developmental Screening and Assessment||Breaking the Cycle/Mothercraft||Mothercraft|
|Developmental Group||Breaking the Cycle||Mothercraft|
|Individual Pre-Postnatal Counselling||Paediatric/toxicologist/Dept. of Public Health /Mothercraft||Dept. of Public Health/Mothercraft|
|BASIC NEEDS SUPPORT|
|Clothing Exchange||Breaking the Cycle||Mothercraft/Jean Tweed|
|Daily Lunch||Second Harvest||Mothercraft/Jean Tweed|
|Transportation||Breaking the Cycle||Mothercraft/Jean Tweed|
|Individual Counselling||Clients/Peers||Mothercraft/Jean Tweed|
|SERVICES DELIVERED AT BREAKING THE CYCLE BY NON-PARTNER AGENCIES|
|Mental Health Counselling||Women's Mental Health Clinic||Clarke Institute of Psychiatry & Women's College Hospital|
I didn't know how to deal with parenting before I came here.
It wasn't the detox treatment that helped me stop drinking.
There's a whole lot of things that make you want to pick up a drink.
I really needed the Self-esteem and Parenting Groups.
I used to think that I wasn't a bad mother if I waited until my son fell asleep before I drank.
But I would just sit there and wish for him to fall sleep.
I was never really there for him.
Most of the mothers for whom complete Intake Form data were available were "Engaged" in the program, since "Non-engaged" mothers, by definition often were not involved enough with BTC staff to provide complete answers to the questions on the Intake Form.
The Mother's portion of the Intake Form was completed first. In some instances, mothers did not stay long enough with the program to complete the Child's portion of the Intake Form or refused
to answer some of the many questions. For these reasons, there is less complete demographic and outcome data available on their children.
The majority of BTC families have had previous involvement with child welfare service ( Table 2 ). (Some of these families may not be an active case at this time.
This question measured whether these families had ever had involvement with child welfare.)
In another analysis, research indicated that over one-fifth of BTC mothers had been Crown Wards or had been in foster care themselves as children.
Of the 251 children born to BTC mothers, the custody arrangements of 233 of them is as follows:
|87||(37%) in the custody of BTC mothers|
|70||(30%) in foster care|
|76||(33%) in other's custody (grandparents, other family)|
|233||children (for whom information is available)|
One-quarter of women who came to BTC during its first 2.5 years of operation were pregnant at intake (Table 3). By contrast, between January 1995 and December 1997 less than 1% of women seen for treatment at Jean Tweed Centre, a mainstream treatment centre, were pregnant. BTC's objective of "early identification and engagement" is being met in that 32.1% (9/28) were in their first trimester of pregnancy at intake. The remaining two-thirds were in their second trimester (13/28) or third trimester (6/28). BTC clients were on average 5 months pregnant at admission (standard deviation = 2.22). Most women who were pregnant at intake reported that they had seen a doctor about this pregnancy. However, the data do not distinguish between the doctor at BTC
or one outside of the program.
Numerous prenatal risk factors were identified for children of substance using mothers and were investigated for this sample. These factors included exposure to alcohol, crack/cocaine, nicotine, prescription drugs, and other drugs. Factors related to pregnancy were also examined, including minimal prenatal care, history of miscarriages, placenta previa, low weight gain. The risk assessment also included factors related to maternal health such as anemia, high blood pressure, diabetes, infections, and obesity. Finally, general characteristics about the mothers were assessed, such as teenage mothers, transience, twin birth, maternal stress, other maternal health factors including Hepatitis C, and mother in a physically abusive relationship (Table 4 ).
|Table 2. Child Welfare Involvement (N = 102)|
|Table 3. Pregnancy Status at Intake (N = 115)|
|Table 4. Number of Prenatal Risk Factors|
|Table 5. Number of Child Separations from Mother|
On average, mothers whose children were born while they attended the BTC program reported that their children were exposed to an average of 5 of the above noted risk factors (standard deviation = 2.7). Children who were born before their mothers attended BTC were exposed to an average of 3 risk factors (standard deviation = 1.7) as per mothers' report.
Reports of substance abuse during pregnancy were equivalent for both groups. Seventy-five percent of mothers whose children were born while they attended BTC stated that they had used some substance during their pregnancy, while 77.6% of mothers of children not born while they attended the program noted they had used substances while they were pregnant.
Women who gave birth while attending BTC may be more aware of prenatal risk factors or health issues in general (e.g. high blood pressure). An increased awareness of these issues may have motivated their attendance.
Significantly, more children whose mothers started attending BTC after they were born had been separated at some time from their mothers (62.1%), than had those in the other group (30.8%) ( Table 5 ).
Only three mothers who had their children while they attended the program had ongoing separations from their children, whereas 16 of the other mothers reported ongoing separations.
The success of early identification is evident by the percentage of pregnant women that are becoming engaged at BTC. Almost one-quarter of the women who access service at BTC are pregnant: this number is significant given this difficult-to-engage population. The outreach objective of this program has also been successful, as a consistent number of families access the program for the first time each month. The client focus group highly recommended even further outreach attempts to engage women who were ready for change but were not aware of the BTC program.
The single-access and integrated services model was assessed by identifying patterns of referral. There have been a consistent number of families accessing service at BTC since its inception. In fact, it is important to note that not only is BTC servicing new families each month, but those families who have previously engaged in the program continue to receive service.
Focus group interviews were also used to assess the service model. The Steering Committee focus group stated that the model had helped to build a strong foundation for the program. The BTC staff focus group noted that a "one-stop shop" was important to mothers who are unlikely to seek individual services for themselves and their children. Finally, the client focus group stated that the BTC program was realistic in its focus and expectations of mothers, and that they appreciate having all the services they need at one location.
BTC's early permanency planning has had a great impact on whether pregnant BTC clients ultimately choose to or are able to parent a child. Also, BTC born children are identified to child welfare agencies at an earlier stage, when required.
Early permanency planning is just one aspect of the case management function at BTC. Advocacy services, like many other services at BTC have developed substantially since the inception of the program, and are, according to client focus group, a key component of BTC. Case management services include advocacy in the areas of child welfare services, legal services, housing services, mental health services, medical services, addiction services and daycare/subsidy services.
Marion A. Paquet, CMC
To refer a patient of yours to BTC, please call (416) 364-7373 or fax (416) 364-8008.
IN MEMORIAM - DR. FRANZ ROSA
Dr. Franz Rosa, a leading clinical teratologist, and a close friend and supporter of Motherisk died in the fall of 1997. In his role as the chief teratologist for the American FDA, Dr. Rosa was instrumental in establishing evidence-based standards for human teratogenesis. He was the first to identify Accutane and Carbamazepine as human teratogens.
He visited with us at Motherisk several times and was one of the first supporters of the new methodologies used by Motherisk in the mid-eighties.
Franz Rosa, a superb scientist, a warm and kind human being, will be painfully missed.
A PROGRESS NOTE ABOUT HIV TESTING IN PREGNANCY
Testing Women for HIV Infection, an article featured in the Summer 1997 Motherisk Newsletter (No. 7) reviewed the evidence behind a recommendation to discuss HIV infection with, and offer HIV testing to, all pregnant women. The article failed to note that the Society of Obstetricians and Gynaecologists of Canada (SOGC) supports informed testing. We refer our readers to SOGC Clinical Practice Guidelines on HIV Testing in Pregnancy, published in the SOGC Policy Statement No. 62. These guidelines recommend offering HIV testing to all pregnant women.
THE MOTHERISK HIV HEALTHLINE AND NETWORK 1-888-246-5840
The Motherisk HIV Healthline and Network is now up and running. Our goals are to help women with HIV make informed decisions about and during pregnancy, maximize prevention of vertical transmission of HIV infection to their babies, and minimize toxicities.
The toll-free HIV Healthline - 1-888-246-5840 provides confidential counselling and access to care to pregnant women who are, or may be, HIV positive. A specially-trained team provides information to women, family members and healthcare professionals, about the possible effects of HIV and its treatment on the unborn child.
The HIV Network - Shares new knowledge about HIV in pregnancy with Network members nationwide, and registers cases of HIV positive pregnant women for long-term study of the fetal effects of HIV infection and treatments in pregnancy. The program also promotes informed HIV testing of all pregnant women.
The HIV Healthline is open to all callers (women, partners, family members, healthcare providers). It is a vital resource for all women of childbearing age and their healthcare providers.
The HIV Healthline operates Monday through Friday, 9:00 a.m. to 5:00 p.m.
A Healthline counsellor completes a detailed questionnaire for each call, provides information and refers callers to diagnosis and treatment facilities and local community support groups. All calls are treated as fully confidential. The counsellor will provide information to callers who wish to remain anonymous. However, those who are willing to be included in the Network's national registry are asked to provide their name, telephone number and date of birth in order to facilitate follow-up.
Network members across Canada are supplied with blank Intake and Follow Up forms to facilitate data collection for the Network's national registry. All Network members are updated as this data and other on-going research produce new findings about HIV in pregnancy.
Collaborating with community members and groups
The HIV Network currently has 55 members. Participation is open to all healthcare and community support groups that provide information about HIV, assist women and their families dealing with HIV, and/or treat HIV positive pregnant women.
The program welcomes new Network members. For more information please call Motherisk, (416) 813-8084 or fax (416) 813-7562.
The HIV Healthline and Network is a joint project of the Motherisk and the HIV/AIDS Comprehensive Care programs at The Hospital for Sick Children.
The HIV/AIDS Program was created in 1988 to provide care for children and their families with HIV. It is one of the largest pediatric HIV programs in Canada, following over 100 families. Care is provided by a multidisciplinary team of pediatric infectious disease specialists, nurses, social workers, a psychologist, psychiatrist and dietician. The team provides counselling support for parents and children of all ages, street youth and pregnant women.
The HIV Healthline and Network is a natural extension of Motherisk's current services, since HIV may cluster with other antenatal risk factors already familiar to Motherisk (e.g., maternal medication for chronic diseases; drug and alcohol abuse; disease and infection). Motherisk counselling and follow-up protocols meet well-established ethical and quality assurance guidelines.
Gideon Koren , MD, ABMT, FRCPC, Director, The Motherisk Program, HSC
Susan King , MD, FRCPC, MSc, Co-director, Pediatric HIV Program, HSC
MOTHERISK HELPLINE FOR WOMEN SUFFERING FROM NAUSEA AND VOMITING DURING PREGNANCY (NVP) 1-800-436-8477
Motherisk now offers a toll-free phone counselling service in English and French, to assist women suffering from severe nausea and vomiting during pregnancy (NVP).
The NVP Helpline is staffed by an NVP counsellor, Monday to Friday from 9 a.m. to 5 p.m. (EST). Women in Toronto may also book an appointment for a clinic visit.
This new service was established in part as a result of a study (June, 1997) of nearly 7,000 pregnant women in Canada and the United States. The study found that some women suffering with nausea and vomiting declined treatment due to unfounded fears that approved medication would be harmful to the unborn child.
Fifty to 70 percent of all pregnant women suffer from nausea and vomiting that may affect their ability to work and socialize. Severe nausea and vomiting (hyperemesis gravidarum), which affects up to one percent of pregnant women puts them at risk of dehydration and malnutrition.
The emotional stress and guilt related to constantly feeling unwell may also strain personal relationships. "In the extreme, we found that some women attributed their decision to terminate an otherwise wanted pregnancy to severe nausea and vomiting," says Dr. Gideon Koren, Director of the Motherisk Program.
The ability to safely treat most cases of nausea and vomiting in pregnancy is well established. "We are now better able to provide evidence-based information on the condition," says Dr. Koren.
TREATING MORNING SICKNESS BY NON-PHARMACOLOGICAL MEANS
Nausea and vomiting during pregnancy (NVP) is a common ailment that affects some 200,000 pregnant women in Canada each year.
Although many women prefer non-pharmacological treatments to relieve these symptoms, few studies have been done to show their safety and/or effectiveness. A brief review of published studies is presented below.
The Neiguan pressure point is point 6 on the pericardial meridian, two Chinese inches proximal to the distal wrist crease, between the tendons of the flexor carpi radialis and palmaris longus muscles, and 1 cm deep (a Chinese inch is approximately the width of the thumb across the interphalangeal joint). This point has been used to reduce postoperative and chemotherapy related nausea and vomiting.
Out of eight studies on the effectiveness of the seaband or the P6 on NVP,( 1-8 ) six had significant bias, or no control group or placebo, and did not use the same acupressure point as a reference.
The remaining two, which had a placebo and a control group, were each conducted on 60 women. They both showed 50% improvement compared with the placebo.( 1,4)
Although both studies were significant (p<0.5), they were conducted with a small population and over a short period, which makes it difficult to say whether acupressure is an effective treatment for NVP over a long period.
Safety is not mentioned in any of the studies, although this treatment is understood to be safe.
Powdered ginger root is often recommended for NVP.
Only one study comments on the effectiveness of ginger. ( 9 ) This study was done on only 27 women, with a control group, using 250 mg of ginger. The results showed that 70.4% preferred using the ginger over the placebo and that ginger provided significantly greater relief of the hyperemesis symptoms than did the placebo.
More studies are needed to confirm the success of this treatment. No claims were made regarding the safety of the fetus. Furthermore, there are no regulatory controls on the use of ginger, so there is no possibility of confirming that the quality, dosage and amount of ginger stated on the bottle corresponds to the contents of the tablets.
Vitamin B 6
( PYRIDOXINE )
Vitamin B6 is often recommended for NVP. Three studies have been done on its effectiveness. ( 10-11 ) The first used 30 mg per day. ( 10 ) The mean change in nausea scores in the pyridoxine group was significantly greater than in the placebo group. However, after five days of treatment, the difference in the proportion of women with nausea (61/168 in the pyridoxine group vs 56/165 in the placebo group) was not statistically significant.
The second study used 25 mg of vitamin B6. ( 11 ) A significant improvement in the difference in nausea mean score was observed after vitamin B6 therapy in the severe nausea subgroup. There was no significant change in the score in the mild-to-moderate nausea subgroup or in the overall group.
The third study was done within the D.E.S.I. study, in 1975. Comparing 268 patients taking pyridoxine to 265 taking the placebo. ( 12 ) Pyridoxine alone excelled over placebo in the reduction of nausea, with 20 to 40 mg of pyridoxine given over a 6 day period.
From a safety viewpoint, it has been shown that vitamin B6 is not teratogenic in combination with doxylamine in Diclectin/Bendectin. A retrospective study did not link pyridoxine to an increase in major birth defects when compared with a control group (18/458 and 29/991). ( 13 )
More studies have to be done to determine the amount of vitamin B6 required to stop NVP (is it 30 mg, 25 mg or even less?).
There are four case studies on the effectiveness of hypnosis, ( 14-17 ) with no control or placebo, and conducted individually or in a group.( 17 ) These studies are inconclusive. There is insufficient data to regard this approach as being effective to treat NVP.
Studies with a placebo and a control group are needed.
LIFESTYLE OR DIET
Most of the suggestions found in the literature are generally anecdotal, and have no supporting data. There is very little information about these dietary suggestions, and although they were reported as helping most pregnant women with NVP, no evidence was offered to substantiate these claims. No conclusive evidence was given regarding their effectiveness or safety. Instead, their safety is often based on the fact that dietary recommendations cannot be harmful to the baby and can be helpful to the