Eloise Gibson explains why New Zealand needs more pregnant women in healthcare trials
My life as a medical guinea pig does not start well. The ideal research subject has thick, plump veins and knows how to follow instructions.
Apparently my veins are puny and, making matters worse, I have failed to follow the nurses’ directions to drink plenty of water. Eulyee Ahn, a sweet and friendly research assistant at the Liggins Institute, has a plastic basket containing about 20 empty vials lined up on a trolley at the end of my princess-themed bedspread.
The decor resembles a kid’s bedroom, but right now the only patients in the room are me and a heavily pregnant IT consultant. I’m here because I’ve answered an ad for a clinical trial in women who plan to get pregnant.
The Liggins Institute, which is based at the University of Auckland, specialises in tracking how what happens in utero shapes a baby’s adult life. Apparently, as a future mother, what I do today affects my offspring forever — including the burden they will place on the health system.
Since a baby’s life begins being moulded even before its mother is pregnant, it makes sense that the researchers wanted to see me before I conceive. So here I am, plugged into an IV tube. The cloggy red trickle that is seeping from my arm is not going to fill the basket of vials, so Ahn tries my other arm, with much more success. Then she pours me a large plastic cupful of clear liquid. It tastes like flat lemonade. In two hours’ time, she will take another blood sample to see how well my body has metabolised the sugar.
In the meantime, I’m busy. How much lamb did I eat this month? How much chocolate? How many smoothies? Were they milk-based, or fruit-only? Do I take sugar in coffee? Does my house get condensation on the windows? Do I live with a smoker? Work in a desk job? Feel depressed today? How depressed, exactly, on a scale from “not” to “very”?
Ahn offers to fix me a coffee when I’m done completing the survey. Would I like sugar? Yes please. She swiftly reminds me that I just ticked “no” on the do-you-take-sugar-in-your-coffee question. They’re sharp, these Liggins people. This seems like an appropriate time to remind her that I haven’t eaten in 11 hours — a requirement of the blood sugar screening test. Sometimes, the nurses confess, being part of this trial seems like a lot to ask of the unpaid participants.
If I choose to go the distance in this clinical trial, I’ll be tested and prodded, swabbed and scanned, and asked to share the results of my toilet trips. Should I fall pregnant within a year — as the researchers (and my mother) hope I will — the clinic will carry out five pregnancy ultrasounds, checking the foetus’ growth. When I go into labour, I’ll text Ahn, who, if I agree, will drive to the hospital where I’m delivering and take samples of the placenta. A nurse from the study will visit my house to check on my newborn’s progress. When the child turns 18, Ahn or her successor will write to it asking if he or she is willing to remain in the study.
The only “medication” we’ll receive is this: Half of us will drink flavourless, Raro-hued sachets containing a blend of probiotics and vitamins, before and during pregnancy. The rest, the control group, receive vitamins alone.
Personally, I’m here out of journalistic curiosity. The trial is known as the Nipper study, and it’s a little special. Women in Auckland, London and Singapore are being recruited for what the researchers hope will become a long-term, detailed study of their offspring. While most studies of babies start at birth or a few months into pregnancy, this one will reveal information starting when the babies are just proverbial twinkles in their parents’ eyes.
One goal is to confirm whether taking probiotics helps keep a mum’s blood sugar levels healthy and cuts the children’s risk of developing obesity, diabetes and other problems. The study will explore epigenetic effects — whether a pregnant woman’s actions switch on or off unhelpful genes in her baby. Ultimately, the researchers hope to help to reduce New Zealand’s rates of chronic illnesses. They’ll take millions of tiny samples and countless measurements of weight, nutrient status and other things. Later I ask the principal investigator, Wayne Cutfield, about the study. “By the time these babies are born there will be no kids on the planet we know more about at birth than these ones,” he says.
Starting a study this far back is expensive. Not only is following a whole pregnancy time-consuming, the trial needs to recruit many more women than it ultimately needs, says Cutfield. Some women will not conceive and others will miscarry. Sitting on the hospital bed, I feel a little performance anxiety, as if I’ll let the nurses down if I don’t get pregnant. My first job, though, is to avoid pregnancy. The trial needs me to drink at least a month’s worth of vitamins before conception. I’m given a large white box of sachets and what I can only describe as a cardboard bed pan, which Ahn tells me is strictly optional to use.
In the end it’s not an issue, because within a few weeks I’ve dropped out of the study. I send the nurses an apologetic email explaining that I’m worried about juggling clinic visits with a toddler and a full-time job. I’m too embarrassed to tell them about the weird extra pressure I felt to conceive for the sake of the trial. I feel bad for Ahn, who spent a lot of time measuring and testing me. But I also feel guilty because of what I know about pregnant women in medical trials — or, rather, the lack of them.
Researchers say that what I do today shapes the health of my future children. Trials carried out at Liggins and elsewhere show pregnancy – and pre-pregnancy – is critical, not just for me, but for the lifelong health of my children. But that doesn’t mean a doctor can tell me how to produce a healthy future adult. I probably won’t smoke in the lounge, like my mum did (she didn’t know). But; “If you put a gun to my head and said, what’s the ideal pregnancy diet, we actually don’t know,” says Cutfield. “We say to eat fruit and vegetables and limit fat intake and certainly we know alcohol and high sugar is definitely bad. But things like the amount of leafy green vegetables you should eat are less clear.”
Good, evidence-based information is hard to come by, even when it comes to simple decisions like taking a painkiller. Overseas, much of the money for drug trials comes from pharmaceutical companies, and often these companies don’t want pregnant women in their trials. Dealing with pregnancy means dealing with two patients: the mother and the foetus. Usually, what helps the mother also helps the foetus, but that is not always the case. There are physical complications, too. A pregnant woman has about twice as much blood in her body as normal, posing obvious challenges for estimating drug doses. She also metabolises food and drugs differently.
In 1994, an American Institute of Medicine report recommended pregnant women be presumed eligible to take part in clinical studies, saying trials should only exclude them when there was no prospect of medical benefit and/or obvious or known risk to the baby. Yet, in 2013, researcher Mary Blehar and others from the U.S. National Institutes of Health and U.S. Food and Drug Administration found pregnant women were still being left out of the vast majority of drug trials.
Jane Harding, a distinguished professor and paediatrician at the Liggins Institute, says companies tend to be wary of potential damage to the mother or unborn baby, and the resulting risk of lawsuits. “That’s an understandable concern but it does mean that the trials that are done in pregnant women and babies all need to be publicly funded, which means they very often simply don’t happen, because there isn’t enough money,” she says.
In some countries, governments won’t approve or fund trials unless pregnant women are in them. But there are always exceptions allowing trials to justify leaving pregnant women out. “Of course, it’s pretty easy to justify,” says Harding. Harding says animal studies are useful but not a replacement for human trials. Sometimes a treatment that seems safe in animals harms people, or harms animals but benefits people. “There is no doubt funding specifically for trials in women and newborns would make a huge difference. But of course the people who set the priorities are rarely babies and pregnant women,” she says. “Most of the dos and don’ts we give to women during pregnancy are based on extrapolating from what we know of physiology, which isn’t the same as actually trying it.”
It makes sense not to run unnecessary risks. But sometimes the alternative to controlled trials is, effectively, a mass experiment. Take fish oil. A Liggins Institute study in rats — which may or may not translate to humans — suggested there might be serious dangers to babies from mothers taking “off” (oxidised) fish oil. Studies show many capsules on the shelves are off, and a woman has no way of knowing. “Fish oil is being heavily promoted, that if you take it you might get a smarter child,” says Cutfield. “The evidence for that doesn’t exist but between 1/5 and 1/10 of women take it thinking it will help their child’s intelligence. The question is, is it harmful? We are not certain.”
Cutfield will never test the effects of bad fish oil in humans. “We’d never do that, morally, because there is a risk it would be harmful.” But he’d like to study whether pure fish oil has health benefits for babies. “Pure fish oil may actually help the offspring prevent diabetes and obesity, which would be a huge benefit.” But first he needs funding.
A study like Nipper, that starts before conception, could never have proceeded using government money alone, he says. It was possible only after scientists approached the food giant Nestle for money. “In this country there isn’t a funding agency or source especially for large clinical trials and so they have to sit within, say, the Health Research Council framework, which caps out at $1.2 million. That sounds a lot, but it’s not,” he says. “If you were to look at how many pregnancy studies are funded in New Zealand every five years it wouldn’t be many because they tend to need to be larger and of longer duration.”
It’s not only supplements like fish oil that raise questions. Women who are pregnant, like everyone, suffer from conditions that need drugs and medical treatment. They have pain, hypertension, diabetes, asthma, mental illness, cancer, autoimmune disorders and other problems. Yet very few treatments are approved for safe use during pregnancy, as Blehar and others pointed out in 2013.
The results can be farcical. When the swine flu pandemic hit in 2009, health authorities identified pregnant women as being at high risk. But there wasn’t any data to tell doctors the correct dose of antivirals or vaccines. Earlier, during a 2002 anthrax scare, pregnant women exposed to anthrax were prescribed different antibiotics from non-pregnant people, on the basis that amoxycillin was safest during pregnancy. Researchers later discovered the treatment was probably useless. Pregnant women metabolise amoxycillin so quickly they probably couldn’t get a high enough dose to combat anthrax.
Chris McKinlay, a senior lecturer at Liggins and a paediatrician at Middlemore Hospital, says the health system is engaging in a kind of constant, ad hoc experimentation. It’s entirely well-meaning, it’s just that the evidence is not always there. “We are applying treatments from our best knowledge but often we don’t actually have the confidence to know that they are beneficial. There are lots of treatments we do every day that actually don’t have a lot of evidence for,” he says. “There are examples over the decades of doing trials of things that were thought to be sensible, and finding out they were actually ineffective or harmful.”
McKinlay gives the example of administering antibiotics to women who are at risk of a preterm birth. “Giving antibiotics seems a logical thing to do because most cases of preterm labour are caused by an infection,” he says. But when a proper study was done, it turned out antibiotics were beneficial only in women whose membranes were ruptured or with a clear case of infection. Otherwise, antibiotics needlessly increased the baby’s risk of growing up with cerebral palsy. “It’s a difficult thing for people to get their heads around,” says McKinlay. “Because they go to a big hospital and see a good specialist they think they are getting treatments that have been proven and it’s not always true. They are getting the best advice and treatment currently available but sometimes those treatments are only a best guess — sensible but not always right.”
McKinlay is working on improving the evidence. He’s involved in ON TRACK, a national network of midwives, doctors, nurses, obstetricians and paediatricians who are working together on a list of priorities for clinical trials. Already they have seven new ideas for research, from testing interventions for preterm birth to postnatal depression. “We are hoping through this network we can really give clinical trials a huge boost. We want to shift from seeing trials as something universities do to seeing them as the core business of healthcare improvement.”
One of the challenges is recruiting seemingly healthy women — like me. A bloke who turns up at the doctor with a heart problem gives healthcare workers an obvious opening to mention a new drug trial. A healthy woman with a straightforward-seeming pregnancy is a less obvious target. Yet researchers need all kinds of women, because problems can show up later.
Happily, New Zealand women have proven enthusiastic, says Cutfield. Nipper, which I encountered through Facebook, has been particularly successful. Cutfield says recruiting in Auckland has been much faster than in London or Singapore, and they almost have the 600 women they need. The day I visit, the nurses and researchers are going out for a small celebratory lunch. It seems that this time the quest to advance healthcare doesn’t need me and my puny veins, which is just as well. I’m not very good at following instructions.